Pneumonia - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

PNEUMONIA A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES J AMES N. ...

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PNEUMONIA A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2003 by ICON Group International, Inc. Copyright 2003 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Pneumonia: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-83634-5 1. Pneumonia-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on pneumonia. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes & Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON PNEUMONIA ............................................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Pneumonia .................................................................................... 5 E-Journals: PubMed Central ..................................................................................................... 148 The National Library of Medicine: PubMed .............................................................................. 175 CHAPTER 2. NUTRITION AND PNEUMONIA.................................................................................. 313 Overview.................................................................................................................................... 313 Finding Nutrition Studies on Pneumonia ................................................................................. 313 Federal Resources on Nutrition ................................................................................................. 316 Additional Web Resources ......................................................................................................... 317 CHAPTER 3. ALTERNATIVE MEDICINE AND PNEUMONIA ........................................................... 319 Overview.................................................................................................................................... 319 National Center for Complementary and Alternative Medicine................................................ 319 Additional Web Resources ......................................................................................................... 330 General References ..................................................................................................................... 334 CHAPTER 4. DISSERTATIONS ON PNEUMONIA ............................................................................. 335 Overview.................................................................................................................................... 335 Dissertations on Pneumonia...................................................................................................... 335 Keeping Current ........................................................................................................................ 336 CHAPTER 5. CLINICAL TRIALS AND PNEUMONIA ........................................................................ 337 Overview.................................................................................................................................... 337 Recent Trials on Pneumonia...................................................................................................... 337 Keeping Current on Clinical Trials ........................................................................................... 357 CHAPTER 6. PATENTS ON PNEUMONIA ........................................................................................ 359 Overview.................................................................................................................................... 359 Patents on Pneumonia ............................................................................................................... 359 Patent Applications on Pneumonia ........................................................................................... 368 Keeping Current ........................................................................................................................ 373 CHAPTER 7. BOOKS ON PNEUMONIA ............................................................................................ 375 Overview.................................................................................................................................... 375 Book Summaries: Federal Agencies............................................................................................ 375 Book Summaries: Online Booksellers......................................................................................... 376 The National Library of Medicine Book Index ........................................................................... 378 Chapters on Pneumonia............................................................................................................. 380 CHAPTER 8. MULTIMEDIA ON PNEUMONIA ................................................................................. 387 Overview.................................................................................................................................... 387 Video Recordings ....................................................................................................................... 387 Audio Recordings....................................................................................................................... 388 Bibliography: Multimedia on Pneumonia.................................................................................. 391 CHAPTER 9. PERIODICALS AND NEWS ON PNEUMONIA .............................................................. 395 Overview.................................................................................................................................... 395 News Services and Press Releases.............................................................................................. 395 Newsletter Articles .................................................................................................................... 399 Academic Periodicals covering Pneumonia ............................................................................... 402 CHAPTER 10. RESEARCHING MEDICATIONS................................................................................. 405 Overview.................................................................................................................................... 405 U.S. Pharmacopeia..................................................................................................................... 405 Commercial Databases ............................................................................................................... 407 Researching Orphan Drugs ....................................................................................................... 408

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APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 413 Overview.................................................................................................................................... 413 NIH Guidelines.......................................................................................................................... 413 NIH Databases........................................................................................................................... 415 Other Commercial Databases..................................................................................................... 419 The Genome Project and Pneumonia ......................................................................................... 419 APPENDIX B. PATIENT RESOURCES ............................................................................................... 423 Overview.................................................................................................................................... 423 Patient Guideline Sources.......................................................................................................... 423 Associations and Pneumonia ..................................................................................................... 430 Finding Associations.................................................................................................................. 431 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 433 Overview.................................................................................................................................... 433 Preparation................................................................................................................................. 433 Finding a Local Medical Library................................................................................................ 433 Medical Libraries in the U.S. and Canada ................................................................................. 433 ONLINE GLOSSARIES................................................................................................................ 439 Online Dictionary Directories ................................................................................................... 444 PNEUMONIA DICTIONARY..................................................................................................... 445 INDEX .............................................................................................................................................. 551

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with pneumonia is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about pneumonia, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to pneumonia, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on pneumonia. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to pneumonia, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on pneumonia. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON PNEUMONIA Overview In this chapter, we will show you how to locate peer-reviewed references and studies on pneumonia.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and pneumonia, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “pneumonia” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Prognosis of Streptococcus Pneumoniae-Induced Hemolytic Uremic Syndrome Source: Pediatric Nephrology. 16(4): 362-365. April 2001. Contact: Available from Springer-Verlag. Service Center Secaucus, 44 Hartz Way, Secaucus, NJ 07094. (201) 348-4033. Summary: Streptococcus pneumoniae induced hemolytic uremic syndrome (HUS) is known to be a severe acute disease leading to death in one third of cases, but data regarding the long term followup are lacking. This article reports on a series of 11 patients with HUS induced by the bacteria Streptococcus pneumoniae; all patients had meningitis and pneumonia. Among 9 patients with a severe acute infectious disease, 3 died from meningitis (infection of the meninges, or outer membranes of the brain) and 1 from neurological sequelae after a partial recovery of renal (kidney) function. The mean

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duration of dialysis was 32 days in patients with acute renal failure (ARF) who survived the acute infectious period. Cortical necrosis (tissue death) was documented in five of six kidney specimens. Among the 7 surviving patients, 5 developed end stage renal disease (ESRD) between 4 and 17 years later. The authors note that S. pneumoniae induced HUS is a rare disease, and they recommend the use of a registry of patients, in order to follow prospectively a larger number of patients. 1 table. 21 references. •

Impact of Oral Diseases on Systemic Health in the Elderly: Diabetes Mellitus and Aspiration Pneumonia Source: Journal of Public Health Dentistry. 60(4): 313-320. Fall 2000. Contact: Available from American Association of Public Health Dentistry. 3760 SW Lyle Court, Portland, OR 97221. (503) 242-0712. Fax (503) 242-0721. E-mail: [email protected]. Summary: Evidence is increasing that oral health has important impacts on systemic health. This article presents data from the third National Health and Nutrition Examination Survey (NHANES III) describing the prevalence of dental caries and periodontal diseases in the older adult population. The authors then evaluate published reports and present data from clinical and epidemiological studies on relationships among oral health status, chronic oral infections (including caries and periodontitis), and certain systemic diseases, specifically focusing on type 2 diabetes and aspiration pneumonia. Both of these diseases increase in occurrence and impact in older age groups. The NHANES III data demonstrate that dental caries (cavities) and periodontal diseases occur with substantial frequency and represent a burden of unmet treatment need in older adults. The authors found clinical and epidemiological evidence to support considering periodontal infection a risk factor for poor glycemic control in type 2 diabetes; however, there is limited representation of older adults in reports of this relationship. For aspiration pneumonia, several lines of evidence support oral health status as an important etiologic factors. Additional clinical studies designed specifically to evaluate the effects of treating periodontal infection on glycemic control and improving oral health status in reducing the risk of aspiration pneumonia are needed. Although the associations are complicated, there is evidence to support recommending oral care regimens in protocols for managing type 2 diabetes and preventing aspiration pneumonia. 8 tables. 71 references.

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Implications of Oral Infections on Systemic Diseases in the Institutionalized Elderly with a Special Focus on Pneumonia Source: Annals of Periodontology. 3(1): 262-275. July 1998. Contact: Available from American Academy of Periodontology. Suite 800, 737 North Michigan Avenue, Chicago, IL 60611. (312) 787-5518. Fax (312) 787-3983. Website: www.perio.org. Summary: This article considers the implications of oral infections on systemic diseases in the institutionalized elderly; the author offers a special focus on pneumonia. The extent to which oral organisms cause systemic infections through hematogenous (through the blood) dissemination in this population is still unknown. The author hypothesizes that a more likely and common route of systemic infection by oral microorganisms is through aspiration of oropharyngeal fluids containing oral pathogenic microorganisms, which colonize the lower respiratory tract and cause pneumonia. Respiratory pathogens emerge in the dental plaque of elderly patients with very poor oral hygiene and severe periodontal disease. This is also a problem in

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intensive care units in the hospital setting. Selective digestive decontamination, a technique involving the topical application of antimicrobials to reduce the risk of colonization of the respiratory tract, has been used to reduce the incidence of nosocomial pneumonia in the acute care setting of hospitals. This technique has not been employed in the nursing home setting. The author concludes by discussing the parameters of studying this problem, including ethical issues, and research design. 2 tables. 117 references. (AA-M).

Federally Funded Research on Pneumonia The U.S. Government supports a variety of research studies relating to pneumonia. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to pneumonia. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore pneumonia. The following is typical of the type of information found when searching the CRISP database for pneumonia: •

Project Title: 2-5A ANTISENSE INHIBITION OF RESPIRATORY SYNCTIAL VIRUS Principal Investigator & Institution: Cramer, Hagen; Ridgeway Biosystems, Inc. 9500 Euclid Ave, Nd-50 Cleveland, OH 44195 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2004 Summary: (Adapted from Applicant's Abstract): Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract disease in infants, young children and the elderly, particularly those that are institutionalized. It is the most common cause of viral bronchiolitis and pneumonia in children, and outbreaks frequently reach epidemic proportions during the winter months, accounting for roughly 90,000 hospitalizations and 4,500 deaths per year. Gemini Technologies, Inc. is developing novel antisense chimeras for use in the treatment of RSV infections. These chimeras are comprised of an antisense component to the targeted viral RNA genome, while the 2-5A portion of the chimera attracts and activates RNase L, an endoribonuclease that can cleave the associated genomic RNA strand. In the phase I studies, we succeeded in synthesizing and testing a second generation anti-RSV chimera that had potent antiviral activity in cultured cells and in primates. Here we propose to carry this compound through more definitive animal studies, utilizing aerosol delivery to mimic the clinical application of this compound. In addition, we propose medicinal chemistry-based studies aimed at improving chimera synthesis, and preliminary toxicology studies. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE

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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACELLULAR VACCINES AGAINST FRANCISELLA TULARENSIS Principal Investigator & Institution: Conlan, Joseph W. Senior Research Officer; National Research Council of Canada Ottawa Kiaor6, Canada Ottawa, Timing: Fiscal Year 2001; Project Start 15-JUN-2001; Project End 30-APR-2006 Summary: (Provided by Applicant): The facultative intracellular bacterial pathogen, Francisella tularensis, can cause severe pneumonia and death following the inhalation of very small numbers of infectious particles. For this reason, F. tularensis is considered a primary biological warfare agent. Acquired host immunity against this pathogen is predominantly T-cell-mediated rather than humoral. An attenuated strain of F. tularensis is an effective live vaccine against virulent strains of the pathogen. However, this strain retains its virulence for mice, and might cause disease if administered to immunocompromised individuals. Thus, for mass-vaccination purposes, a defined fastacting acellular vaccine would be preferable to the current live vaccine. Our institute has developed a novel vaccine delivery technology based on liposomes manufactured from the total polar lipids of various Archaebacteria. These liposomes termed, archaeosomes, generate robust cell-mediated immune responses to model antigens entrapped within them, without the aid of any additional immune stimulants. Recently, we showed that a short peptide antigen of another intracellular pathogen, Listeria monocytogenes, packaged in archaeosomes, provides a high level of protective immunity against this pathogen in a murine listeriosis model after only a single vaccination. Because multiple studies indicate that the same host defenses are needed to combat F. tularensis and L. monocytogenes, it is likely that appropriate antigens of the former pathogen encapsulated in archaeosomes will provide effective acellular vaccines. This proposal will explore this possibility. It is expected that the findings from the proposed studies will be applicable to the development of acellular vaccines against other intracellular respiratory pathogens such as Mycobacterium tuberculosis, and Chlamydia pneumoniae. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ACTG 254--PHASE II/III STUDY OF AT/AZ AS COMPARED TO TMP/SMX IN CHILDREN Principal Investigator & Institution: Vandyke, Russell B.; Tulane University of Louisiana New Orleans, LA 70118 Timing: Fiscal Year 2001 Summary: Pneumocystis carinii pneumonia (PCP) is the most common opportunistic infection reported in HIV-infected children. While trimethoprim-sulfamethoxazole (TMP/SMX) remains the drug of choice for PCP prophylaxis, drug sensitivity may limit its effective use; in addition, the efficacy of the most common alternative therapiesincluding dapsone and pentamidine has yet to be determined in infants and children. Atovaquone, an oral medication requiring only once daily administration, has demonstrated activity against P. carinii and Toxoplasma gondii, and has been shown to be both safe and with no defined adverse or toxic effects. Primary objectives of this multi-centered, two-armed, double blind, placebo controlled study will be to compare TMP/SMX and AT/AZ in the prevention of serious bacterial infections; determine and compare long-term safety and tolerance; and assess the likelihood of pharmacokinetic interaction between atovaquone and azithromycin in a subset of two to 18 year old patients.

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Project Title: ACTG888: DISCONTINUING W/ANTIRETROVIRAL THERAPY

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Principal Investigator & Institution: Goldman, Mitchell; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, IN 462025167 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADULT ACTG CENTRAL GROUP Principal Investigator & Institution: Benson, Constance A. Professor of Medicine; Social and Scientific Systems 7101 Wisconsin Ave, Ste 1300 Bethesda, MD 20814 Timing: Fiscal Year 2002; Project Start 01-JAN-1996; Project End 31-DEC-2004 Summary: (adapted from the application's abstract): The Adult AIDS Clinical Trials Group (AACTG) is a multicenter, multidisciplinary clinical trials group dedicated to the study of HIV pathogenesis and therapy. Since its inception in 1987, the AACTG has evolved into a cooperative group consisting of the Central Group (composed of the Office of the Group Chair, Executive, Scientific and Resource Committee, a state-of-theart laboratory network, a Community Constituency Group, and the Operations Center), 30 AIDS Clinical Trials Units (ACTUs) located at major academic medical centers, and the Statistical and Data Management Center. The AACTG has had an impact on elucidating the current understanding of AIDS pathogenesis and therapy, and has played a role in the development of novel trial designs and analysis strategies. AACTG clinical trials have helped define guidelines for the use of antiretroviral agents and for the prophylaxis and treatment of HIV- associated opportunistic complications. Over 200 manuscripts have been published by the AACTG describing this body of work since submission of the prior competing renewal application in 1995. Group productivity has been aided by collaborations with a wide variety of external investigators and laboratories, U.S. and international clinical trials networks, and members of the pharmaceutical and medical diagnostics industries. The AACTG proposes to build on its accomplishments with the goal of further reducing, and ultimately eliminating, HIVassociated morbidity and mortality. The applicants propose to undertake investigations in a structure that allows for a high degree of efficiency and flexibility in the design and implementation of a broad array of clinical trials with patient management principles, according to the applicant, which are reflective of contemporary clinical practice and designed to ensure the relevance of research findings. Over the next several years the Group proposes to address a number of issues including how best to: provide initial and subsequent treatment to maximally suppress HIV replication; provide optimum treatment strategies following treatment failure; develop approaches to individualization of therapy based on genotypic and phenotypic characteristics of the virus and/or host; eliminate reservoirs of HIV-1 in latently infected cells; ameliorate virologic, immunologic, pharmacologic, and behavioral factors (adherence) that contribute to treatment failure; incorporate new therapies and treatment strategies into future regimens; evaluate new strategies for enhancing immune reconstitution to HIV and OIs; and delay or prevent HIV disease progression, opportunistic complications, complications of therapy, and mortality. To accomplish this agenda, the Group requests funds for 35 ACTUs that are to be evaluated on objective performance criteria. New sites and laboratories have been added to the Group in order to provide additional expertise

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in virology, immunology, and pharmacology. The Group remains committed to enrolling women and minorities and to continuing support of the Minority AIDS Training Program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADULT AIDS CLINICAL TRIALS UNIT Principal Investigator & Institution: Balfour, Henry H. Professor of Laboratory Medicine, Pathol; Lab Medicine and Pathology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, MN 554552070 Timing: Fiscal Year 2001; Project Start 01-MAR-1992; Project End 31-DEC-2004 Summary: (adapted from the application's abstract): The Minnesota AIDS Clinical Trials Unit (ACTU) requests to continue to be a unit of the Adult AIDS Clinical Trials Group (AACTG). The Minnesota ACTU is committed to the Scientific Agenda of the AACTG, in which they have participated continuously since January 1, 1987. In addition to recruiting and retaining a cohort of new HIV-infected patients in clinical trials (estimated to be 85 patients in main studies and 54 patients in substudies annually), the Minnesota ACTU plans to contribute to the Group Scientific agenda with the following specific aims: (1) to correlate the quantity and replication competence of HIV at the cellular level in lymphoid tissue (LT), peripheral blood fractions and other compartments; (2) to develop more sensitive methods to detect HIV and apply these to selection of more effective therapies; (3) to define the natural history of cytomegalovirus (CMV) disease in the era of potent antiretroviral therapy and determine the best assays (virologic and immunologic) to monitor its clinical course (AACTG 360); (4) to identify and properly manage the patients who are at risk for complications of the dyslipidemias associated with potent antiretroviral therapy; (5) to identify resistant CMV strains and assess their pathogenicity; (6) to study relationships between the production of neurotoxins in plasma and cerebrospinal fluid of HIV-infected patients, neuronal loss as measured by proton magnetic resonance spectroscopy and the development or progression of HIV-associated dementia (HAD); and (7) to understand and characterize pharmacokinetic behavior, including drug-drug interactions, of antiretrovirals and other HIV-related drugs in biologic fluids. To help achieve these specific aims, the Minnesota ACTU has both Virology and Pharmacology Advanced Technology Laboratories (ATL). The Virology ATL is focusing on quantitation and characterization of HIV in lymphoid tissue and other body compartments. This laboratory also has expertise in HIV and CMV resistance. The Pharmacology ATL is developing assays for simultaneous determination of levels of protease inhibitors and measurement of intracellular antiretroviral anabolites. The Nebraska subunit has a special interest in neuroAIDS and has identified neurotoxins putatively responsible for pathology in HAD. The Iowa subunit has expertise in the detection of hepatitis C and will be collaborating in studies of the pathogenesis of coinfection with HIV and hepatitis C. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ADULT AIDS CLINICAL TRIALS UNIT Principal Investigator & Institution: Bartlett, John A. Professor; Medicine; Duke University Durham, NC 27706 Timing: Fiscal Year 2001; Project Start 01-JAN-1996; Project End 31-DEC-2004 Summary: (adapted from applicant's abstract): The Duke University Adult ACTU has contributed to the ACTG scientific agenda over the past three years. The most notable contributions from Duke include the introduction of two pathogenesis-based ACTU

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protocols (380 and A5049), and the integration of Duke investigators into the scientific leadership as the Chairs of five ACTG trials and as members of numerous ACTG scientific committees. Duke University contributions to the AACTG are facilitated by the clinical and basic science expertise in HIV infection at the Medical Center, and environment of collaboration in translational research. A Scientific Advisory Committee composed of basic and clinical scientists assists the Duke ACTU site investigators in the development of potential ACTG studies. The Duke University Adult ACTU has steadily increased its enrollment into ACTG studies, especially labor intensive scientifically rigorous trials, and studies enrolling treatment-naive subjects. In 1998, the unit enrolled 72 subjects into main ACTG studies and 44 subjects into ACTG substudies. As a result of these efforts and efficiency at the site, Duke ranked fourth among the 30 existing ACTUs in the lowest median cost per weighted accrual during 1997- 1998. The Duke ACTU also had the lowest loss to follow-up rate in the ACTG. The applicant proposes to make substantial contributions to longitudinal research such as the Longitudinal Linked Randomized Trial (ALLRT) protocol. Subjects enrolled through the Duke University Adult ACTU reflect the demographics of HIV infection in North Carolina. The recruitment of historically underrepresented persons is assisted by the efforts of the Community Advisory Board (CAB) and Outreach Core, the provision of comprehensive on-site primary care, the Women s Clinic, and a NIDA supplement to the ACTU which supports on-site substance abuse counseling. During the next five years, the Duke University Adult ACTU proposes to emphasize investigations into the cellular reservoir of HIV, immunologic recovery during antiretroviral therapy, the enhancement of HIVspecific immune responses, and the development of improved antiretroviral treatment strategies such as treatment intensification. The Duke ACTU also proposes to continue to enter 75 new patients into main ACTG studies and 20 new patients into ACTG substudies annually. Given the continuing referrals of newly diagnosed persons with HIV infection to Duke, the Duke University Adult ACTU plans to provide the opportunity for recruitment of these persons into ACTG studies of treatment initiation. The applicants anticipate that Duke will continue as an efficient, cost-effective ACTU that contributes to the ACTG scientific agenda. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADULT AIDS CLINICAL TRIALS UNIT Principal Investigator & Institution: Collier, Ann C. Assistant Professor; Medicine; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2001; Project Start 30-JUN-1986; Project End 31-DEC-2004 Summary: (adapted from application's abstract): This application responds to NIH RFA NIAID-98-013. It describes the renewal application of the University of Washington (UW) Adult AIDS Clinical Trials Unit (AACTU). The purpose of the UW AACTU is to perform exemplary HIV/AIDS treatment research in support of the Adult AIDS Clinical Trials Group (AACTG) scientific agenda. UW AACTU was one of 14 original centers funded in 1986 to study therapies for HIV infection. The UW AACTU has made contributions to the AACTG through leadership and participation of its faculty in AACTG committees and protocols, accrual of 1758 patients into AACTG studies, and generation of high quality data. Since 1996, UW AACTU investigators have been members of 38 committees, subcommittees, and focus groups; Chair or Vice-chair for seven of these; Protocol Chair or Co-chair of 23 studies and substudies; and the UW AACTU has enrolled 419 patients in AACTG protocols. The UW AACTU application describes three specific aims: (1) contribute to the pathogenesis-based scientific agenda of the AACTG by providing scientific expertise and leadership in HIV disease,

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complications of HIV, neurology, immunology, women's health and outcomes; and provide technical expertise to support protocol-mandated procedures; (2) participate in AACTG clinical trials by maintaining the UW AACTUs infrastructure and its experienced staff; enroll 90 patients in main studies and 50 in substudies per year and follow them with a 106) H37Rv. The 2 low dose Erdmaninoculated monkeys (15 cfu) remained clinically normal 9 weeks post-challenge and at 19 wk had minimal clinical manifestations, but fibrotic granulomatous pulmonary lesions with spread to other tissues. We conclude that chronic disease can be established by low dose Erdman inoculation with a wider distribution of lesions being produced compared to the H37Rv strain. FUNDING Base Grant, Venture Research PUBLICATIONS Didier PJ, Blanchard JL and Gormus BJ. Pulmonary Tuberculosis in Normal Rhesus Monkeys Produced by M. tuberculosis H37Rv. Am J Soc Trop Med Hyg 57:156, 1997 [Abstract]. Didier PJ, Blanchard JL and Gormus BJ. Chronic Tuberculosis Produced by Low Dosage of M. tuberculosis (Erdman) in Rhesus Monkeys. Am J Soc Trop Med Hyg 59:361, 1998. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANTIBODY EPITOPES OF PNEUMOCYSTIS IN HIV PATIENTS Principal Investigator & Institution: Daly, Kieran R. Internal Medicine; University of Cincinnati 2624 Clifton Ave Cincinnati, OH 45221 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2005

20 Pneumonia

Summary: (provided by applicant): Pneumocystis (Pc), a fungal opportunistic pathogen of humans, is the causative agent of Pneumocystis pneumonia (PcP), a leading cause of serious illness in immunocompromised people. As an alternative approach to treatment of PcP in HIV+ patients, which typically involves the long-term use of anti-Pc drugs, offers no protection from subsequent infections with Pc, and may lead to the acquisition of drug resistance by the microorganism, we propose to study antibody reactivity to Pc epitopes in HIV+ patients that did or did not have a previous bout of PcP. The Iong term goal is to identify epitopes for following Pc-specific immune reconstitution in HIV+ patients undergoing HAART. The overall goal of this proposal is to compare serum antibody recognition of the major surface glycoprotein (Msg) of Pc in patients that did or did not have a bout of PcP. Msg is a highly variable protein expressed on the surface of Pc which is recognized by the immune system, and may be involved in antigen switching and immune evasion. We will concentrate on the carboxy terminus of Msg (MsgC) which has previously been shown to differentiate between PcP+ and PcPpatients. The specific aims of this proposal are to define the spectrum of MsgC fragments that are recognized by human serum in health and PcP disease, and to identify individual antigenic epitopes found on disease relevant Msgs. We will determine if these epitopes are unique or cross-reactive with other variants of Msg, and will define the hierarchy of epitopes seen by individual patients. We will also study the frequency of immune recognition of the individual epitopes in different patient populations. We propose to identify the spectrum of MsgC fragments recognized by human serum by generating a phage display library expressing a diversity of MsgC fragments, and will use positive and negative phage selection to identify disease relevant MsgC fragments. These fragments will be studied for individual epitopes using a single chain variable region (scFv) antibody phage library. This library will be a set of monoclonal probes of human origin useful for identifying individual epitopes of MsgC. These newly identified epitopes will, in the long term, be used to probe immune reactivity in HIV+ patients undergoing HAART. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: APOPTOTIC T CELL CLEARANCE FROM MURINE LUNGS Principal Investigator & Institution: Curtis, Jeffrey L. Professor of Internal Medicine; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2001; Project Start 01-MAY-1996; Project End 30-APR-2005 Summary: (Applicant's Abstract): Apoptotic T cells must be cleared efficiently by macrophages to prevent tissue damage, but ingestion of apoptotic cells causes macrophages to downregulate their own production of proinflammatory cytokines such as TNF and IL-8 and of chemokines. Hence, while ingesting apoptotic T cells during resolving pneumonia is beneficial, the same process could be immunosuppressive if pulmonary alveolar macrophages ingest dying T cells before or during encounters with pathogens. Indeed, studies funded by this project made the novel observation that many apoptotic lymphocytes are found in the lungs of mice. Thus, the lungs, a mucosal surface frequently exposed to pathogens, present a unique challenge in regulating macrophage clearance of apoptotic T cells while maintaining host defense. It is likely that this challenge is relevant both to the normal state, in which single alveolar macrophages encounter isolated apoptotic T cells, and when larger numbers of T cells die (e.g., following acute viral pneumonias and in chronic HIV infection). New preliminary data from this project suggest that ingestion of apoptotic T cells by lung macrophages is regulated, as an evolutionary adaptation, to minimize the

Studies 21

immunosuppressive effect that could otherwise result at this site of frequent pathogen exposure. The goal of this project is to define the molecular basis and significance of regulated phagocytosis of apoptotic T cells in the lungs. It will test the following hypotheses: that downregulated phagocytosis of apoptotic T cells by resident murine alveolar macrophages results both from altered adhesion of apoptotic T cells and from altered signal transduction relative to control peritoneal macrophages; that effective clearance of apoptotic T cells during resolving lung inflammation depends on acquisition of an ingesting phenotype, probably mostly by differentiation of recruited monocytes by inflammatory cytokines; and that ingestion of apoptotic T cells carries a risk of impaired lung host defense against bacterial and fungal pathogens. Both primary resident alveolar and peritoneal macrophages from normal mice, and two immortalized murine macrophage cell lines (MH-S and J774A.1) will be used. Techniques will include static adhesion and phagocytosis assays, specific enzyme inhibitors, immunoprecipitation, Western blotting, flow cytometry, and use of in vivo murine models of fungal (Cryptococcus neoformans) and bacterial (Staphylococcus aureus) pneumonia. It is anticipated that the results will provide important new information about immunoregulation that will be relevant to viral, bacterial, and fungal infections in normal and immunocompromised hosts, development of autoimmunity and lung fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: APPROPRIATE PNEUMOCOCCAL VACCINATION IN INFANTS IN FIJI Principal Investigator & Institution: Mulholland, Edward K.; University of Melbourne Parkville 3052, Australia Parkville, Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2005 Summary: (provided by applicant): Streptococcus pneumoniae (Pnc) is the leading vaccine preventable cause of serious infection in infants. The current Pnc conjugate vaccines are safe, immunogenic, and effective. However, the vaccine is very expensive (approximately USD $200/infant) so it is unlikely to be affordable for most developing countries. Moreover, as health care access in developing countries may be episodic and unreliable, many children do not receive either complete or timely vaccine courses. Therefore, it is important to investigate affordable and flexible ways to deliver this vaccine, which are safe and effective. A recent World Health Organization (WHO) / Global Alliance for Vaccines and Immunization (GAVI) meeting to address impediments to the introduction of these vaccines in developing countries recognized the need to evaluate other regimens of Pnc conjugate vaccine as an important research priority. This study has been deliberately formulated with that need in mind. The proposed site for this research is Fiji. Although health services are good, Pnc disease, particularly pneumonia, remains the commonest cause of childhood morbidity and mortality. Fiji has good vaccine coverage and was the first Pacific country to introduce Hib vaccine. The arrival of the new, expensive Pnc conjugate vaccine presents a dilemma for Fiji and many similar countries. The expense of this vaccine if used in the recommended 3 or 4-dose schedule would consume a large portion of the health budget. This study has two components, aimed at addressing these two issues:1. A phase 2 immunogenicity study (involving 750 infants) to evaluate regimens using reduced numbers of doses of Pnc conjugate vaccine, and using timing of dosing and combinations with polysaccharide (PS) vaccine that may be more suited to the epidemiology of Pnc disease in developing countries.2. An epidemiological study will measure the burden of invasive Pnc disease, pneumonia, and otitis media (OM) in Fiji.

22 Pneumonia

This will be part of a global effort to address these issues, and will be used to develop rapid assessment tools for these diseases in developing countries. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AZITHROMYCIN AND CORONARY ARTERY DISEASE Principal Investigator & Institution: Grayston, J T. Professor of Epidemiology; Epidemiology; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2001; Project Start 04-SEP-1998; Project End 31-JAN-2004 Summary: There is increasing evidence supporting a possible role for C. pneumonia in the pathogenesis of coronary atherosclerosis and its complications. This evidence stems from the results of seroepidemiologic studies, indicating an association between C. pneumonia seropositivity and coronary heart disease (CHD) and from microbiologic studies, indicating that C. pneumonia may be detected in a large proportion of atherosclerotic plaque specimens. The preliminary results of two human treatment trials, which have been recently published, suggest that treatment with antibiotics activate against C. pneumonia may be effective in secondary prevention of cardiovascular events. The strength of the evidence currently available in support of a role for C. pneumonia in the pathogenesis of atherosclerosis, and the magnitude of the potential public health importance of this finding, support further research involving clinical treatment trials of patients with atherosclerotic cardiovascular disease. The proposed study is a randomized, double-blind trial of azithromycin vs. placebo among adults with documented prevalence coronary artery disease. Patients will be treated for one year and followed for a mean of 3.75 years (range 3.0 to 4.5 years) for the composite primary study outcome of CHD death, non- fatal myocardial infarction, hospitalization for unstable angina, and requirement for revascularization procedures. Completed follow-up of 3500 subjects will provide 95 percent power to detect a 25 percent decrease, and 80 percent power to detect a 20 percent decrease, in the rate of the primary outcome in the treatment group, assuming a 6.5 percent per year event rate in the placebo group. Serologic testing for C. pneumonia will be performed on all subjects at enrollment and at intervals during the follow-up period for a random 25 percent of subjects. The results of this study will provide important information on the potential role of antibiotic therapy for the secondary prevention of complication of coronary artery disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AZITHROMYCIN AND CORONARY EVENTS Principal Investigator & Institution: Cohn, Peter; State University New York Stony Brook Stony Brook, NY 11794 Timing: Fiscal Year 2001 Summary: This study is to determine whether the antibotic, azithromycin, decreases the risk of having a heart attack or other complication related to coronary artery disease in people with heart disease. Azithromycin is an antibiotic that is used to treat infections with a bacteria called Chlamydia pneumoniae. Some studies suggest that Chlamydia pneumoniae infection may be a risk factor for heart attacks and other complications related to coronary artery disease. Chlamydia pneumoniae is spread from person-toperson by sneezing and coughing (unlike a related bacteria, Chlamydia trachomatis, it is not a sexually transmitted disease). Studies show that people who have been infected with Chlamydia pneumoniae in the past have a higher chance of having a heart attack. Other studies show that Chlamydia pnreumoniae is present in the plaque, or material blocking the heart vessel, in many people with heart disease.

Studies 23


Project Title: RESPONSE

BACTERIAL

MODULATION

OF

LUNG

INFLAMMATORY

Principal Investigator & Institution: Russo, Thomas A. Associate Professor; Medicine; State University of New York at Buffalo 402 Crofts Hall Buffalo, NY 14260 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 31-MAY-2005 Summary: (Unedited Applicant's Abstract): Gram-negative bacilli (GNB) are pathogens that are capable of causing severe, life-threatening pneumonia. More than 60 percent of nosocomial pneumonias are caused by GNB and associated mortality rates are often >50 percent. Over the last 10-15 years, there has been little improvement in outcome from this infection. As a result, this syndrome continues to cause significant morbidity and mortality and strongly contributes to the economic burden of our national health care system. The successful use of immune intervention in the treatment or modulation of infections has marked the beginning of a new era in the management of infectious diseases. There exists a delicate balance between an efficacious and injurious host defense response. An understanding of the host response in GNB pneumonia and how bacterial components affect this response will, in turn, lead to the development of rapid diagnostic tests that will enable the clinician to effectively utilize a variety of biologic modulators. It is also necessary to understand the relative role of bacterial components versus host factors in mediating damage to the lungs prior to therapeutic manipulations on which little is known. This information will enable us to appreciate the relative risk benefit ratio of altering the host response. Further, a more precise clarification of which host components are damaged is also needed. This knowledge may identify independent therapeutic interventions. Their global hypothesis is that surface components of GNB and/or secreted proteins differentially alter host antibacterial defenses and directly, and/or indirectly (by inflammatory mechanisms) promote lung injury. Preliminary data supports this hypothesis. These responses will have significant implications when attempting therapeutic immune interventions. The goals of this proposal are to determine the mechanisms by which the bacterial capsule and 0-specific antigen modulate neutrophil recruitment into the lungs in a diametrical manner and extend our evaluations on the relative roles of bacterial factors (e.g. hemolysin) and bacterially induced host response elements in directly mediating the pathogenesis of lung injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BACTERIAL PHOSPHORYLCHOLINE AND PATHOGENESIS Principal Investigator & Institution: Weiser, Jeffrey N. Associate Professor; Microbiology; University of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-JUL-2004 Summary: Description (Adapted from Applicant's Abstract): The bacterial cell surface is generally considered to be highly divergent from species to species. An exception to this rule is the expression of phosphorylcholine (ChoP). This unusual prokaryotic structure is now known to be exposed on the surface of the most common pathogens infecting the human respiratory tract; Haemophilus influenzae, mycoplasma, and Streptococcus pneumoniae. In addition, based on cross-reactivity to a MAb recognizing this structure, ChoP may be present on diverse phase-variable structures on N. meningitidis, N. gonorrhoeae, P. aeruginosa, and A. actinomycetemcomitans. We have defined the genetic basis of ChoP expression and the molecular mechanism

24 Pneumonia

controlling its phase variation in H. influenzae. This has allowed direct genetic analysis of clinical samples to show that the ChoP+ phase variants predominate on the mucosal surface of humans. The structure, however, is the target of innate immunity mediated by binding of C-reactive protein (CRP), which is bactericidal in the presence of complement. The focus of this proposal is to define the biological role of variants both with and without ChoP using H. influenzae as a prototype human respiratory tract pathogen. In Aim 1, we will determine whether switching to the ChoP- phenotype is required in natural H. influenzae infection (otitis media, pneumonia, bacteremia, and meningitis) to evade clearance by CRP and bactericidal anti-ChoP IgG. The ChoP phenotype in vivo will be determined by direct genetic analysis and compared to the local concentration of CRP and anti-ChoP antibody during infection. The local expression and concentration of CRP in the upper respiratory tract will be investigated. In Aim 2, we will determine how ChoP contributes to persistence on the mucosal surface. Genetically defined H. influenzae mutants with constitutive ChoP-on and ChoP-off phenotypes will be used to determine whether this host membrane-like structure contributes to (a) resistance to respiratory tract antibacterial peptides including LL-37 and tracheal antimicrobial peptide (TAP), and (b) colonization by functioning as a bacterial adhesin to host epithelial cells via putative ChoP ligands including GalNAcb 14Gal on the asialo-GM1 glycolipid and the platelet activating factor receptor. The blocking of complement mediated killing by naturally acquired secretory IgA recognizing ChoP will be explored as an explanation for the selection of the ChoP+ phenotype on the mucosal surface, despite the increased susceptibility of this phenotype to CRP and complement. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PNEUMONIA

BACTERIAL

PREDICTORS

OF

SEVERE

NOSOCOMIAL

Principal Investigator & Institution: Hauser, Alan R. Microbiology and Immunology; Northwestern University Office of Sponsored Programs Chicago, IL 60611 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-DEC-2007 Summary: (provided by applicant): The long-term objective of the proposed study is to better understand the pathogenesis of hospital-acquired pneumonia caused by Pseudomonas aeruginosa. The general strategy is to characterize the role of the P. aeruginosa type III secretion system in hospital-acquired pneumonia. This complex secretion pathway transports and injects four known effector proteins into host cells: ExoS, ExoT, ExoU (also known as PepA), and ExoY. Interestingly, clinical isolates differ in the combination of effector proteins they secrete. Recent studies are beginning to define the role of individual effector proteins in pathogenesis. Preliminary studies using bacterial mutants indicate that ExoS, ExoT, ExoU, and ExoY all have cytotoxic effects on mammalian cells in cell culture systems. ExoT, ExoU, and possibly ExoS contribute to virulence in animal models of pneumonia. In addition, ExoU secretion is associated with worse clinical outcomes in humans with hospital-acquired pneumonia. Together, these findings support an important role for type III effector proteins in the acute pneumonia, although the exact role of each effector protein and the mechanisms by which these proteins lead to the pathophysiological consequences of pneumonia remain to be defined and are the subject of this proposal. Our preliminary data suggest that type III secretion contributes to bacterial persistence, dissemination, and mortality as well as neutrophil killing and suppression of proinflammatory cytokine release in a mouse model of pneumonia. Further defining the role of individual effector proteins in these processes is crucial to our understanding of the pathogenesis of hospital-acquired

Studies 25

pneumonia caused by P. aeruginosa. It is hypothesized that specific effector proteins play an important role in the pathogenesis of hospital-acquired pneumonia, including the prevention of bacterial clearance by neutrophils. Furthermore, it is hypothesized that because of these effects secretion of specific effector proteins can be used as markers for strains associated with especially severe hospital-acquired pneumonia in human patients. Studies using both mice and humans will be performed to define the roles of these effector proteins in the pathogenesis of acute pneumonia, including modulation of the inflammatory response and resistance to neutrophil-mediated clearance, and to determine whether secretion of particular effector proteins serves as a marker for strains capable of causing especially severe disease in human patients with hospital-acquired pneumonia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BBA EFFECTS ON GEOGRAPHIC VARIATION IN POST-ACUTE CARE Principal Investigator & Institution: Lin, Wen-Chieh; Family and Community Medicine; University of Missouri Columbia 310 Jesse Hall Columbia, MO 65211 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2004 Summary: (Provided by Applicant): In response to the rapid growth in payments for post-acute care (PAC) services, Congress enacted Medicare reforms as part of the Balanced Budget Act of 1997 (BBA) for each PAC service. The reforms mandated a series of separate case-mix adjusted prospective payment systems, each with its own implementation timeline. In addition to the overall effects, the BBA's effects on PAC use varied substantially across geographic areas. For example, in the case of skilled nursing facility use from 1998 to 2000, the average change relative to 1996 for stroke patients was 2.7%.at the national level, but it ranged from -12% to 24% across regions (the nine United States Census Bureau divisions). This varied response raises concerns that the hospital discharge process may be driven by payment policy rather than by clinical needs and individual preferences. Furthermore, varied changes in PAC use across regions might lead to untoward consequences, such as early hospital readmission. As efforts continue to reform PAC services and payment systems, it is essential that policymakers understand how different payment mechanisms associate with geographic variation in PAC use. The proposed study seeks to: 1) analyze geographic variation in PAC use before and after the BBA changes; 2) explore whether utilization and cost have shifted among PAC settings and whether early hospital readmission has increased; and 3) investigate how the contributions of patient, hospital, and market area characteristics in explaining PAC use differ between pre- and post-BBA periods. We will analyze the Center for Medicare & Medicaid Services' 5% sample of Medicare claims data from 1996 to 2000 to study the initial effect of the BBA changes on geographic variation in PAC use. We will focus on six diseases associated with high PAC use: stroke, hip procedure, hip fracture, chronic obstructive pulmonary disease, pneumonia, and congestive heart failure. The selected diseases provide a contrast between rehabilitative and medical conditions. The stability, the degree, and the association of geographic variation in PAC use before and after the BBA changes will be examined. Shifts in utilization and costs will be presented as correlations between changes in PAC use, hospital length of stay, and early hospital readmission. Finally, we will estimate multinomial logit models to explore changes in contribution to explain PAC use by patient, hospital, and market area characteristics after the BBA changes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

26 Pneumonia

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Project Title: BIOLOGY OF PCRV Principal Investigator & Institution: Wiener-Kronish, Jeanine P. Professor; Anesthesia and Perioperative Care; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001; Project Start 01-MAY-2000; Project End 30-APR-2005 Summary: Nosocomial pneumonia is the second most common nosocomial infection and the leading cause of death from infection acquired in the hospital. P. aeruginosa is the most frequent gram negative bacteria involved in nosocomial pneumonia, and nosocomial pneumonias associated with P. aeruginosa infections have up to a 60% mortality despite appropriate antibiotic treatment. Also patients who are chronically infected with P. aeruginosa (i.e.: cystic fibrosis, HIV patients and bronchiectasis patients) become resistant to antibiotics and may die from their4 infections. Thus, there is an urgent need for novel treatments of P. aeruginosa infections. The long-term objectives of this grant are to determine the cell biology of a Pseudomonal protein, PcrV. PcrV is part of the bacterial type III secretory system; PcrV is involved in the translocation of bacterial toxins by P.aeruginosa into eukaryotic cells. It is also highly homologous to LcrV, a Yersinia protein also involved in the translocation. of that bacteria's toxins into eukaryotic cells. Antibodies to LcrV can protect animals from infections caused by Y. pestis and other Yersinia strains. Yet, although there are similarities between LcrV and PcrV, there are also important differences in the roles of LcrV compared to PcrV in the regulation of toxin secretion in the two strains. Therefore, PcrV warrants independent investigation. This group has shown that PcrV is accessible to antibody neutralization, that antibody attachment to PcrV blocks the translocation of the Pseudomonal toxins into eukaryotic cells and that antibody to PcrV protects animals infected with virulent P. aeruginosa from lung injury, sepsis and death. Therefore, therapies targeting PcrV appears clinically useful. Finally, many virulent gram negative bacteria utilize the type III secretory system which delivers bacterial toxins into eukaryotic cells. These gram negative bacteria, including enteropathic E. coli, Yersinia, Salmonella, produce bacterial proteins and structures similar to those found in P.aeruginosa. Therefore, understanding the mechanism of PcrV's role in bacterial translocation into eukaryotic cells may help in the development of other therapies targeting this widespread gram negative bacterial secretory system. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BODY TEMPERATURE AND REGULATING HOST DEFENSES Principal Investigator & Institution: Hasday, Jeffrey D. Professor; Medicine; University of Maryland Balt Prof School Baltimore, MD 21201 Timing: Fiscal Year 2001; Project Start 01-MAR-1999; Project End 28-FEB-2003 Summary: Fever is a key element of the initial response to infection. In general, fever is associated with improved survival during infections, but the mechanisms of its protective effects are largely unknown. We hypothesize that the increase in core temperatures that occurs during febrile illnesses is essential for optimal orchestration of the host defenses. Our overall research objective is to determine the mechanisms through which increases in core temperature during fever influence morbidity and showed that increases in core temperature to febrile levels enhances the early cytokine responses to bacterial endotoxin (LPS), a non-replicating agonist. We have taken advantage of the partial ectothermic nature of young (8-10 week old) mice to develop a method to passively maintain core temperatures at febrile (39-40 degrees Celsius) or afebrile (36.5- 37.5 degrees Celsius) levels during infections. We will use this model to

Studies 27

directly determine the following potential effects of core temperatures changes in mice infected with Klebsiella pneumoniae, a clinically relevant and virulent bacterial pathogen: (1) determine if febrile core temperatures enhance containment and reduce dissemination of K. pneumoniae peritonitis; (2) determine if increasing core temperature to febrile levels enhances collateral tissue injury during K. pneumoniae peritonitis; (3) evaluate the potential roles of altered TNFalpha expression or tissue responsiveness to TNFalpha; and (4) determine if an increase in core temperature in core temperature to febrile levels is required for optimal orchestration of the host response and survival in K. pneumoniae pneumonia. The results of the proposed research will provide important information about the mechanisms through which changes in core temperature regulate host defenses. Because technology is available to modify body temperature, the results of the proposed experiments can be rapidly translated to the clinical area. Understanding the role of core temperature in regulating host defenses may lead to new protocols for managing body temperature during infections and may identify novel modalities for treating and preventing septic shock. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BRONX/LEBANON PEDIATRIC ACTU Principal Investigator & Institution: Bakshi, Saroj S.; Bronx-Lebanon Hosp Ctr (Bronx, Ny) 1276 Fulton Ave New York, NY 10456 Timing: Fiscal Year 2001; Project Start 11-MAR-1992; Project End 28-FEB-2002 Summary: The Bronx Lebanon Hospital Center (BLHC) Pediatric AIDS Clinical Trial Unit (ACTU) has been very productive site of the Pediatric AIDS Clinical Trials Group (ACTG) since initiation of funding in 1992. It is located in an HIV epicenter in New York City and is the only funded PACTU in the Bronx. In the past seven years, the combined BLHC Division of Women and Children's HIV Services has provided comprehensive, integrated medical and psychosocial to 600 HIV exposed children and is now caring for 380 HIV infected. The major strength of the BLHC PACTC lies in its ability to recruit and retain large numbers of HIV infected children and pregnant women into protocols as demonstrated by past performance. Clinical care is integrated with research programs including a CDC funded Maternal-Infant Transmission Study (MITS) and the Pediatric AIDS Foundation Ariel Project. As with our performance in the PACTG, we have exceeded targeted accrual in each of these studies. The target for the first study year of this proposal is 94 participants which exceeds the minimum requirements stated in the RFA. The recent expansion and renovation of our clinical space has created an environment in which the PACTG obligations can be met with sensitivity. The site has implemented an extensive and comprehensive data quality assurance plan which has resulted in excellent data management summaries as per the DAIDS. The staff of the BLHC- PACTU is contributing to the development and implementation of the scientific mission of the PACTG. Therefore, the BLHC PACTU is an excellent site to continue as a participant in the scientific agenda of the PACTG. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: C3-BINDING AND -DEGRADING PROTEINS IN S. PNEUMONIAE Principal Investigator & Institution: Hostetter, Margaret K. Professor and Director; Pediatrics; Yale University 47 College Street, Suite 203 New Haven, CT 065208047 Timing: Fiscal Year 2002; Project Start 23-SEP-2002; Project End 22-SEP-2004 Summary: (provided by applicant): Streptococcus pneumoniae remains a leading cause of morbidity and mortality in community acquired respiratory infections. The third

28 Pneumonia

component of complement, C3, stands as the central mediator of host defense in susceptible patients who lack anti-capsular antibody. Over the past 5 years, we have identified two C3-degrading enzymes from S. pneumoniae: CppA, which degrades the C3 beta-chain; and PhpA, which cleaves the C3 alpha-chain into previously unrecognized fragments. Neither proteinase has any homolog in the database, and both are expressed by a wide variety of encapsulated clinical isolates. Intranasal immunization of mice with recombinant rCppA reduced nasopharyngeal colonization with a serotype 3 organism. Immunization of mice with rPhpA significantly reduced bacteremia and increased survival; in separate experiments, immunization with rPhpA was more effective than the serotype 3 conjugate vaccine in reducing nasopharyngeal colonization. In addition to the protective effects of CppA and PhpA in vivo, cppA- and phpA- mutants are more susceptible to C3-mediated opsonophagocytosis in vitro than is the isogenic parent. This revised proposal focuses on the mechanisms by which CppA and PhpA enable S. pneumoniae to elude C3-mediated killing in blood and lung. In Specific Aim One, we will characterize the mechanism of proteolysis by which CppA degrades the C3 beta-chain using chromogenic substrates and standard protease inhibitors. Truncation constructs expressed in Lactococcus lactis will be used to map the active site. A cppA- mutant in an encapsulated serotype 4 will be constructed. Specific Aim Two will focus on PhpA, a 79 kDa proteinase that cleaves the C3 alpha-chain into novel fragments of 97 and 83 kDa. Possible biologic activities of these C3 fragments in inhibiting C3 or neutrophils will be assayed. Biochemical techniques will be employed to understand how full-length PhpA liberates an internal 20 kDa polypeptide that appears to account for the majority of C3-cleaving activity. A phpA- mutant in an encapsulated serotype 4 will be constructed. Specific Aim Three will use a standard killing assay and a double mutant to test for additive or synergistic effects of CppA and PhpA. Other opsonins in blood (fibronectin) and lung (surfactant protein A) will be assessed as potential substrates for CppA and PhpA. Specific Aim Four will employ cppA- and phpA- mutants in the encapsulated strain to understand whether the effects of CppA and PhpA on C3-mediated killing contribute to virulence in a rabbit model of pneumonia and bacteremia. This revised proposal will define the role of two potent immunogens in pneumococcal pathogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CARET-CHLAMYDIA PNEUMONIA AND RISK OF LUNG CANCER Principal Investigator & Institution: Goodman, Gary E. Associate Professor; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, WA 98109 Timing: Fiscal Year 2001; Project Start 01-JUL-1994; Project End 31-MAY-2004 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CCSP IN INNATE DEFENSE AGAINST LUNG VIRAL INFECTION Principal Investigator & Institution: Harrod, Kevin S.; Lovelace Biomedical & Environmental Res Environmental Research Inst Albuquerque, NM 87185 Timing: Fiscal Year 2001; Project Start 20-AUG-2000; Project End 31-JUL-2004 Summary: The present application seeks to determine the role of Clara cell secretory protein (CCSP) in modulating host responses to viral infection in vivo. The lung is continually exposed to inhaled pathogens; yet, in healthy individuals, it remains remarkably free from infection. CCSP is an abundant protein of the lung airway fluid, and may have anti- inflammatory properties. Thus, CCSP may constitute an important

Studies 29

component of the innate immune system of the lung. CCSP is decreased in the lungs of smokers and patients with ARDS, suggesting a role for CCSP in the modulation of host inflammatory responses. Viral infection is a major cause of lung disease in humans, especially children. To directly determine the role of CCSP in vivo, gene-targeted mice lacking CCSP (CCSP -/-) were generated. These mice survive normally, with no apparent abnormalities. However, recent experiments demonstrate that CCSP -/- mice are susceptible to pulmonary adenoviral infection. CCSP - /-mice following adenoviral infection have increased infiltration of inflammatory cells early during the course of viral-induced inflammation. The infiltrating inflammatory cells consist predominantly of neutrophils. Cytokine and chemokine production is also increased in the lungs of CCSP -/- mice following adenoviral infection, coinciding with the infiltration of inflammatory cells into the lung. These results suggest that CCSP alters the host response to pulmonary adenoviral infection in vivo and may constitute an important mechanism of innate defense in the lung. The present application tests the hypothesis that CCSP modulates host responses through the regulation of lung phagocyte function and augments viral clearance during infection. To determine the role of CCSP in viral innate defense, experiments will determine if CCSP alters phagocyte activation and function in vivo following adenoviral infection. Viral uptake and killing will be assessed in the lungs of CCSP -/- mice following adenoviral infection to determine the role of CCSP in viral clearance. Temporal studies of recombinant CCSP (rCCSP) administration to CCSP -/- mice will determine the role of CCSP in modulating the initiation and resolution of viral-induced lung inflammation. CCSP expression will be restored in CCSP -/- mice through the development of CCSP transgenic mice, and subsequently bred into the CCSP -/- mouse model to assess the spatial relationship of CCSP expression in altering host defense to lung viral infection. This application will determine the role and delineate mechanisms by which CCSP provides innate immunity to viral infection in the lung. Such data may be useful in designing treatment and prevention of viral pneumonia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CD-18 DEPENDENT/INDEPENDENT WBC RESPONSES IN THE LUNG Principal Investigator & Institution: Doerschuk, Claire M. Professor of Pediatrics and Pathology; Pediatrics; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2003; Project Start 01-AUG-1994; Project End 31-MAY-2008 Summary: (provided by applicant): Neutrophil emigration into the lungs can occur through at least two different pathways depending upon the stimulus, one that requires the CD11/CD18 adhesion complex, and one that does not. Our studies provide evidence that mice deficient in the NF-kappaB p65 (Rel A) subunit, mice deficient in both TNF R1 and IL-1R1, or mice with blockade of ICAM-1 have defects in E. coli-induced CD18dependent emigration. In contrast, mice deficient in the leukocyte non-receptor Src tyrosine kinases Lyn, Fgr, and Hck, in the small GTPase Rac2, or in interferon-(IFN-g) have defects in S. pneumoniae-induced CD18-independent but not E. coli-induced CD18-dependent emigration. Moreover, exogenous IFN-( switches CD18-dependent to CD18-independent emigration, whereas genetic deficiency of IFN-( switches CD18independent to CD18-dependent emigration. Studies comparing gene expression during these bacterial pneumonias also provided many new ideas. Our goal is, to understand the mechanisms, through which CD18-dependent and CD18-independent adhesion pathways are elicited and function; and to identify ways of modulating the acute

30 Pneumonia

inflammatory process to benefit the host. Our working hypothesis is that neutrophil emigration occurs through CD11/CD18-dependent pathways when early stages of host defense result in nuclear translocation of NF-kappaB, production of TNF-alpha and IL-1, and increased expression of ICAM-1 on pulmonary capillary endothelial cells, while CD11/CD18- independent mechanisms are selected when IFN-( is produced and the leukocyte Src kinases Lyn, Fgr, and Hck and the small GTPase Rac2 are activated. The proposed Aims will test this hypothesis and examine the role of each of these required molecules in the mechanisms of neutrophil emigration. Aim 1 will determine the role of NF-(B -mediated gene transcription and the function of TNF-alpha and IL-1 in CD18dependent and -independent neutrophil emigration. Aim 2 will determine the role of IFN-g in CD18- independent emigration. Aim 3 will determine the role of Lyn, Fgr, and Hck and of Rac2, and the functional relationships between these molecules and IFN-g in neutrophil recruitment and function. Aim 4 will determine the functional role of molecules identified by gene microarray technology to be differentially expressed in S. pneumoniae but not E. coli pneumonia. These studies will help to elucidate the molecular mechanisms of neutrophil recruitment and identify potential targets for therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CD8 T CELL DEPENDENT DAMAGE IN PNEUMOCYSTIS PNEUMONIA Principal Investigator & Institution: Harmsen, Allen; Professor and Head; Veterinary Molecular Biology; Montana State University (Bozeman) Bozeman, MT 59717 Timing: Fiscal Year 2001; Project Start 01-JUL-2000; Project End 30-JUN-2005 Summary: (from applicant's abstract): During Pneumocystis carinii pneumonia (PCP) in CD4 depleted mice, P. carinii specific CD8 T cells shift from a protective T1-type to a nonprotective and deleterious T2-type response. This detrimental response of cytotoxic T cells is further down regulated by interferon gamma and subsequent NO production. This general hypothesis will be addressed through three specific aims. First, Harmsen and colleagues will investigate the antigen specificity of CD8 T cells as they accumulate in the lungs of CD4 T cell-depleted mice during PCP. They will further investigate the role of class I MHC antigens in the activation of these cells. Next, they will determine the roles of interferon gamma and iNOS-dependent NO production in mediating the effects of CD8 T cells during PCP. Under the final aim, they will determine the mechanisms by which CD8 T cells damage the lung during PCP. They will investigate both the roles of T-cell derived perforin and recruited neutrophils in mediating this CD8 dependent lung injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CELLULAR MECHANISMS THAT CONTROL SIV & DEVELOPMENT OF P* Principal Investigator & Institution: Clements, Janice E. Professor; Comparative Medicine; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2003; Project Start 19-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): HIV establishes infection in lung during acute infection. However, virus replication appears to be controlled after acute infection, and HIV interstitial pneumonia does not develop until the late stages of infection prior to the development of AIDS. The goals of these studies are to elucidate the mechanism that regulates acute HIV/SIV replication in the lung and cells in the bronchoalveolar lavage

Studies 31

and to establish a testable model for control of HIV/SIV replication in the lung. Using an SIV/macaque model of HIV pneumonia in which all infected animals develop interstitial pneumonia and AIDS by 3 months, we demonstrated that there is viral replication in the lung during acute infection that is controlled during the asymptomatic infection, but virus replication resurges during the late stages of disease when there are lymphocytic infiltrates in the lung and pneumonia. Because active virus replication continued in the periphery during this time, these findings suggested the existence of a mechanism in the lung that mediates down-regulation of acute HIV/SIV replication. Alveolar macrophage is the predominant cells in the lung productively infected with HIV/SIV. Because HIV replication in macrophages requires C/EBP sites in the HIV LTR, we considered the possibility that negative regulation of C/EBP-dependent transcription is integral to the mechanism suppressing acute HIV/SIV replication in the CNS. Consistent with this notion is the ability of IFNbeta to inhibit active HIV transcription via induced expression of a dominant-negative isoform of C/EBPbeta. Based on preliminary studies demonstrating up-regulated expression of IFNbeta and the dominant-negative isoform of C/EBPbeta in the lung, our hypothesis is that acute virus replication in the lung is controlled by IFNbeta and increased expression of the dominant-negative form of C/EBPbeta in macrophages. Resurgent virus replication in the lungs during terminal disease is the result of increased influx of CXCR3+/CD8+ cells, decreased inhibition by the dominant-negative form of C/EBPbeta protein due to and increased activation of NF-kappaB in macrophages. Intervention with exogenous IFNbeta during asymptomatic infection will inhibit influx of CXCR3+ CD8+ cells, maintain the control of HIV transcription by the dominant-negative form of C/EBPbeta protein and inhibit resurgent virus activation in the lung and the development of associated lesions. These studies will be supported by our collaborators, Dr. William Bishai, an expert in AIDS and M. tuberculosis, in humans, and Dr. Christopher Karp, an immunologist who has studied HIV and Multiple Sclerosis and is actively involved in therapeutic treatment of MS patients in INFbeta. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CELLULAR TUBERCULOSIS

NECROSIS

INDUCED

BY

MYCOBACTERIUM

Principal Investigator & Institution: King, C Harold. Medicine; Emory University 1784 North Decatur Road Atlanta, GA 30322 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 14-SEP-2003 Summary: (provided by applicant): A key step in the pathogenesis of M tuberculosis is its ability to cause caseating necrosis, parenchymal lung destruction, and cavity formation, which develop into the characteristic necrotizing bronchointerstitial pneumonia and bronchiolitis of tuberculosis. M tuberculosis is cytotoxic to epithelial cells in vitro, and we have shown that this cytotoxicity is associated with cell membrane permeation to lactose dehydrogenase and is mediated by necrosis of lung epithelial cells after infection with virulent mycobacteria (Dobos, K. M., Quinn, F. D. and King, C. H. 2000, Infect. Immun. 68:6300-6310). Interestingly, the attenuated M bovis BCG does not induce necrosis in this epithelial cell model suggesting that necrosis is related to the virulence of mycobacteria. Our working hypothesis is that M tuberculosis possesses factors that cause necrosis. We intend to identify the genes that encode or synthesize such factors and determine their functions. Towards this goal, we have been successful in isolating two such (necrosis-deficient) mutants with insertions into genes that have no known function by screening a transposon library of the Erdman strain of M tuberculosis (TN5370) for mutants that have lost their ability to cause cell membrane

32 Pneumonia

permeation and necrosis. Both nec mutants possess extremely interesting phenotypes when grown in mice. The first mutant (necA) appears to be highly attenuated for growth and virulence in SCID mice. This is an important result as it suggests that we have identified a gene whose product either directly causes necrosis or induces necrosis and thus should enhance our understanding of tuberculosis pathogenesis. Interestingly, the second mutant (necB) appears to kill SCID mice more rapidly than the parental strain. We intend to characterize these mutants, characterize the functions of the gene products, and extend this mutant isolation strategy to identify a large battery of mutants defective for necrosis of host cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHEMOKINE AND CHEMOKINE RECEPTORS IN IPF Principal Investigator & Institution: Hogaboam, Cory M. Associate Professor; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2002; Project Start 26-DEC-2001; Project End 30-NOV-2006 Summary: (Applicant's Abstract) Interstitial lung disease (Il-D) encompasses a group of pulmonary inflammatory disorders that are characterized by excessive tissue injury and progressive fibrosis. Clinical and laboratory evidence suggest that ILD is a consequence of a poorly regulated pulmonary inflammatory process because of the persistence of one or several inflammatory signals. Recent experimental data suggest that the lung fibroblast is not a bystander during chronic inflammatory responses in the lung, rather this structural cell has a very specialized role in the recruitment and regulation of immune cells that infiltrate the interstitial space. The role of the fibroblast during ILD has expanded because of the recent recognition that this cell markedly increases the generation of chemotactic proteins (chemokines) and directly responds to these factors through the expression of high-specialized chemokine receptors. Chemokines affect both the proliferation and synthetic capacity of pulmonary fibroblasts. Although increased chemokine levels during ILD have been reported, little is known about changes in the chemokine and chemokine receptor expression in the fibroblast during ILD, nor is it known whether the temporal pattern of expression of chemokine receptors by these cells may aid in differentiating the various pathologically distinct types of ILD or success of ILD treatment. Thus, the overall aim of this proposal is to characterize the pattern of chemokine and chemokine receptor expression associated with non-specific interstitial pneumonia (NSIP)-cellular, NSIP-fibrotic, usual interstitial pneumonia (UIP)-discordent, and UIP-cordent in open lung biopsies (OLB), fibrotic foci and cultured fibroblasts from OLB and transbronchial biopsies. The following specific aims will be addressed using powerful new techniques including TAQMAN quantitative polymerase chain reaction (PCR) and laser capture microscopy: 1) to characterize the chemokine and chemolcine receptor profile in OLB from patients at the time of ILD diagnosis, and specifically identify the chemokine receptor profile in fibrotic foci from histological samples. 2) to characterize the chemokine and chemokine receptor profile in fibroblasts cultured from open lung biopsies at the time of ILD diagnosis. 3) to examine changes in the chemokine and chemokine receptor profile in cultured transbronchial biopsy fibroblasts at defined intervals after initial ILD diagnosis and during a defined ILD treatment regimen. Taken together, these studies entail an examination of the expression of chemokines and their receptors in OLB, fibrotic foci and cultured lung fibroblasts at the time of diagnosis and during ILD treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies 33

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Project Title: CHIMERIC VIRUS VACCINES FOR P. AERUGINOSA INFECTIONS Principal Investigator & Institution: Staczek, John; Professor; Microbiology and Immunology; Louisiana State Univ Hsc Shreveport P. O. Box 33932 Shreveport, LA 71103 Timing: Fiscal Year 2003; Project Start 01-JUL-1998; Project End 31-MAR-2007 Summary: (provided by applicant): Pseudomonas infection is an underappreciated cause of morbidity and mortality. Nosocomial infections can be life-threatening in immunocompromized populations, cancer patients, the elderly, and patients with cystic fibrosis. Physicians try to protect patients with antibiotic therapy, but the bacteria quickly develop antibiotic resistance. A complementary approach to antibiotic therapy is therefore urgently needed, and one such approach is vaccination. Our long-range goal is to develop vaccines that protect against Pseudomonas lung infection. We have developed two effective outer membrane protein F (OprF)-based vaccines that protect against both nonmucoid and mucoid Pseudomonas phenotypes. These vaccines are called F/I and F/HG. The F/I vaccine consists of three biolistic inoculations of naked DNA sequences for the fusion protein OprF/l. The F/HG vaccine uses a prime-boost strategy with two biolistic inoculations of naked DNA-oprF sequences followed by an intramuscular booster containing the chimeric influenza virus HG10-11. Each vaccine appears to induce a polarized immune response. The F/I vaccine induced antibodymediated immunity (AMI) while F/HG induced cell-mediated immunity (CMI). Insufficient information is available regarding the immune mechanisms whereby Pseudomonas infection is controlled or how Pseudomonas vaccines work. AMI in pulmonary Pseudomonas infection is believed to be important, but the definitive mechanism for clearance is unknown. We propose to define the mechanisms of antibody protection by identifying antibody isotypes and serum cytokines in infected and F/Iimmunized mice that are immune-intact or immune-deficient. Likewise, the role of CMI in Pseudomonas pneumonia is poorly understood. Our F/HG vaccine will allow us to define the mechanism(s) of Pseudomonas-specific, cell-mediated protection in the lungs of infected and immunized mice that are immune-intact or immune-deficient. Defining these mechanisms will allow us to rationally modify immune responses to protect more effectively against pulmonary Pseudomonas infection. As researchers delineate the immune responses to pulmonary Pseudomonas infection in humans, we will be uniquely positioned to modify our vaccines to induce specific Th-1 or Th-2 responses. These rationally designed vaccines tested in a pulmonary chronic infection model will provide guiding principles to prevent and treat more effectively Pseudomonas pneumonia in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHLAMYDIA ATHEROSCLEROSIS

PNEUMONIAE

AND

MACROPHAGES

IN

Principal Investigator & Institution: Byrne, Gerald I. Professor & Chairman; Medical Microbiol & Immunology; University of Wisconsin Madison 750 University Ave Madison, WI 53706 Timing: Fiscal Year 2001; Project Start 15-FEB-1999; Project End 31-JAN-2004 Summary: (Adapted from the Applicant's Abstract): Chlamydia pneumoniae, a causative agent in human community acquired pneumonia, also has been implicated in a variety of sequelae associated with chronic disease and re-exposure to the organism. One important sequel associated with C. pneumoniae infection is the development of atherosclerotic lesions that define the pathology of cardiovascular disease in people.

34 Pneumonia

Cardiovascular disease due to atherogenic processes is a major health problem in most of the world, accounting for about 50% of all deaths. It is clear that vascular injury is crucial in the development and progression of atherosclerosis and that this injury can result from a variety of causes, including infection. Several lines of evidence support the hypothesis that C. pneumoniae infection is linked to the development of atherosclerosis. Initially, seroepidemiological evidence was generated to establish a relationship between C. pneumoniae and cardiovascular disease. Subsequently, evidence for the presence of the organism in atherosclerotic lesions was obtained using either direct antigen detection methods or probes specific for C. pneumoniae nucleic acids. In addition, the organism has been isolated from an aortic lesion and grown in cell culture. Finally, two pilot secondary prevention antibiotic treatment trials have provided evidence to suggest that treatment of C. pneumoniae in individuals with coronary heart disease significantly reduces cardiac events in treated versus placebo administered populations. Thus, although the association of C. pneumoniae and atherosclerosis is well-established, existing data do not prove an etiology or pathogenic role for the organism in disease, although both rabbit and murine animal models have been developed to determine if C. pneumoniae is causally associated with development or progression of atherosclerotic lesions in vivo. Activation and modification of mononuclear phagocyte function is associated with atherosclerotic lesion development. Characteristic changes include development of cholesteryl ester-laden monocytes (foam cells) and oxidation of lipids to form tissue-damaging derivatives. The hypothesis to be tested here is that infection of human monocytes, monocyte-derived macrophages or murine monocyte cell lines with C. pneumoniae results in changes in macrophage morphology and function that are consistent with a role for C. pneumoniae in the pathogenesis of atherosclerosis. This hypothesis will be tested by determining if C. pneumoniae causes mononuclear phagocytes to form foam cells in the presence of low density lipoprotein (LDL) or other cholesterol-containing serum lipoprotein complexes. Studies also will be conducted to determine if C. pneumoniae contributes to the oxidative modification of LDL and molecular characterization of C. pneumoniae antigens involved in these processes will be identified. Finally, a murine model will be developed to provide in vivo correlates to cell culture observations. Results will help establish links between C. pneumoniae infection and the atherosclerotic disease process. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHLAMYDIA SIGNIFICANCE

PNEUMONIAE

ANTIGENS

OF

BIOLOGICAL

Principal Investigator & Institution: Campbell, Lee A. Professor; Pathobiology; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAR-2007 Summary: (provided by the applicant): Chlamydia pneumoniae is a human respiratory pathogen that causes 5 percent to 10 percent of pneumonia, bronchitis, and sinusitis. Virtually everyone is infected in his or her lifetime and reinfection is common. Infection is difficult to treat even with sensitive antibiotics. Chronic infection is common and has been associated with asthma, reactive airway disease, Reiter's syndrome, erythema nodosum, and sarcoidosis. The potential public health impact of infection with this pathogen is underscored by the association of C. pneumoniae with atherosclerosis and related clinical manifestations such as coronary heart disease, carotid artery stenosis, aortic aneurysm, claudication, and stroke. If C. pneumoniae infection plays a role in atherogenesis, there will be an urgent need to facilitate diagnosis and develop strategies for intervention and prevention. The overall goal of this proposal is two fold. First, C.

Studies 35

pneumoniae specific antigens that are recognized during human infection will be exploited to facilitate serodiagnosis and identify putative vaccine candidates. The second goal is to define chlamydial/host cell interactions that lead to entry and survival of C. pneumoniae in host cells relevant to atherosclerosis. The specific focus will be on the interaction of the chlamydial glycan moiety with carbohydrate binding receptors on the host cell. Importantly, infection of epithelial cells can be inhibited with N-linked high mannose type oligosaccharide, the major component of the glycan. The novel hypothesis to be tested is that C. pneumoniae enters through the mannose-6 phosphate receptor by binding to the site involved in transport of phosphomannosylated residues to the lysosome and this differs from C. trachomatis, which utilizes the mannose receptor. The ultimate goals of these studies are to identify C. pneumoniae specific antigens to facilitate laboratory diagnosis and virulence factors playing a role in pathogenesis to guide vaccine development or develop anti-adhesive strategies for prevention of infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COLUMBIA-ADARC AIDS CLINICAL TRIALS UNIT Principal Investigator & Institution: Hammer, Scott M. Director; Medicine; Columbia University Health Sciences New York, NY 10032 Timing: Fiscal Year 2001; Project Start 01-JAN-2000; Project End 31-DEC-2004 Summary: (adapted from the application's abstract): The overall goal of this application is the formation of a clinical site within the Adult AIDS Clinical Trials Group (AACTG) which will effectively execute studies designed to improve the understanding and treatment of HIV disease. This site, a linkage of the Columbia Presbyterian Medical Center (Columbia) with the Aaron Diamond AIDS Research Center (ADARC) will be designated the Columbia-ADARC AIDS Clinical Trials Unit. Columbia will serve as the main unit and ADARC as the sub-unit in this collaboration of two institutions already scientifically linked by the recently awarded Center for AIDS Research (CFAR) grant. The intent is to bring together extensive and complementary clinical trials and basic investigative expertise to facilitate execution of the Group's scientific agenda. A Columbia-ADARC unit may possess the elements necessary to successfully carry out a diverse array of pathogenetically and strategically based clinical trials in a demographically diverse population. The specific aims of this application are: (1) to establish a clinical trials unit that has the capability to conduct studies which advance the knowledge of HIV pathogenesis and treatment. Specifically, this unit will be dedicated to further the AACTG's research agenda through active accrual to protocols sponsored by the scientific committees of the Group; (2) to recruit and retain a diverse population of HIV infected persons in AACTG trials who reflect the affected population in Manhattan, particularly Northern Manhattan, a region which has been severely affected by the HIV epidemic and one that is representative of the penetrance of the epidemic into the inner cities. This will be achieved through recruitment of patients from a large primary care base and broad regional referral network; and (3) to promote the Group's scientific mission by active participation in AACTG protocols and committees by Columbia-ADARC investigators. This will include sharing of new technologies that enhance the sophistication of patient monitoring and thereby generate new hypotheses to test in the context of AACTG trials. Thus, the Columbia-ADARC ACTU will be an active participant in the Group's mission to improve the health of HIV infected individuals and set standards for treatment of HIV disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

36 Pneumonia

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Project Title: CONST OF VACCINE CTR: PNEUMONIA, FLU Principal Investigator & Institution: Lucas, Alexander H. Senior Research Immunologist; Children's Hospital & Res Ctr at Oakland Research Center at Oakland Oakland, CA 94609 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2003 Summary: (provided by applicant): This application seeks funds from the National Center for Research Resources (NCRR) to support construction of the CIVD being established at the CHORI. The Center will consist of new laboratories, core facilities and office spaces suitable to house the research, research training and research support activities of several integrated scientific programs. The investigators who will occupy the Center conduct molecular, cellular and clinical studies in the inter-related areas of immunobiology, infectious diseases, pathogenesis, vaccine development and vaccine evaluation. As a group, the CIVD investigators have 18 extramural awards with total direct costs in year 2001 that exceed $3 million of which 75 percent derives from the National Institutes of Health (NIH). Dr. Dan Granoff will be the Scientific Director of the Center. Dr. Alexander Lucas, Deputy Director of Medical Research at CHORI, is the Principal Investigator (PI) and will be responsible for the space utilization and the administrative management of the Center. CHORI has made a substantial financial commitment to this project and has designated the CIVD as a high priority in its Strategic Plan. Approximately 8,000 sq. ft. of undeveloped shell space will be used for construction of the CIVD. The Center will provide interactive laboratory and office spaces as well as specialized shared core facilities, such as a Biosafety Level 3 (BSL3) facility and a DNA clean room for polymerase chain reaction (PCR) assembly. Construction of the CIVD will expand investigators' research capabilities, promote programmatic interaction and growth, increase training opportunities, and permit recruitment of additional scientists. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE -- IMMUNIZATION AND PNEUMONIA DISPARITIES RESEARCH Principal Investigator & Institution: Zimmerman, Richard K.; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 29-SEP-2007 Summary: CORE ABSTRACT NOT PROVIDED Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--CLINICAL Principal Investigator & Institution: Martinez, Fernando J.; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2002; Project Start 26-DEC-2001; Project End 30-NOV-2006 Summary: (Applicant's Abstract) The mission of the Clinical Core is to provide the personnel, facilities, and organizational structure necessary to generate the clinical database and patient specimens for Projects 6, 2 and 7. These resources will support individual protocols within the Center, facilitate interactions between investigators, and provide a cohesive framework for the formulation, execution, and data analysis of clinical research projects. The clinical protocols are designed to approximate the best available strategies for diagnostic assessment and therapy for subsets of idiopathic interstitial pneumonias (11P), including idiopathic pulmonary fibrosis (usual interstitial

Studies 37

pneumonia, UIP) and nonspecific interstitial pneumonia (NSIP). The specific aims are to: Manage the clinical studies involving patients with UIP and NSIP including: (a) Identify eligible patients and coordinate patient flow from the Fibrotic Lung Disease Network (FLDN) physicians to the University of Michigan Health System (UN4HS) for initial evaluation (b) Obtain informed consent, enroll patients, collect clinical data (physiologic testing, scoring chest roentgenograms and high resolution computed tomography) (c) Select the biopsy site based on HRCT findings, communicate this to thoracic surgeons at the UMHS and at FLDN sites; coordinate the interpretation of histologic, samples by collaborating pathologists (d) Manage outpatients on prednisone, prednisone/azathiopnine and zileuton at UMBS or the FLDN Procure Tissues and cells for individual investigators including: (a) Performing bronchoalveolar lavage and transbronchial biopsies at appropriate time points (b) Coordinate procurement of surgical lung biopsy specimens at LTMHS or at the FLDN and deliver specimens to appropriate SCOR investigator at the UNIHS Provide data management services to individual investigators including: (a) Organizing and managing the clinical database, advisino on study design, sample size calculation and selection of appropriate outcome variables (b) Assisting with statistical applications and data analysis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--CLINICAL Principal Investigator & Institution: Shasby, D Michael. Professor; University of Iowa Iowa City, IA 52242 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2002 Summary: While there are some optimistic reports, the mortality for ARDS remains near 50%. Of the patients who die, one half survive beyond the first three days. In these patients who survive more than 3 days, signs of persistent lung and systemic inflammation are associated with increased mortality. Early autopsy series detected a large number of unsuspected cases of bacterial infection of the lung in persons dying with ARDS. In more recent clinical studies culture of bronchoscopic samples from live patients without clinical signs of pneumonia have not yielded a high prevalence of results that meet strict criteria for pneumonia. However, a large fraction of samples did contain bacteria and the prevalence of samples with bacteria increased with time on the ventilator. In addition to bacterial colonization of the lung itself, translocation of bacteria across the intestinal wall occurs in severely ill patients, and especially those with shock. The use of broad spectrum antibiotics in patients with ARDS limits the sensitivity of strict quantitative culture criteria to accurately quantify the bacterial burden in ARDS patients. We hypothesize that a significant portion of the persistent acute inflammation present in the lungs of ARDS patients derives from bacteria which colonize the lung surfaces and/or translocate into the blood stream. In the case of bacteria which translocate into the blood stream the primed lung becomes the subject of a response similar to the Shwartzman phenomenon. Recent studies have not detected high levels of lung colonization or blood stream invasion by bacteria because of the ubiquitous use of broad spectrum antibiotics. We will measure bacterial burden in the lung and blood stream of ARDS patients using PCR for bacterial DNA, the sensitivity of which is not as limited by the presence of antibiotics. We will determine if the bacterial burden in the lung and blood as an independent predictor of mortality and if it correlates with indices of acute inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CTRS FOR EDUCATION AND RESEARCH ON THERAPEUTICS (CERTS) Principal Investigator & Institution: Strom, Brian L. Professor of Medicine and Pharmacology; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2003 Summary: There remain enormous gaps in the information available to the public about the effects of their drugs, and in the application of that information to optimizing prescribing and thereby improving the risk/benefit balance from drugs. Centers for Education and Research on Therapeutics (CERTs) offer the opportunity to address many of these deficits, and this proposal goes a long way toward filling that gap. In particular, we propose to: 1. Establish a CERT with a coordinated infrastructure, including: a. Logistical support, including faculty time and core staff; b. Governance, including regular coordination and business meetings; c. Programmatic coordination, including linkage of the pharmacoepidemiology skills of the Center for Clinical Epidemiology and Biostatistics (CCEB) with the pharmacoeconomics skills of the Leonard Davis Institute of Health Economics, the experience in patient -oriented research of the General Clinical Research Center; basic science laboratories interested in evaluating the molecular mechanisms of drug effects; and the social science skills of non-biomedical researchers in other parts of the University; d. Regularly scheduled educational conference series; e. Active participation in the national network of CERTs; and f. A pilot research grant program targeted at the development of R01 quality grants and proposals. 2. Testing and building the capabilities of the current Penn ambulatory drug use evaluation program as a laboratory, expanding it to broader populations; 3. Improve the use of antibiotics locally and nationally, with studies leading to grant funding for larger scale efforts, as well as formal dissemination of evidence-based data both known and to be known. The initial studies will: a. evaluate techniques to reduce the use of antibiotics for acute bronchitis in the outpatient setting b. evaluate the impact of antimicrobial formulary interventions at different hospitals on the resistance patterns of extendedspectrum beta-lactamase- producing Escherichia coli and Klebsiella species; c. simulate data, in order to expand the use of meta-analysis to study rare adverse outcomes from antibiotics; d. study the effects of tetracycline used to treat acne in a dermatology clinic on antibiotic resistance patterns; and e. study the use of the GPRD Database to explore the epidemiology of drug -resistant pneumococcal pneumonia 4. Conduct an extensive education program, including: i) a Masters in Clinical Epidemiology (MSCE) and PhD pharmacoepidemiology fellowship training program; ii) opportunities for MSCE and PhD students in epidemiology and biostatistics to use existing in-house databases to answer new questions, to participate in ongoing research, and to develop new research projects; iii) courses for university physicians housestaff, nurses, and nursing students; iv) courses for pharmacists and pharmacy students; v) courses for medical students; and vi) a degree credit course in pharmacoepidemiology for MSCE students. 5. Organize and formally disseminate the results of our work, consisting of: publications and presentations for the Scientific/Professional community; ii) the FDA, AHCPR, other CERTs, etc. and iii) the public, building on the dissemination program of the Leonard Davis Institute of Health Economics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies 39

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Project Title: CYSTEINE PRESENTATION

PROTEASES

IN

MHC

CLASS

II

ANTIGEN

Principal Investigator & Institution: Chapman, Harold A. Professor; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001; Project Start 01-JAN-1993; Project End 31-DEC-2002 Summary: (Adapted from the applicant's abstract): Presentation of foreign antigens by MHC class II gene products is a central arm of immunity. The process of MHC class IIdependent antigen presentation involves several discrete steps mediated by proteolytic enzymes: generation of peptides for their subsequent presentation as antigens in peptide complexes with MHC alpha/beta dimers and the stepwise breakdown of the class IIassociated molecular chaperone, the invariant chain (Ii). Degradation of Ii promotes loading of MHC class II alpha/beta with newly formed peptides. A single protease, cathepsin S, was recently found to be essential to the process of Ii breakdown and efficient MHC class II peptide loading. These studies are aimed at elucidating the mechanisms by which cathepsin S promotes antigen presentation and at understanding the consequences of inhibition of cathepsin S on MHC class II function. Toward that end, cellular models of antigen presentation in which the activity of cathepsin S, and other cysteine proteases can be manipulated have been developed. Ii resistant to cleavage of cathepsin S will be generated by site-directed mutagenesis and the function of mutant Ii assessed in vitro and in vivo. The importance of cathepsin S in vivo to MHC class II-dependent immune responses, including allergic pulmonary reactions, will be tested by creating a selective, systemic deficiency of cathepsin S with low molecular weight protease inhibitors. And finally, mice with targeted disruption ("knockout") of the cathepsin S gene are being generated in order to assess the consequences of longstanding cathepsin S deficiency on MHC class II function and to provide a fertile background on which to search for additional proteases important to antigen presentation. These studies should provide new information on the basic events important to MHC class II peptide loading and establish whether there is a clear rationale for therapeutic inhibition of cathepsin S to suppress inflammation in lung diseases promoted by MHC class II-dependent immune reactions such as asthma, hypersensitivity pneumonitis, and transplant rejection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CYTOKINE PNEUMOCYSTIS

CONTROL

OF

HOST

SUSCEPTIBILITY

TO

Principal Investigator & Institution: Beck, James M. Associate Professor; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2001; Project Start 30-SEP-1997; Project End 31-AUG-2003 Summary: An improved understanding of the factors contorlling host susceptibility to Pneumocystis carinii could provide novel therapeutic modalities directed against this opportunistic pathogen. Our laboratory utilizes immunodeficient mouse models of P. Carinii pneumonia to study susceptibility to this organism, modeling the immune deficits present in HIV-infected individuals. Using these immunodeficient mouse models of P. Carinii pneumonia, we confirmed the roles of both CD4+ and CD8+ T cells in host defense against P. Carinii. Both CD4+ and CD8+ T cells are likely to control susceptibility to P. Carinii by elaboration of cytokines. Recent information shows that both of these T cell subsets can express either Th1 or Th2 cytokine repertoires. In an increasing number of model systems, it is apparent that the balance between

40 Pneumonia

susceptibility and defense does not depend on single cytokines with isolated actions. Rather, coordinated responses, precisely modulated in intensity and in sequence, control susceptibility. In preliminary data presented in this application, we characterize Th1 and Th2 cytokine production in the lungs of immunocompetent and immunodeficient mice after P. Carinii inoculation. We demonstrate differential, time-dependent patterns of cytokine production in vivo. Furthermore, we have successfully used mice deleted of specific cytokine genes ("knockout" mice) to examine suceptibility to P. Carinii in vivo. Based o these data, we hypothesize that coordinated Th1 and Th2 responses are required for successful defense against p. Carinii, requiring early Th2-like responses and late Th1-like responses. There are four specific objectives: (1) to determine the cellular sources of cytokines responsible for successful defense against or susceptibility to P. Carinii in vivo; (2) to determine whether cytokine blockade can alter defense against or susceptibility to P. Carinii in vivo; (3) to isolate P. Carinii-specific CD4+ T cells with specific cytokine profiles in vitro and to determine whether these cells maintain their cytokine profiles in vivo; and (4) to determine whether reconstitution with CD4+ T cells of defined repertoire alters susceptibility to infection in vivo. These powerful animal models allow us to test the roles of cytokines in control of susceptibility to P. Carini using in vivo approaches that model human P. Carinii pneumonia. Ultimately, these studies can be extended to develop therapeutic strategies directed against this important opportunistic pathogen. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CYTOKINES IN RADIATION LUNG INJURY Principal Investigator & Institution: Blackstock, Arthur W. Associate Professor Radiation/Oncology; Radiation Oncology; Wake Forest University Health Sciences Winston-Salem, NC 27157 Timing: Fiscal Year 2002; Project Start 05-JUL-2002; Project End 30-JUN-2004 Summary: (provided by applicant): Non small cell lung cancer (NSCLC) is the leading cause of cancer related deaths in the United States. Traditional radiotherapy delivered with standard fractionation to standard doses is ineffective at sterilizing the primary tumor and results in local control rates of 20-40 percent. The overall outcome for patients with inoperable NSCLC is a five year survival rate of less than 10 percent. Advances using combined modality therapy and altered radiation fractionation schedules have resulted in modest improvements in survival, although local and distant failure rates remain high. There is increasing evidence that pro-inflammatory cytokines (chemokines) can be induced in response to ionizing radiation. Macrophage inflammatory protein 1-alpha (MIP-1alpha) appears to be an important cytokine mediator of pulmonary inflammation and injury. Growing preclinical and clinical data suggest a potential relationship between serum MIP-1alpha levels and the risk of lung injury following thoracic radiation. A pilot study to determine the clinical significance of MIP-1alpha levels in patients receiving thoracic radiation will be evaluated in this study. A phase I/II trial has been initiated to determine the toxicity of induction/concurrent chemotherapy and 3-dimensionally planned - thoracic radiation therapy for patients with locally advanced NSCLC. In conjunction with this clinical trial, we will collect and analyze pre-treatment, weekly (during treatment) and post-treatment MIP-1alpha levels. Our specific aims are to: Ia) define the temporal changes in MIP-1alpha levels over the course of therapy and in follow-up to ascertain if these changes are predictive for the clinical development of radiation pneumonitis, Ib) define these same temporal changes in MIP-l-alpha and ascertain if they are predictive for the clinical development of pulmonary fibrosis, and II) discern if the temporal changes in MIP-1alpha can be

Studies 41

correlated with the lung volume irradiated, changes in pulmonary function after therapy or overall clinical outcome. By determining that changes in MIP-1alpha levels correlate with the acute and chronic lung injuries associated with thoracic irradiation, we may more rationally develop and incorporate their use in future clinical trials employing thoracic radiation therapy. Even further, understanding the temporal expression of MIP-1alpha during thoracic radiation may allow the future utilization of anticytokine reagents, e.g. antibodies, receptor and synthesis blockers during treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DATA INFORMATICS

MINING

AND

MODEL

BUILDING

IN

MEDICAL

Principal Investigator & Institution: Buchanan, Bruce G. Professor; Computer Science; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2001; Project Start 01-MAY-1999; Project End 30-APR-2003 Summary: Our long-term goal is to assist biomedical scientists by extracting and codifying new knowledge from large biomedical databases routinely by computer. As large collections of data become more readily accessibly, the opportunities for discovering new information increase. We propose here to work toward this goal by extending our prior research on machine learning in two important directions: (1) codification of disparate pieces of knowledge into a coherent model (model building), and (2) discovery of new information in medical databases (data mining). Machine learning programs find classification rules (or decision trees or networks) that separate members of a target class from other individuals. They have emphasized predictive accuracy, with some attention to tradeoffs between accuracy and cost of errors or between accuracy and simplicity. We propose a framework in which these, and other, tradeoffs are explicit and the criteria by which tradeoffs are made are available for modification. We also include semantic considerations among the criteria to control the internal coherence of models. "Data mining" is a recently-coined term for using computers to explore large databases, with a goal of discovering new relationships but usually with no specific target defined at the outset. In addition to accuracy, simplicity, coherence, and cost, a program that purports to discover new relationships must be able to assess novelty. We propose to measure the extent to which proposed relationships are novel by comparing them against existing knowledge in the domain of discourse, and to look for unusual rules (and other relations) that would be very interesting if true. The computer program we are primarily building on, RL, is a knowledge- based learning program that learns classification rules from a collection of data. RL has been demonstrated to be flexible enough to allow guidance from prior knowledge, and powerful enough to learn publishable information for scientists working in several different domains. Both parts of the research will requires extending the RL system in new ways detailed in the research plan, which are consistent with the overall design philosophy of the present system. We will primarily work with data already collected on pneumonia patients with with which we have considerable. We will test the generality of the criteria used to evaluate models and discoveries with a Baynesian Net learning. We will test the generality of the generality of the criteria used to evaluate models and discoveries with Bayesian Net learning system, K2. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DELIVERY OF CLINICAL PREVENTIVE SERVICES Principal Investigator & Institution: Buchwald, Debra; University of Colorado Hlth Sciences Ctr Uchsc at Fitzsimons Aurora, CO 800450508

42 Pneumonia

Timing: Fiscal Year 2001 Summary: American Indians and Alaska Natives (AI/ANs) are especially susceptible to respiratory diseases. According to Indian Health Service statistics, influenza/pneumonia is the 6th leading cause of death among all AIs and the 4th among Native elders. Moreover, mortality increases markedly with age; for persons greater than or equal to 65 years, mortality due to AI/ANs are not available, minority populations receive influenza (IV) and pneumococcal (PV) vaccinations at substantially lower rates than whites. Since minority adults utilize preventive services loss, present for care at more advanced stages of disease, and have greater morbidity and mortality than higher income individuals, AI/AN elders are at risk for not obtaining IV and PV. In this regard, our pilot work with urban Native elders in a primary care practice found that only 31% and 21%, respectively, in accordance with published guidelines. Thus, the Specific Aims of this project are to: 1) compare the effectiveness of "usual care" to 2 patient-targeted interventions in promoting immunizations among AI/AN elders at a large urban health center (either receipt of culturally appropriate educational materials addressing knowledge, attitudes, and beliefs informed by focus groups or an incentive); 2) assess the effectiveness of provider-targeted peer feedback versus usual care in increasing vaccination rates; and 3) examine patient-related factors influencing receipt of immunizations. To accomplish this we will conduct a randomized, controlled, clinical trial to assess improvement in IV and PV rates among an elderly AI/AN clinic population. During Year 1, focus groups will help develop culturally appropriate educational materials determine the incentive, as well as facilitate an understanding of reasons for non-adherence to guidelines. In Year 2, eligible Native elders will receive culturally appropriate educational materials, an incentive, or usual care. In Year 3, a physician- targeted feedback intervention will consist comparisons to rates of peer administration of IV and PV. During Years 4 and 5, we will complete the data collection and analysis, than meet with health leaders from 5 Northwest tribes to evaluate the feasibility of putting into practice the successful portions of the planned intervention in local reservation-based communities. These objectives are consistent with the Healthy People 2000 National Health Promotion and Disease Prevention Objectives to achieve IV and PV coverage rates of greater than or equal to 60% among community-dwellers aged greater than or equal to 65 living and high-risk populations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DETECTING ASPIRATION ASSOCIATED WITH TUBE FEEDINGS Principal Investigator & Institution: Metheny, Norma A. Dorothy A. Votsmeier Professor; None; St. Louis University St. Louis, MO 63110 Timing: Fiscal Year 2002; Project Start 01-AUG-1999; Project End 31-MAY-2005 Summary: (provided by applicant) The ultimate goal of the proposed study is to increase the safety of mechanically ventilated (MV) tube-fed patients. This group is at high risk for aspiration of regurgitated gastric contents with deleterious consequences including transient hypoxemia, chemical pneumonitis, and potentially life-threatening nosocomial pneumonia. Efforts are made in practice settings to detect aspirations early so that interventions can be initiated to prevent morbidity and mortality. However, clinicians are unsure about how to accomplish this since currently available bedside methods to detect aspirations are unreliable. A laboratory method of detecting aspirations based on pepsin was tested in an animal model in the current study (8/1/997/31/02) and found to be highly sensitive and specific. Preliminary studies have indicated that the laboratory assay can detect pepsin (a proxy for the aspiration of gastric contents) in tracheal secretions suctioned from critically ill tube-fed patients. To

Studies 43

determine the extent to which pepsin in tracheal secretions predicts the development of pneumonia, daily Clinical Pulmonary Infection Scores will be calculated. Another problem in the management of tube-fed MV patients is uncertainty about how to assess for significantly slowed gastrointestinal (GI) motility, a condition that predisposes to aspiration. Especially problematic is difficulty in determining when indicators of slowed GI motility, such as large GI residual volumes, are of sufficient magnitude to warrant temporary withholding of feedings. As a result feedings are often withheld unnecessarily, leading to significantly reduced caloric intake. Therefore, another aim of the proposed study is to identify the signs of slowed GI motility that are most predictive of aspirations of gastric contents. Additional aims are to examine the effect of risk factors for aspiration on the detection of pepsin in tracheal secretions as well as the effect of risk factors for pneumonia on the development of pneumonia. The proposed work is a prospective, descriptive study of 680, critically ill, tube-fed patients who will be monitored 24 hours a day for the first 3 days of tube feedings to assess for: pepsin in suctioned tracheal secretions, signs of GI intolerance to tube feedings (large GI residual volumes, absence of bowel sounds, and presence of vomiting), and risk factors for aspiration and pneumonia. In addition, Clinical Pulmonary Infection Scores will be calculated daily for the first 4 days of tube feedings. Patients will be recruited from 5 intensive care units at a Level I trauma center. Data collection will occur over a 24month period and the data will be analyzed by logistic regression and multiple linear regression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DETECTION OF PULMONARY ASPIRATION USING PULSE OXIMETRY Principal Investigator & Institution: Edwards, Sharon J. None; St. Louis University St. Louis, MO 63110 Timing: Fiscal Year 2001; Project Start 01-MAY-2001 Summary: Mechanically ventilated patients are at high-risk for frequent small- volume aspirations of regurgitated gastric contents with potentially harmful consequences (e.g., pneumonia). Detection of micro-aspirations is a major clinical problem since the two most commonly used methods for this purpose (observing for dye and glucose in suctioned tracheobronchial secretions) have questionable sensitivity and specificity. The purpose of this study is to determine the extent to which a commonly used apparatus (pulse oximetry) can be used to detect micro-aspiration in an animal model. A pulse oximeter (a NONIN 8600 MV) will be applied to the animal's shaved tail and readings made at baseline and every 15 minutes for a period of 6 hours. The sample will consist of 30 anesthetized New Zealand White rabbits who are undergoing forced microaspiration of a solution of human gastric juice and dye-stained enteral formula. Since the presence of fiber in an enteral formula is likely to increase airway obstruction, two types of formulas will be analyzed, fiber-free and fiber-containing. There will be 12 rabbits placed in each formula group and 6 rabbits used as a control group (which will receive forced micro-aspirations of 0.9% normal saline). This sample size achieves a power of 80% at an alpha level of.01. Detection of aspiration will be considered to have occurred if there are 2 or more decreases in oxygen saturation >3% below baseline. The analysis of the proposed hypotheses will include a z-test to compare the proportion of experimental animals in which aspiration is detected by pulse oximetry. A 2 x 3 x 8 repeated measures analysis of covariance and planned comparisons will also be used to analyze relationships between the variables. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

44 Pneumonia

•

Project Title: DETERMINANTS OF UREAPLASMA-MEDIATED NEONATAL LUNG INJURY Principal Investigator & Institution: Viscardi, Rose M. Associate Professor; Pediatrics; University of Maryland Balt Prof School Baltimore, MD 21201 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2004 Summary: (provided by applicant): Respiratory tract colonization with Ureaplasma urealyticum (Uu) in preterm infants is a highly significant risk factor for Bronchopulmonary Dysplasia (BPD). In a prospective cohort of infants less than 32 wk gestation, 50 percent mod-severe BPD, 29 percent mild BPD, and 19 percent non-BPD subjects were Uu tracheal aspirate (TA) positive. Five of six (83 percent) infants who were TA Uu positive and serum or CSF PCR positive had BPD, suggesting invasiveness of the organism may be associated with increased pulmonary pathogenicity. However, invasive disease alone was not significantly associated with BPD, suggesting local immunomodulatory effects of Uu in the lung are required to develop BPD. We previously observed that Uu respiratory tract colonization in preterm infants was associated with greater levels of the pro-inflammatory cytokines tumor necrosis factor (TNF) and interleukin (IL)-1B in TA during the first week of life. In vitro studies of cultured preterm monocytes, Uu serovar 3 alone stimulated TNF and IL-8, and, in combination with bacterial endotoxin (LPS) augmented LPS-induced TNF release, but blocked LPS-induced IL-6 release. We used a clinical Uu isolate (biovar 2) to develop the first non-neonatal mouse model of Uu pneumonia. While these mice develop little detectable illness and minimal signs of lung injury, Uu infection caused a biphasic influx of neutrophils peaking 24h and again 14d after inoculation, and of macrophages peaking 48h and 14-28d after inoculation. Our long-term objective is to determine how Uu modulates the pulmonary immune response alone and in the presence of coinflammatory stimuli. The specific aims of this proposal focus on the central hypothesis that the Uu serovars; differ in their ability to promote the development of BPD due to differences in capacity to augment the pulmonary inflammatory response. The specific aims are: 1) determine whether the risk for BPD is Uu biovar or serovar specific by PCR typing of archived TA isolates, blood and CSF samples from preterm infants with and without BPD, and 2) characterize pathologic properties of TA Uu isolates from BPD and nort-BPD infants using our cell culture and murine Uu pneumonia models. These studies will provide new insights into how certain serovars contribute to the prolonged inflammatory process in BPD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: DEVELOPMENT AND CHARACTERIZATION OF CD14 DEFICIENT MICE Principal Investigator & Institution: Freeman, Mason W. Chief; Massachusetts General Hospital 55 Fruit St Boston, MA 02114 Timing: Fiscal Year 2001; Project Start 15-FEB-2001; Project End 31-JAN-2006 Summary: (Adapted from the applicant's abstract): CD14 is a 55 kDa glycosyl phosphatidylinositol-linked protein that is also present in a soluble form in serum. CD14 binds lipopolysaccharides (LPSs) derived from the outermost layer of Gram-negative bacteria and activates a signaling cascade that results in the production of inflammatory cytokines that include tumor necrosis factor alpha, interleukin-6, and interleukin-1. This response has been shown to be important in the pathogenesis of septic shock following Gram- negative septicemia. Recent data have also suggested that a similar response may play a role in accelerating atherosclerotic plaque development and in enhancing the

Studies 45

formation of the macrophage foam cell, the histologic hallmark of the early atheroma. Several lines of evidence also implicate this pathway in the pathogenesis of PID, a leading cause of infertility in the developed world, and in the phagocytosis of apoptotic cells, an essential event in tissue remodeling and development. Investigators working on inflammatory bowel disease, periodontal disease, and a variety of inflammatory pulmonary disorders have also postulated an important role for CD14 in these conditions. Given the widespread interest in understanding the contributions of CD14 to normal physiology and pathologic conditions, the applicant's laboratory has generated homologous recombinant mice lacking this protein. This grant application proposes to generate a breeding colony of these animals and to distribute these mice to the many investigators that have requested them. These investigators, working on diseases supported by a diverse group of NIH Institutes, can then utilize these animals in experiments that explore the biological processes in which CD14 activity has been implicated. In addition to developing the breeding colony of CD14 deficient mice, this application proposes to characterize the utility of these animals as models for diseases that represent major human health problems in which the principal investigators of the grant have established research efforts. Thus, the CD14 deficient animals will be bred into mouse strains that are susceptible to atherosclerosis in order to explore the role of Chlamydial infections in the pathogenesis of cardiovascular disease. In addition, CD14null mice will also be used to explore the role of the endotoxin signaling pathway in mouse models of PID. This work is intended to broaden the applicability of CD14 deficient mice to research involving acute and chronic inflammatory disease and to make a critical animal resource available to the investigative community at large. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEVELOPMENT OF NOVEL ANTIFUNGAL ANTIPC NATURAL PRODUCTS Principal Investigator & Institution: Avery, Mitchell A. Associate Professor; Medicinal Chemistry; University of Mississippi University, MS 38677 Timing: Fiscal Year 2001; Project Start 01-JUN-1999; Project End 31-MAY-2003 Summary: (Adapted from Applicant's Abstract): The development of a new drug candidate for the treatment of Pneumocystis carinii pneumonia and azole-resistant Candida albicans, and the identification of one or more potential new therapeutic targets in these OI pathogens is proposed. Pseudolaric Acid B (PLAB), a diterpene acid isolated from the bark of a Chinese medicinal plant, Pseudolarix kaempferi, is proposed as a lead compound for the development of a new class of antipneumocystic and antifungal agents. PLAB appears to exert its antifungal activity and antipneumocystic activity by a novel mechanism of action involving a previously unrecognized therapeutic molecular target in these AIDS-related OI pathogens. To accomplish the objectives of new drug development and validation of the proposed new therapeutic target(s), pharmacophore-based tools for drug design by synthesis and bioassay are proposed. Parallel mechanisms of action studies are also proposed. Specifically, these goals will be met by completing ongoing studies directed towards the total synthesis of PLAB using methods that will also provide for construction of analogs not available by semi-synthesis (including carbon-14 labeled PLAB for use in mechanism of action studies); by preparing through semi-synthesis, PLAB analogs from PLAB and PLAC, both of which are in the process of being isolated from bulk quantities of Pseudolarix amabilis; by evaluating all prepared PLAB analogs for in vitro and in vivo inhibition of P. carinii and other fungal OI pathogens and for inhibition/activation of specific molecular targets; by determining the mechanism of action of PLAB and its active

46 Pneumonia

analogs by correlating effects on specific molecular targets with whole cell inhibitory effects; and, utilizing data derived above to design mechanism-based inhibitors/ activators of a specific therapeutic target. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EARLY PULMONARY HOST DEFENSE IN M. TUBERCULOSIS INFECTIO Principal Investigator & Institution: Sherman, David R. Senior Scientist; Pediatrics; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2003; Project Start 30-SEP-1999; Project End 31-JUL-2004 Summary: Although a lung is a portal of entry for this M. tuberculosis and chronic pneumonia is the most common disease caused by M. tuberculosis infection, the specific nature of the pulmonary host response to this pathogen is relatively unknown. The central goal of the studies outlined in this proposal is to determine whether components of the early pulmonary immune response are critical determinants for resistance or susceptibility to disease caused by M. tuberculosis. The specific aims will address the role of TNF-alpha, beta chemokines and the B7/CD28/CTLA4 costimulation pathway in the initiation and amplification of the pulmonary host response to aerosol infection with M. tuberculosis. Preliminary studies using transgenic mice with a local inhibition of TNF-alpha in the lung (SPCTNFRIIFc mice) indicate that blockade of TNF-alpha selectively in the lung results in early deaths, severe lung pathology and an alteration of antigen specific immunity. These studies also indicate that transgenic mice with local inhibition of the immune response in the lung are a useful model to study pulmonary host defense. Further studies are proposed to compare the response that develops in the lung vs. regional lymph nodes in wildtype and SPCTNFRIIFc mice. To investigate the role of beta chemokines in the pulmonary host defense, transgenic mice that secrete a virally encoded inhibitor of all chemokines has been generated. The phenotype of these mice will be determined then used to investigate the role of beta chemokines in the initiation of the pulmonary host response to M. tuberculosis. To investigate the role of the B7/CD28/CTLA4 costimulation pathway in the initiation and amplification of the pulmonary host response to M. tuberculosis, transgenic mice that secrete an inhibitor of the B7/CD28/CTLA4 co stimulation pathway will be generated, characterized then used in experiments examining the immune response to M. tuberculosis. To determine the relative importance of the intrapulmonary component of the immune response vs the systemic immune response, in each of the project specific aims, mice will be included with both local inhibition of the immune response and systemic inhibition. In the studies examining the pulmonary host response to M. tuberculosis, infections will occur via the aerosol route because inhalation is the usual route of infection in humans. The primary endpoints will include bacterial burden, lung histology, survival and the phenotypic and functional characteristics of the immune response. The proposed studies should advance the existing knowledge of the specific nature of the pulmonary immune response to M. tuberculosis, will directly test the role of these mediators in host defense against M. tuberculosis, suggest important targets for novel therapies and elucidate role of specific mediators of the host immune response that are critical for the induction of an antigen specific immune response by candidate vaccines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies 47

•

Project Title: EFFECT OF ZINC SUPPLEMENTATION ON PNEUMONIA IN CHILDREN Principal Investigator & Institution: Fataki, Maulidi R.; Muhimbili University Coll of Health Scis of Health Sciences Dar Es Salaam, Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-AUG-2006 Summary: (provided by applicant) Randomized trials carried out elsewhere in the developing countries have shown that dietary zinc supplementation in apparently healthy children reduces pneumonia incidence by 41%, however, all the studies that were analyzed had looked at the efficacy of zinc supplementation on the incidence of pneumonia during a prospective follow-up period and none had looked at the effect of zinc supplements on an episode of respiratory disease during the course of treatment. We propose to undertake a randomized, double blind, placebo-controlled trial to examine whether daily oral supplement of 10 mg of elemental zinc will reduce severity of respiratory disease among children admitted at Muhimbili National Hospital, Dares Salaam, Tanzania with radiographically confirmed pneumonia. Six hundred children aged between 6 months and 5 years who will be admitted because of radiologically confirmed pneumonia and whose parents/caretakers will give consent will be recruited during a 3-year study period and will be randomly assigned to receive either daily zinc supplements or placebo and the outcome between the two groups will be closely monitored and documented to determine any beneficial effects of zinc supplements on the course of hospital treatment of pneumonia with duration of hospital stay, fever, rapid respiratory rate and hypoxia as endpoints of interest After discharge from hospital each patient will be followed for duration of 6 months, once every month at study clinic at Muhimbili National Hospital to determine the effect of zinc supplements on growth patterns using increment in weight and height as endpoints. Baseline laboratory investigations to determine serum zinc levels, hematological profile and on consent HIV status will be done and a repeat of serum zinc levels will be done at the end of 6 month follow-up period for each child. At the end of the study appropriate statistical tests will be done to analyze the effects between the two study groups and dissemination of the information will be done. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: EFFECTS OF TOBACCO SMOKE ON AIRWAY BACTERICIDAL ACTIVITY Principal Investigator & Institution: Di, Yuan-Pu P. Environ & Occupational Health; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2002; Project Start 18-SEP-2002; Project End 31-JUL-2005 Summary: (Taken from the Investigator's Abstract) Environmental stresses such as microorganisms and toxic chemicals have profound effects on lung injury and pulmonary disease. Airway bacterial infection has been associated with various lung diseases such as pneumonia, cystic fibrosis, and tuberculosis. Tobacco smoke (TS) is known to induce pulmonary diseases such as emphysema and lung cancer and has effects on the host defense mechanism against pathogens, but the molecular mechanisms by which this occurs is not completely understood. The long-term goal of this proposal is to investigate the functional characteristics of a novel airway specific gene, DD4, its regulation and its potential role in health and human lung diseases that relate to tobacco smoke. The human DD4 gene is specifically expressed in serous cells of submucosal glands where bactericidal proteins such as lysozyme and lactoferrin are secreted. This novel gene has exhibited significant response to promoting agents of

48 Pneumonia

mucous cell differentiation such as UTP and retinoids, as well as to several mediators of inflammation and proliferation such as tumor necrosis factor-alpha (TNF-alpha) and epidermal growth factor (EGF). Of potential significance, the candidate?s preliminary studies revealed that DD4 has antibacterial properties and that its secretion varied dramatically between different lung diseases. In addition, the candidate?s laboratory also observed that human DD4 MRNA expression is elevated upon TS stimulations in both time and dose dependent manner. The objective of this application is to elucidate effects of TS on the regulatory mechanism of DD4?s gene expression and to examine DD4?s function after TS exposure both in vitro and in vivo. The central hypothesis to be tested is that DD4 is a secreted bactericidal protein that plays a role in airway defense mechanisms against pathogens. The rationale behind this research is that modulation (such as TS exposure) of the secretary DD4 protein is one means of directly affecting host defense response against human airway infection. Therefore, regulation of DD4 gene expression and protein secretion in response to pathological stimuli must be understood before the mobilization of host defenses and the pathogenesis of airway diseases that are related to DD4 can be fully appreciated. To accomplish the objectives of this application, they will pursue three specific aims: (1) to characterize the bactericidal activity of DD4; (2) to elucidate the regulatory mechanism of TS exposure on DD4?s bactericidal function; (3) to evaluate DD4?s antibacterial effect in vivo. At the completion of this research, the candidate expects to have determined the bactericidal potency of DD4 and the regulation by TS of the antibacterial defense mechanism of DD4. The candidate expects that regulation of DD4 will prove to be related, at least in part, to the inflammatory response and tobacco smoke exposure. Finally, the candidate may obtain a better understanding of the pathogenesis of bacterial infections in certain lung diseases under effects of tobacco smoke, and the development of new therapeutic strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECTS OF TRAUMATIC STRESS ON GASTRIC SECRETIONS Principal Investigator & Institution: Mercer, David A.; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, TX 77225 Timing: Fiscal Year 2001 Summary: Over the last decade, the Trauma Research Center has explored the role of the gut in the pathogenesis of multiple organ failure (MOF). It is our working hypothesis that the gut is a source of pro-inflammatory mediators in early MOF and serves as a reservoir for pathogens and toxins in late MOF. This research proposal contends that the stomach becomes a reservoir for bacteria during traumatic stress because inhibition of gastric acid secretion occurs with resultant loss of natural bactericidal activity. The inevitable bacterial overgrowth in the stomach may play a significant role in the development of nosocomial pneumonia which occurs in 10%- 65% of IC patients and is associated with case fatality rates ranging from 13-55%. The current research proposal is designed to identify mechanisms regulating inhibition of gastric acid secretion during traumatic stress cause inhibition of gastric acid secretion by the gastric H/K-ATPase, the enzyme responsible for acid secretion, via changes in gut peptide (somatostatin and gastrin) expression which are nitric oxide and prostaglandin sensitive. To address this hypothesis, we will utilize the mesenteric ischemia/reperfusion model as well as the LPD model in rats, because of their abilities to mimic the syndrome of MOF. The specific aims to prove or disprove this hypothesis are as follows. The first aim will be to elucidate the effects of traumatic stress induced experimentally with lipopolysaccharide (LPS( and mesenteric ischemia/reperfusion, on

Studies 49

gastric acid secretion. The second aim will evaluate the effects of traumatic stress on the gastric H/K-ATPase. The third aim will determine whether gut peptide (i.e. gastrin and somatostatin) expression is altered following traumatic stress. The fourth aim will examine the role of nitric oxide synthase in traumatic stress induced changes in gastric secretion. The fifth aim will assess whether cyclooxygenase expression modifies gastric secretion following traumatic stress. The results of this research proposal will clarify the mechanisms regulating inhibition of gastric acid secretion during traumatic stress and may allow identification of new therapeutic strategies that could ultimately prevent or decrease the likelihood of developing nosocomial pneumonia in patients with or at high risk for MOF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ELDERLY POLYSACCHARIDE

IMMUNE

RESPONSE

TO

PNEUMOCOCAL

Principal Investigator & Institution: Westerink, Ma J. Medicine; Medical College of Ohio at Toledo Research & Grants Admin. Toledo, OH 436145804 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: Infection is one of the leading causes of morbidity and mortality in the elderly. Streptococcus pneumoniae is the organism most commonly isolated from elderly patients with pneumonia. Increased susceptibility to infections that occur in the elderly has been attributed to deteriorating health, decreased pulmonary function and a functional decline of the immune system. The immune system is unique in that it may be manipulated to achieve a desirable response. Studies in aged mice demonstrate both quantitative and qualitative changes in the immune response to T-independent type 2 (TI-2) antigens. Reports indicate age related loss of affinity, fine specificity and protective immunity are associated with a molecular shift in V gene usage and changes in cytokine profile. Studies of the in vivo immune response in elderly have been limited to vaccine efficacy studies and quantitative analysis of the magnitude and duration of the post-vaccination antibody response. The results of these studies suggest that despite adequate quantitative immune response the elderly show decreased vaccine efficacy. Current knowledge concerning the aging immune response to TI-2 antigens is mostly based on animal models and may not be applicable to humans. Human studies are fragmented and address quantitative and qualitative immune response as separate issues. We propose to study and characterize the immune response to S. pneumoniae capsular polysaccharide in the elderly. We will focus on both quantitative and qualitative changes in the immune response on molecular and functional levels. The quantitative immune response, isotype and IgG subclass, will be correlated with opsonophagocytic activity. We hypothesize that the discrepancy between the quantitative and qualitative immune response in the elderly results from altered V region sequence. We will characterize the immunoglobulin gene usage pattern and V-DJ joint diversity of the antibody response to pneumococcal polysaccharides (PPS) of serotypes 4 and 14 in elderly and young adults. This will be accomplished by gene family specific ELISA and by isolating single responding cells and determining the sequence of the V chains. Second, we propose to evaluate the influence of soluble regulatory factors on the aging immune response. The reconstituted SCID mouse model will be used to study the aging human B cell response to PPS 4 and 14 in a controlled cytokine environment allowing us to differentiate altered response intrinsic to the B cells versus altered responses secondary to environmental factors such as cytokines. The results of these studies will form the essential baseline for the rational development of vaccine and adjuvant strategies for the elderly.

50 Pneumonia


Project Title: ELR-CXC CHEMOKINES IN LUNG ANTIBACTERIAL HOST DEFENSE Principal Investigator & Institution: Standiford, Theodore J. Professor; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2002; Project Start 01-DEC-1996; Project End 30-NOV-2005 Summary: (provided by applicant): Bacterial pneumonia is the second most common cause of hospital-acquired infection, and is leading cause of death among all nosocomial infections. Innate, or natural immunity, is the principal pathway for effective elimination of bacterial organisms from the lung. While ELR-CXC chemokines have been shown to be expressed during the generation of Th1 cell-mediated immune responses against intracellular microbial pathogens, the contribution of this family of chemokines to innate immunity against common gram-positive and gram-negative bacterial pathogens is unknown. We have focused this competitive renewal on ELRCXC chemokines, as our preliminary observations indicate that the in-vivo depletion of selected ELR-CXC chemokines substantially impairs bacterial clearance and survival of mice with pneumonia due to Klebsiella pneumoniae. It is the hypothesis of this proposal that ELR-CXC chemokines are integral components of the innate neutrophildependent immune response against gram-negative bacterial infection of the lung. A murine model of Klebsiella pneumonia will be employed to achieve the following specific aims: 1) to determine the time course of expression and cellular sources of ELRCXC chemokines and their common receptor (CXCR3) during the evolution of gramnegative bacterial pneumonia; 2) to determine the contribution of ELR-CXC chemokines and their receptor to leukocyte recruitment, proinflammatory cytokine expression, bacterial clearance, survival in Klebsiella pneumonia using specific neutralizing antibodies or knockout mice; 3) to determine the effect of IP-10 or MIG administration/transgenic expression on proinflammatory cytokine expression, bacterial clearance, and survival in murine Klebsiella pneumonia in-vivo and on alveolar macrophage effector cell function in-vitro; and 4) to identify endogenous signals that regulate the expression of ELR-CXC chemokines during the evolution of Klebsiella pneumonia in-vivo and in isolated lung cells in-vitro. Elucidation of specific cellular and molecular mechanisms of lung antibacterial host defense, in conjunction with the use of novel gene therapy approaches will provide important insights into the treatment of patients with serious multi-drug resistant bacterial infections of the lung. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ENTERAL VS IV FEEDING: EFFECT ON MUCOSAL IMMUNITY Principal Investigator & Institution: Kudsk, Kenneth A. Surgery; University of Wisconsin Madison 750 University Ave Madison, WI 53706 Timing: Fiscal Year 2002; Project Start 01-FEB-1998; Project End 31-MAR-2006 Summary: Hospital acquired pneumonia costs up to 2 billion dollars per year in the United States, and any inexpensive therapy which reduces this septic complication could greatly impact health care costs. Enteral feeding significantly reduces the complications of pneumonia compared with intravenous (IV-TPN) feedings by 60-70 percent in trauma patients. Our experimental and clinical work implicates previously unrecognized defects in mucosal immunity which develop when the intestinal tract is not stimulated with enteral feeding or when surrogates of enteral feeding are not

Studies 51

provided. The principal specific immunologic defense at mucosal surfaces is secretory IgA produced by the mucosal-associated lymphoid tissue (MALT). The principal anatomic site for immunologic sensitization of Peyer's patches within the small intestine. Adhesion molecules direct unsensitized immunocytes through the Peyer's patches where these lymphocytes are sensitized and change their own surface integrins. They are then directed to both intestinal and extraintestinal sites, such as the respiratory tract, where they produce IgA against those antigens. The antibody binds to bacteria, preventing their attachment and their ability to infect. This proposal focuses on how route and type of nutrition affects the expression of the specific adhesion molecules, modified MAdCAM-1, unmodified MAdCAM-1, and ICAM-1 which are important in directing unsensitized immunocytes into Peyer's patches. The proposal tests the hypothesis that interaction between these adhesion molecules and their ligands on naive T and B cells are critical in maintaining mucosal immunity in both intestinal and extraintestinal sites. The proposal is designed to test the hypothesis that inhibition of these interactions recreates the defects in in vivo mucosal defenses that are induced when enteral feeding is not provided. It also focuses on previous observations that a specific immunocyte fuel, glutamine, and the enteric nervous system neuropeptide, bombesin, can act as surrogates for enteral feeding and exert beneficial effects upon the MALT in IV-TPN-fed animals by upregulating MAdCAM-1 and ICAM- 1 expression. The experiments are designed to confirm that IgA is a critical element of specific immunity and respiratory defenses against pneumonia with in vivo experiments. These experiments use a monoclonal antibody produced by a hybridoma cell line which is specific for polysaccharide antigen(s) found on a high percentage of clinical isolates of Pseudomonas aeruginosa. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENVIRONMENTAL AND MOLECULAR EPIDEMIOLOGY OF P CARINII Principal Investigator & Institution: Vermund, Sten H. Professor; Medicine; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2001; Project Start 15-AUG-1998; Project End 30-APR-2004 Summary: Despite the recent declines in incidence Pneumocystis carinii pneumonia (PCP) remains the leading cause of mortality among those individuals diagnosed with AIDS. Although antimicrobial compounds are available for treatment and prophylaxis, many individuals fail to respond to treatment, develop infections in spite of prophylaxis, or have serious toxicity from the available medications. Controlling the source of infection could lead to lower PCP incidence. However, due to research limitations from the lack of an in vitro culture system for Pneumocystis carinii (PC), the source of transmission remains unknown. Previously, the prevailing assumption was that reactivation of a latent infection with PC occurs in severely immunosuppressed individuals. However, recent studies indicate that PC has a limited persistence in immunocompetent persons implying that PCP results from de novo acquisition of the organism during periods of immunosuppression. Furthermore, animal studies have demonstrated airborne transmission of PC between immunosuppressed rodents, and clinical studies have suggested airborne patient-to-patient transmission. The Investigator proposes to determine if the horizontal transmission of PC from infected to susceptible humans is possible and if this mode of transmission contributes significantly more than other possible airborne environmental sources to the occurrence of PCP in susceptible persons. In order to accomplish these goals the Investigator plans to use a recently developed molecular assay that detects human PC DNA as well as a typing

52 Pneumonia

system that can track strain types from patient to environment. Further, the Investigator proposes to develop and validate an RT-PCR assay to assess the viability of PC organisms once collected from the environment. Using these molecular tools, the researchers will characterize the occurrence of viable human PC in the home and hospital environment, identify potential sources, and determine the influence of seasonal factors and indoor climate conditions on the presence, persistence, and viability of this organism. The long-term objective of this research is to prevent the transmission of PC in the health care as well as the home setting, thereby reducing the risk of PC infection among immunosuppressed individuals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EPITHELIAL INFLAMMATION

CELL

GENE

EXPRESSION

IN

AIRWAY

Principal Investigator & Institution: Brasier, Allan R. Professor; Internal Medicine; University of Texas Medical Br Galveston 301 University Blvd Galveston, TX 77555 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2003 Summary: (Adapted from applicant's abstract): The human pathogen respiratory syncytial virus (RSV) induces mucosal inflammation by replication in the airway epithelium. In particular, severe lower respiratory tract infection (pneumonia and bronchiolitis) with RSV produces inflammatory mononuclear cell recruitment, airways remodeling and post-infectious airway hyper-reactivity (asthma). We and others have shown that RSV replication is a potent inducer of CC- and CXC-type chemokine synthesis, chemokines that play an important role in the subsequent immune response. Here we will comprehensively pursue our observations that lower respiratory tract cells produce greater amounts of eosinophilic CC chemokines than do upper respiratory tract cells. We hypothesize that the pathogenesis of RSV-induced respiratory tract inflammation is partly due to the consequence of cell type- dependent effects on inducible gene expression where lower respiratory tract cells express a different profile of inflammatory genes. Three aims pursued in this project are: (1) we will apply cDNA microarrays to profile the pattern of inflammatory gene expression in RSV-infected lower airway epithelial cells. From this, we will establish a database of constitutive and RSV-inducible immune response genes. We will identify those genes whose expression is activated directly by virus or indirectly (through paracrine factors); (2) we will compare the patterns of RSV-inducible genes in tracheal and upper airway epithelial cells with that of lower respiratory tract cells to establish whether there are distinct patterns of inducible gene expression; and (3) we will identify genes induced following infection with clinical RSV isolates of the two major groups (A and B) associated with mild or severe disease to determine whether there are strain-dependent effects of RSV on epithelial gene expression. This multidisciplinary approach uses specific expertise in molecular biology, immunology and computational biology to systematically characterize the expression of inflammatory gene networks in RSV-infected epithelial cells. These studies are aimed at advancing our understanding of pathogen-induced mucosal inflammation and identifying gene targets whose activity can be modulated by therapeutic agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FOCUS Principal Investigator & Institution: Carson, Jeffrey L. Richard C. Reynolds Professor of Medicin; Medicine; Univ of Med/Dent Nj-R W Johnson Med Sch Robert Wood Johnson Medical Sch Piscataway, NJ 08854

Studies 53

Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant); Red blood cell transfusions are an extremely common medical intervention in both the United States and worldwide; over 11 million units are transfused in the United States. Between 60% and 70% of all blood is transfused in the surgical setting. Despite the common use of red blood cell transfusions, the threshold for transfusion has not been adequately evaluated and is very controversial. A decade ago the standard of care was to administer a peri-operative transfusion whenever the hemoglobin (Hgb) level fell below 10 g/dl (the "10/30 rule"). Concerns about the safety of blood, especially with respect to HIV and hepatitis, and the absence of data to support a 10 g/dl threshold led to current standard of care today to administer blood transfusions based on the presence of symptoms and not a specific Hgb/hematocrit level. However, there are no randomized clinical trials in surgical patients that have tested the efficacy and safety of withholding blood until the patient develops symptoms or the "10/30" approach to transfusion. Patients with underlying cardiovascular disease are at greatest risk of adverse effects from reduced Hgb levels. We propose to conduct a multi-center randomized trial to test if a more aggressive transfusion strategy that maintains postoperative Hgb levels above 10 g/dl improves patient outcome as compared to a more conservative strategy that withholds blood transfusion until the patient develops symptoms of anemia. Eligible patients for the trial will have undergone surgical repair for a hip fracture and have a postoperative Hgb level below 10 g/dl within three days of surgery. Only patients with cardiovascular disease will be entered into the study. Patients will be randomized to one of the two transfusion strategies. The 10 g/dl threshold strategy will use enough red blood cell units to maintain Hgb levels at or above 10 g/dl through hospital discharge. Symptomatic transfusion strategy patients will receive red blood cell transfusions for symptoms of anemia, although transfusion is also permitted but not required if the Hgb level falls below 8 g/dl. Outcomes will include functional recovery (primary outcome: ability to walk ten feet across a room without human assistance at 60-days postrandomization), long-term survival, nursing home placement, and postoperative complications (death in hospital or within 30 days, pneumonia, myocardial infarction, thromboembolism, stroke, delirium). We will randomize 2,600 patients from 25 centers over a 3.5-year period. This will allow us to detect a 16% relative risk reduction in the loss of ability to walk independently with power about 0.90. A pilot study in 84 patients demonstrated the feasibility of the study. Ambulation at 60 days is known to be highly predictive of ultimate functional outcome as well as of mortality at one year. Because inability to walk again has such important implications for quality office, and because, unfortunately, it is a common problem, it far outweighs the remote chance of viral infection or other complications from transfusion in these elderly patients. Also, this study will measure the frequency and 95% confidence intervals of the medical errors that are important in this patient population and are poorly documented in the literature. The medical errors that will be measured are: transfusion errors (blood transfusion to the wrong patient, mislabeling of samples for type and cross match, use of whole blood instead of packed red cells), failure to use thromboembolism prophylaxis, incorrect antibiotic prophylaxis, wrong site surgery and femoral shaft fracture. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTIONAL SENESCENCE OF INNATE IMMUNITY AND PNEUMONIA Principal Investigator & Institution: High, Kevin P. Internal Medicine; Wake Forest University Health Sciences Winston-Salem, NC 27157

54 Pneumonia

Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-AUG-2004 Summary: #14 Functional Senescence of Innate Immunity and Pneumonia Risk in Older Adults.With advancing age, there is a general waning of immune competence collectively termed immune senescence. Previously, immune senescence was felt to primarily affect only the adaptive immune system (e.g. B and T cell responses, delayed typehypersensitivity), the hallmark of which is recognition of specific antigens with memory responses. However, recent data suggest innate immunity is also profoundly affected. Innate immunity does not depend on prior exposure to a specific antigen, but recognizes general patterns of microbial products (e.g. microbial lipoproteins, DNA, peptide sequences). Two important components of innate immunity are profoundly impaired with advanced age, even in the absence of significant co-morbidity. First, phagocytic function (the ability to engulf bacteria) of polymorphonuclear neutrophils (PMNs) is markedly reduced in older adults. This correlates with lower cell surface expression of CD16, an important receptor through which PMNs recognize the Fc portion of immunoglobulin and phagocytose bacteria. Second, very recent animal studies have shown impaired expression of Toll-like receptors (TLRs) and reduced cytokine production after stimulation of TLRs by specific ligands. Human studies are needed to determine if this is true in older humans. Little is known about the relationship between immune senescence, particularly senescent nnate immunity, and the risk of acquiring infections in older adults. The major goals of this proposal are to provide important pilot data to assist in designing of future studies of immune senescence, and to test our general hypothesis that senescent innate immunity contributes to the risk of infection in older adults. Using standard methods of flow cytometry and ELISA cytokine assays within an ongoing study of community-acquired pneumonia (CAP) in older adults, the specific aims are: 1) Determine whether innate and adaptive immune senescence occur in the same individuals or are independent phenomena; 2) Determine the intra-individual variation of innate immune senescence parameters (PMN phagocytosis and CD16 expression, and TLR expression and function) in older adults with and without CAP; and 3) Determine whether there is an association between CAP and senescent innate immunity. These data are essential to design meaningful studies using the case-control method, the most effective means of studying the link between immune senescence and infection risk. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GASTRIC FEEDING TUBES: PATIENT/FAMILY/PROVIDER VIEWS Principal Investigator & Institution: Carey, Timothy S. Professor of Medicine; Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, NC 27599 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 28-FEB-2003 Summary: We propose a two and a half year prospective study of predominantly older individuals with neurologic diseases, head and neck cancer, and severe medical illness who receive gastric feeding tubes. We wish to define the outcomes of this treatment from a patient and caregiver perspectives. The number of gastrostomy feeding tubes used for the Medicare population has grown rapidly, more than doubling during the past decade. The diseases that cause dysphagia also shorten life expectancy, and cause other deficits in cognitive, physical and social functioning. Nutrition, hydration, and the social context of eating are fundamental elements of comfort care for these patients near the end of life. Feeding is a primary act of care giving and nurture, yet tube feedings have become a form of life- sustaining treatment fraught with ethical implications for patients and caregivers. Previous studies have emphasized medical outcomes of this

Studies 55

procedure. No prior study has examined outcomes of this treatment from the patient and caregiver perspective. Our overall aims are: 1. Describe the expectations of patient, family, health care providers regarding the benefits of gastric feeding tubes on: patient longevity, patient functioning, likelihood of hospitalization for pneumonia. 2. Compare perceived benefits of gastric feeding tubes at the time of placement to perceived benefits such as outcomes of survival, functional status and pneumonia at 3 and 6 month followup, from the perspectives of patient, family and health care providers, including physicians and nurses. 3. Describe the true outcomes of patient survival, pneumonia incidence and functional status among those who survive for 3 and 6 months after insertion of the feeding tube. We will recruit 200 patients receiving gastrostomy from two North Carolina hospitals: a university tertiary care center, and a large community hospital. Interviews will be conducted with physicians, nurses, family caregivers and patients shortly following the procedure with follow-up interviews at 3 and 6 months. The interview will include assessment of functional status, perceived benefit, and expectations regarding longevity and future function. These multiple perspectives on the use of gastrostomy tubes will allow a much more complete portrait of the benefits and limitations of this increasingly utilized supportive therapy at the end of life. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENDER-BASED OUTCOME DIFFERENCES IN NOSOCOMIAL PNEUMONIA Principal Investigator & Institution: Evans, Heather L. Surgery; University of Virginia Charlottesville Box 400195 Charlottesville, VA 22904 Timing: Fiscal Year 2002; Project Start 01-SEP-2002 Summary: (provided by applicant): Controversy exists regarding the effect of gender on differences in surgical infectious disease outcomes. Previously, our laboratory reported that the gender-based difference in mortality was greatest among critically ill patients who developed nosocomial pneumonia. Therefore, the proposed prospective, observational cohort study will concentrate on these hospital-acquired infections, stratifying patients not only by gender, but also by estrogen-status. Based on evidence that women who develop nosocomial pneumonia are at higher risk for death, especially if they are elderly, we hypothesize that estrogen-rich pre-menopausal women will be least likely to develop nosocomial pneumonia, while post-menopausal women will have the highest mortality. Thus, we hope to confirm our earlier findings of the incidence and mortality related to nosocomial pneumonia, and to further evaluate three areas of potential gender differences to account for the disparate outcomes: diagnosis, treatment and immune response. We believe that these areas are not only influenced by sex-based biologic and physiologic features, but also social factors. In the future, these data may lead to methods that facilitate either prevention, or earlier diagnosis and more efficacious treatment of nosocomial pneumonia, a disease which accounts for a substantial proportion of the lethal infections in surgical patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE DISCOVERY FOR PNEUMOCOCCAL OTITIS MEDIA Principal Investigator & Institution: Pettigrew, Melinda M. Epidemiology and Public Health; Yale University 47 College Street, Suite 203 New Haven, CT 065208047 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2006 Summary: (provided by applicant): Otitis media (OM) is the most common bacterial infection in the United States among young children for which medical care is sought,

56 Pneumonia

and Streptococcus pneumoniae strains are the leading cause of bacterial OM. These gram-positive diplococci colonize the respiratory tract in up to 50% of healthy children and only cause disease under special circumstances. Recent genomic sequencing projects and advancements in molecular biology have resulted in the identification of numerous putative virulence factors. These factors have mainly been studied in the context of invasive pneumococcal diseases such as pneumonia, or have been studied in one or a few laboratory strains. While more virulence factors remain to be discovered, the new challenge is to identify which of these many factors warrant further study, to link these factors specifically to OM pathogenesis, and to estimate the relative importance of these virulence factors among the S. pneumoniae strains in circulation. This project is built on the observation that S. pneumoniae strains differ in their ability to cause disease, and that these differences are likely due to genetic differences between strains that extend beyond the polysaccharide capsule. The goal of this project is to identify genes associated with pneumococcal OM and to evaluate the relative frequency of pneumococcal virulence genes among a collection of isolates obtained from healthy children and children with clinical disease. A four step interdisciplinary approach utilizing techniques of molecular biology and epidemiology will include: 1. Selection of S. pneumoniae strains for genomic subtraction with the highest potential to identify genes associated with OM. 2. Identification of DNA sequences (sPCR fragments) unique to strains causing OM (tester strains) and absent in strains from healthy carriers (driver strains) using genomic subtraction. 3. Epidemiologic screening of a large collection of isolates from healthy children and children with OM, meningitis, pneumonia, or bacteremia using sPCR fragments. 4. Identification of genes associated with sPCR fragments important for OM pathogenesis and description of their biological and clinical characteristics. Discovery of additional factors involved in streptococcal OM will facilitate the development of new strategies for the control and prevention of this important disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC ANALYSIS OF GBS ADHERENCE TO FIBRONECTIN Principal Investigator & Institution: Tamura, Glen S.; Children's Hospital and Reg Medical Ctr Box 5371, 4800 Sand Point Way Ne, Ms 6D-1 Seattle, WA 98105 Timing: Fiscal Year 2001; Project Start 15-AUG-1998; Project End 31-JUL-2003 Summary: GBS adherence to epithelial cells may play an important role in pathogenesis of GBS pneumonia. I propose that GBS adherence to epithelial cells is mediated, at least in part, by GBS adherence to fibronectin. I have isolated four transposon mutants with single insertions which show decreased adherence to fibronectin; 3/4 of these show decreased adherence to epithelial cells. One mutant has been tested in a neonatal rat model of pulmonary colonization, and shows a significantly decreased ability to persist in the lungs of neonatal rats at 24 hours. I have cloned the transposon insertion sites from two of these mutants. One mutant contains a mutation in a gene which shows significant homology to ABC transporters, while the other contains a mutation immediately upstream of a gene with homology to multiple surface receptors. Disruption of the ABC transport gene by plasmid insertional mutagenesis demonstrates that this gene is required for maximal fibronectin adherence. I propose to study the role of GBS adherence to fibronectin in the pathogenesis of neonatal pneumonia and sepsis. I propose to clone the transposon insertion sites of the additional two mutants, and to create targeted mutations in genes of interest as well as complement mutants to confirm the role of the transposon insertion in the phenotype. Using this strategy, I propose to clone the structural gene for the fibronectin adhesin. If necessary, I will create additional

Studies 57

fibronectin adherence mutants. The role of these genes will be further studied in the mouse model of neonatal pulmonary colonization. These studies will establish a role for fibronectin adherence in the pathogenesis of GBS disease. The role of these putative adhesin genes will then be tested after hyperexpression of the adhesin gene by blockade of binding of GBS to fibronectin with both the cloned adhesin and antisera to the adhesin. These studies will allow for identification of the structural gene(s) for fibronectin adhesin(s). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC AND INFLAMMATORY MARKERS OF SEPSIS Principal Investigator & Institution: Angus, Derek C. Anestheslgy/Critical Care Med; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: (Verbatim from the Applicant's Abstract): Sepsis, a diffuse inflammatory response to infection, occurs in over 450,000 cases per year in the US and frequently progresses to organ dysfunction and death. Although experimental studies using cells and animals have greatly improved our understanding of the pathophysiology of sepsis, there remains a remarkable paucity of biochemical and genetic data regarding the natural history of this important public health problem. In particular, there is a need for better markers of sepsis and outcome and a more rigorous evaluation of the complex relationships among the many genetic, inflammatory, and clinical factors that appear to influence the development and outcome of sepsis. Because pneumonia is the most common cause of sepsis, patients with this infection represent an excellent clinical model for studying sepsis in a relatively homogeneous population. We propose to study a large cohort of patients (n=2,703) with community-acquired pneumonia (CAP). Our study will be "piggy-backed" onto a multicenter trial of alternative hospital quality improvement initiatives that is already funded and slated to begin enrolling patient's early in 2001. In addition to collecting detailed clinical data, we will carry out careful genetic analyses, focusing on allelic variations in the coding or noncoding regions of genes whose products are important in the expression and/or regulation of the inflammatory response. We will also obtain measurements over time of the plasma concentrations or cell surface expression of several key inflammatory molecules. We will determine the influence of specific polymorphisms on the development, course and outcome of pneumonia and sepsis. We will test whether genetic predisposition to an exuberant inflammatory response protects against infection yet also increases risk for adverse systemic effects and outcome. We will compare genetic data from patients with results obtained from a cohort of healthy controls (n=300). We will test several existing hypotheses regarding the association of circulating inflammatory molecules with outcome. We will use time-varying regression analyses and probabilistic networks to explore in new detail relationships among genetic polymorphisms and the inflammatory response in sepsis. Finally, we will construct and evaluate two sets of clinical decision tools: i.) clinical risk prediction rules that incorporate genetic and inflammatory response variables with existing clinical factors, and; ii.) a state-transition simulation model of the course of sepsis that allows time-dependent estimates of the effects of alternative treatment decisions. This study will generate: new and valuable information regarding existing lines of inquiry and laboratory investigation; new hypotheses arising from the use of time-dependent modeling; and new clinical decision tools that have immediate and practical value for designing clinical trials and improving patient care. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

58 Pneumonia

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Project Title: GENETIC DETERMINANTS OF PATHOGENICITY IN LEGIONELLA Principal Investigator & Institution: Tompkins, Lucy S. Professor; Microbiology and Immunology; Stanford University Stanford, CA 94305 Timing: Fiscal Year 2001; Project Start 01-MAR-1991; Project End 31-JAN-2003 Summary: (Adapted from the applicant's abstract): Legionella pneumophila is a facultative intracellular pathogen that grows inside protozoans in fresh water sources. Susceptible humans may develop a fulminant pneumonia called Legionnaires disease following inhalation of contaminated water aerosols. This opportunistic pathogen contributes significantly to community-acquired and nosocomial pneumonia infection rated and is associated with serious morbidity and mortality. During human infection, and in animal models, virulent L. pneumophila elicits a cellular immune response, including recruitment and activation of macrophages, which serve as the primary cellular target for entry and subsequent growth and the production of specific cytokines. A series of prior studies has demonstrated that the outcome of the interaction with macrophages depends upon the expression of L. pneumophila genes, some of which may be regulated by intracellular environmental signals. Only a few genes that apparently are involved in this interaction have been discovered, and the definitive role of any of these in the pathogenesis of infection and disease in unknown. Studies on a L. pneumophila mutant that lacks the capacity to produce protease strongly suggest that virulence was attenuated in an animal model, and furthermore, that this effect might be directly related to impairment of the host s immune response, including cytokine production. Other studies demonstrated that prior growth of laboratory passaged strains in Acanthamoeba enhanced the invasiveness of L. pneumophila into macrophages. This was associated with the expression of new polypeptides. The specific aims of the proposal are to: 1) further define the contribution of the protease protein to L. pneumophila pathogenesis and host immune response: and 2) detect and define the role of new genes, not yet discovered, that are involved in intracellular growth in eukaryotic cells. Dr. Tompkins propose to study the cell biology of he interaction of macrophages with wild-type strains and mutants to characterize and define the steps in intracellular growth governed by each gene product. She will also use two new genetic selection methods to isolate and identify new genes involved in intracellular growth. Thus, the proposal incorporates novel molecular and genetic methods and utilizes contemporary microscopy techniques, including laser confocal microscopy, to further define and characterize the cell biology of Legionella in eukaryotic cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC RISK FACTORS FOR PNEUMONIA IN SLE PATIENTS Principal Investigator & Institution: Freemer, Michelle M. Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2003; Project Start 15-JUL-2003 Summary: (provided by applicant): Systemic lupus erythematosus (SLE) can be a severely disabling disease and may affect any portion of the respiratory tract. The most frequent lung disease in SLE patients is pneumonia. It constitutes a major source of morbidity as well as mortality in these patients. While many of the clinical factors predisposing SLE patients to infections have been investigated, the genetic risk factors for pneumonia have not been thoroughly examined. The University of California, San Francisco (UCSF) Lupus Genetics Project, represents a well-characterized, ethnically diverse cohort of patients. Furthermore, the availability of genotype analysis for these patients provides an ideal opportunity to determine the impact of genetic

Studies 59

polymorphisms on SLE patients' risk of developing pneumonia. Interestingly, prior investigators have identified genetic risk factors for infections in healthy populations that correspond to some of the polymorphisms associated with the development of SLE Evaluation of the relationship between pneumonia and these polymorphisms in an SLE population will yield insight into whether the genetic risk factors identified in healthy hosts also account for the high infection rate observed in SLE patients. This information has significant clinical implications regarding SLE patients' need for immunization and antibiotic prophylaxis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETICS PNEUMOPHILA

OF

IRON

ACQUISITION

BY

LEGIONELLA

Principal Investigator & Institution: Cianciotto, Nicholas P. Professor; Microbiology and Immunology; Northwestern University Office of Sponsored Programs Chicago, IL 60611 Timing: Fiscal Year 2001; Project Start 01-APR-1995; Project End 31-MAR-2004 Summary: (Adapted from the Applicant's Abstract): Legionella pneumophila, the etiologic agent of Legionnaires' disease, is a significant cause of both communityacquired and nosocomial pneumonia. This gram-negative bacterium is an intracellular parasite of human alveolar macrophages and aquatic protozoa. Although critical for intracellular survival, the mechanisms used by L. pneumophila for iron acquisition have remained largely unknown. However, recent biochemical and genetic studies have uncovered four Legionella strategies for iron uptake. First, a potentially novel siderophore was discovered in the supernatants of virulent strains. The detection of this iron chelator required the universal CAS assay and was strain and culture dependent, explaining the previous negative results. Second, they identified an iron-regulated gene that encodes an analog of aerobactin synthetases and promotes intracellular replication, suggesting the existence of a second L. pneumophila siderophore. Third, the analysis of a mutant that was defective for intracellular infection and virulence revealed a gene (ira216) encoding a di/tripeptide transporter. The reduced ability of this mutant to acquire intracellular iron suggests that L. pneumophila imports iron-loaded peptides during macrophage infection. Finally, another iron acquisition and infectivity mutant appears to lack an ABC- transporter (ira225), which is similar, but not identical, to other bacterial systems that assimilate unchelated iron. This grant renewal will define more precisely the nature of these pathways. Upon demonstration that the siderophores are expressed within infected host cells, a set of mutants will be used to ascertain the role of the iron chelators in intraphagosomal growth. Mass spec and NMR will define the structure of the purified siderophores. CAS and Csaky assays as well as Southern hybridizations will determine whether these iron scavengers are peculiar to the pathogenic Legionella species, as preliminary data suggest. Next ira216 and ira225 mutants will be assessed for reduced abilities to grow in defined media where iron is provided as either iron-loaded peptides or ferric citrate. Conversely, the cloned genes will be examined for the abilities to enhance the iron assimilation of E. coli uptake mutants. To gauge the total number of iron uptake systems that operate intracellularly, double mutants, e.g. Sid-, ira216 negative strain, will be analyzed for iron and infectivity defects. Taken together, the proposed experiments will offer greater insight into Legionella pathogenesis as well as intracellular parasitism and microbial iron acquisition in general. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENOME ANALYSIS OF STREPTOCOCCUS AGALACTIAE Principal Investigator & Institution: Tettelin, Herves' S. Associate Investigator; Institute for Genomic Research Rockville, MD 20850 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 29-SEP-2003 Summary: (provided by applicant): Group B streptococci (GBS) or Streptococcus agalactiae are weakly beta-hemolytic, facultatively anaerobic Gram-positive cocci, which have emerged over the past 50 years as the most significant bacterial cause of neonatal sepsis, pneumonia, and meningitis. GBS account for 30-50 percent of neonatal bacterial infections and increases in adult GBS infections have also been noted. This demonstrates that GBS infections remain an important public health problem. We propose to sequence the 2.1 Mb genome of S. agalactiae serotype Ia strain A909 using a genome-wide random shotgun approach. We will then use the final assembled sequence and its complete annotation to perform detailed comparative genomics analyses between serotype Ia and other organisms causing pneumonia and meningitis. These analyses will allow to identify virulence determinants shared by all organisms or specific to individual ones. These determinants will be related to Drs. Jones and Rubens? experiments on signature tagged mutagenesis and TnphoZ translational fusion (identification of secreted proteins) mutant libraries constructed through transposon insertions in strain A909. Regions where transposons inserted will be aligned to the genome sequence to identify the genes affected. A subset of the mutants conserved across serotypes will be analyzed in the rat sepsis model to evaluate their virulence. This collaborative effort will provide extensive preliminary data for future proposals relevant to understanding the pathogenesis of S. agalactiae infections. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GLOBAL PATHOGENESIS

REGULATORY

INTERACTIONS

IN

BACTERIAL

Principal Investigator & Institution: Akerley, Brian J. Microbiology and Immunology; Microbiology and Immunology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: (provided by applicant): Haemophilus influenzae efficiently and chronically colonizes the human nasopharyngeal mucosa, and is capable of causing invasive disease including otitis media, pneumonia, and, more rarely, meningitis. A number of factors involved in H. influenzae virulence have been identified in the pre-genomic era. Taking advantage of the genome sequence and the advent of new technologies, such as global expression profiling, we intend to advance understanding of critical virulence characteristics of this organism. Lipopolysaccharide (LPS) structural modifications are essential virulence determinants for H. influenzae. Using expression profiling with DNA microarrays, complemented by classical approaches, we have recently uncovered a previously unappreciated link between redox regulation and LPS modifications in H. influenzae. In addition, we have isolated a mariner transposon insertion mutation in H. influenzae that disrupts redox control over one such modification (addition of a phosphorylcholine epitope, termed ChoP, to the LPS) and also results in a pronounced colonization defect in an animal model of H. influenzae infection. These observations are of potential significance for in vivo modulation of the LPS structure by environmental signals. We propose to use such signaling and regulatory mutants generated in our laboratory to examine the role of redox signaling in controlling virulence genes in H. influenzae. Global genomic approaches we have developed for

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studies of H. influenzae will facilitate our analysis of how LPS modifications are modulated in response to environmental conditions. We will also determine whether other genes that play a role in pathogenesis are coregulated, inversely regulated, or constitutively transcribed under the varied redox conditions that affect LPS modification. We believe that these studies will provide important insights into the relationship between physiological adaptations to the host environment and the coordinated production of bacterial cell-surface structures critical for interactions with host cells or for evading the immune response. Specifically, we will: 1. Characterize the redox control mechanisms involved in the regulation of the ChoP cell surface LPS modification. 2. Investigate the role of signaling pathways in H. influenzae in the context of epithelial cell interactions and in a model of respiratory tract infection. 3. Examine coordinate regulation of virulence factors by redox signaling systems. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GUIDELINES INTERVENTION

ADHERENCE

AFTER

CLINICAL

PATHWAY

Principal Investigator & Institution: Dykes, Patricia C. None; Columbia University Health Sciences New York, NY 10032 Timing: Fiscal Year 2002; Project Start 07-FEB-2003 Summary: (provided by applicant): Heart failure is a major public health problem that increases the vulnerability of older Americans. While adherence to practice guidelines is clearly linked with positive patient outcomes, studies to date demonstrate that practitioner adherence with core recommendations of practice guidelines is deficient. Currently a gap exists in the literature regarding strategies to promote interdisciplinary adherence to these guidelines. The overall goal of the proposed research is to study an innovative strategy to promote interdisciplinary guideline adherence and positive patient outcomes in patients diagnosed with heart failure. The aims of this study are to: 1) examine interdisciplinary adherence to core recommendations of the AHA/ACC clinical practice guidelines before and after implementation of an automated clinical pathway model and 2) compare patient outcomes before and after implementation of an automated clinical pathway model, integrated with core AHA/ACC guideline recommendations. Two samples of 150 consecutive patients age 65 or older, admitted to the proposed setting with a primary diagnosis of heart failure will be studied, 150 preand 150 post-implementation of the automated pathway. Similarly, two groups of 150 consecutive patients age 65 or older admitted to the proposed setting with a primary diagnosis of Pneumonia will be used as a nonequivalent comparison group without an automated pathway intervention. Clinician adherence and selected patient outcomes will be compared between treatment and control groups pre and post pathway using analysis of variance models. The study findings will provide the foundation for more extensive research programs whose findings could be generalized to larger patient populations and health care organizations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GUT EPITHELIAL APOPTOSIS IN SHOCK AND SEPSIS Principal Investigator & Institution: Coopersmith, Craig M. Surgery; Washington University Lindell and Skinker Blvd St. Louis, MO 63130 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2006 Summary: Sepsis and noninfectious inflammation lead to organ dysfunction and death in greater than 230,000 people annually in the United States alone. Recent studies

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demonstrate that sepsis and noninfectious inflammation induce excess intestinal epithelial apoptosis in both animal models of critical illness and in human autopsy studies. The central hypothesis of this new laboratory is that increased gut epithelial apoptosis is detrimental in critical illness, and that decreasing levels of cell death will improve experimental survival. Since previous descriptive studies showing elevated intestinal epithelial apoptosis in sepsis and noninfectious inflammation cannot distinguish whether altered gut apoptosis has a functional significance in critical illness, the first aim of this investigation is to demonstrate that inhibiting gut epithelial apoptosis through mechanistically distinct strategies decreases mortality in diverse models of critical illness. Gut epithelial apoptosis will be selectively targeted using transgenic mice that overexpress Bcl-2 in their intestinal epithelium. Gut-directed caspase inhibitors will also be utilized. These apoptosis- inhibition strategies will be complemented with a novel apoptosis-acceleration strategy using the antilymphocyte antibody, anti-CD3 which causes a 40-fold induction of gut epithelial apoptosis. Mechanisms that may underlie the survival advantage conferred by a decrease in gut apoptosis will be investigated as well. Gut permeability studies will be performed using the ex vivo everted gut sac model on transgenic animals that overexpress intestinal Bcl-2 and their control littermates after induction of sepsis or noninfectious inflammation and. Interactions with the immune system will be assessed by the development of mice that simultaneously overexpress Bcl-2 in their intestinal epithelium but are deficient for Tand B- lymphocytes (Rag-1 mice). Throughout these studies, four models of critical illness will be utilized varying the site of injury (intraabdominal vs. lung) and type of infection (polymicrobial vs. monomicrobial). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HARLEM AIDS TREATMENT GROUP-'CPCRA' Principal Investigator & Institution: El-Sadr, Wafaa M. Chief, Division of Infectious Diseases; Medicine; Columbia University Health Sciences New York, NY 10032 Timing: Fiscal Year 2001; Project Start 30-SEP-1989; Project End 31-MAR-2005 Summary: (adapted from application's abstract): The HIV/AIDS epidemic currently affects African Americans, Latinos, women and injection drug users, populations that have traditionally been underrepresented in HIV clinical trials. Alarmingly, while the rate of HIV/AIDS is 10.4 per 100,000 among whites, it is 83.7 and 37.7 per 100,000 among African Americans and Latinos, respectively. The Harlem AIDS Treatment Group (HATG) was established in 1989 with the primary goal of providing access to HIV trials for persons of color, women, and injection drug users. It was recognized, however, that accomplishing this goal would be challenging due to the legacy of mistrust of research and the many social needs of the population. In spite of these challenges, through concerted educational efforts, the building of community support, the recruitment of a talented and committed staff and the provision of the research in the context of state-of-the-art care, HATG has been able to achieve its goals. A total of 957 participants have been enrolled in 27 CPCRA studies with 1,436 separate enrollments including 65.3 percent African American, 15.7 percent Latino, 31.7 percent women and 41.1 percent with a history of injection drug use. Through the, outreach and tracking systems, the provision of support services and the devotion of the participants to their care, HATG has had a 97 percent retention rate. The accomplishments of HATG are firmly embedded in the success of its Community Advisory Board, which has been a vibrant venue for community input and whose functions are solidly linked to unit activities. HATG investigators have made significant contributions to the CPCRA science by providing leadership in the study of tuberculosis, P. carinii pneumonia,

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funga1 infections, and nutrition/metabolic complications. Their efforts have culminated in multiple publications and presentations. HATG expects to follow at a minimum 270 participants in trials at Harlem Hospital Center, the Renaissance Health Care Network, Jacobi Medical Center and the St. Vincent's Comprehensive HIV Center. Overall, HATG sites provide care to more than 4,000 persons living with HIV, predominantly African Americans, Latinos, women and injection drug users. This population spans the spectrum of HIV disease and includes a substantial group with recently recognized HIV infection who are antiretroviral naive. All HATG site investigators have the expertise, experience and commitment to make substantial contributions to the CPCRA science in adherence, metabolic/nutrition, opportunistic infection prophylaxis and hepatitides. They also are committed to the conduct of large long-term studies as a means of answering key questions in HIV management that cannot be answered through shorter trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HIV SURVEILLANCE AFFECTS MACROPHAGE FUNCTION Principal Investigator & Institution: Wewers, Mark D. Professor; Internal Medicine; Ohio State University 1800 Cannon Dr, Rm 1210 Columbus, OH 43210 Timing: Fiscal Year 2001; Project Start 30-SEP-1998; Project End 31-AUG-2003 Summary: Bacterial pneumonia remains one of the most common complications of HIV infections. In spite of our growing understanding of the pathogenesis of the immune deficiency associated with HIV infection, the factors that predispose HIV+ individuals to pneumonia remain obscure. For example, the risk of pneumonia for HIV infected individuals is 6 fold higher than for HIV-individuals. This risk can only partially be explained by lower blood CD4 counts. Our preliminary experiments demonstrate that the lung CD4 counts remain normal in the face of falling peripheral counts when compared to HIV uninfected subjects. However, CD8+ lymphocytes are markedly increased in the lung, a hallmark of HIV infection. These cytotoxic CD8+ lymphocytes (CTLs) are believed to function to suppress viral replication. In this context, the primary defense against bacterial infections in the lung is provided by alveolar macrophages which are also the prime source of HIV in the lung. Since macrophage HIV infection is enhanced by inflammatory events, we have hypothesized that 1) initiation of antibacterial function by lung macrophages induces local HIV replication, and 2) as a consequence of this increase in viral burden, lung CTLs may be signaled to suppress this viral replication. This suppression of virus may in the process suppress macrophage antibacterial function. We therefore, propose to test these hypotheses by studying the macrophage's ability to phagocytose opsonized particles. We will evaluate lung macrophages from HIV infected individuals and normal controls to test whether opsonized phagocytosis induces viral replication in the macrophage. As a corollary we will determine whether CTLs can impair macrophage phagocytosis. These in vitro experiments will be corroborated by studies of lung macrophages taken at the time of bacterial pneumonia. Together these experiments will improve our understanding of how the innate immune defense against bacteria is affected by attempts to suppress HIV in macrophages. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HIV-RELATED ORAL DISEASES AMONG WOMEN IN HARARE Principal Investigator & Institution: Greenspan, John S. Professor; Stomatology; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122

64 Pneumonia

Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2005 Summary: (provided by applicant): As part of the last competing renewal application of the parent program project P01-DE07946 (PI: John Greenspan), we sought to address emerging problems concerning the oral manifestations of HIV/AIDS. To date, our research has focused on HIV-infected populations in the US. However, we are proposing, as part of the present FIRCA application, to expand our study of the role and significance of oral manifestations of HIV infection to a setting that thus far has been understudied: sub-Saharan Africa. Because biologic assays to measure HIV disease progression are rarely accessible in sub-Saharan African countries due to prohibitive cost, other less expensive means of monitoring disease progression are needed. In US populations, visual inspection of the mouth and diagnosis of selected oral mucosal lesions have been found to be good predictors of HIV disease progression. If the predictive role of oral examination can be confirmed in sub-Saharan Africa, this would provide an important new tool for clinicians and public health specialists in this setting with respect to initiation of certain prophylactic drug regimens (such as tuberculosis or pneumocystis pneumonia prophylaxis) or anti-retrovirals. Midion Chidzonga, currently a Fogarty trainee supported by the "AIDS International Training and Research Program" Fogarty grant (2D43 TW00003-11; PI: Art Reingold; UCSF PI for the oral component in Zimbabwe: Caroline Shiboski) is conducting a cross-sectional study among HIV-infected and non-infected women in Zimbabwe to estimate oral mucosal disease prevalence in relation to HIV serostatus in this population. In collaboration with Dr. Chidzonga, we are hereby proposing to conduct a longitudinal study by expanding this ongoing crosssectional study among Zimbabwean women. Our objectives are 1) to estimate oral mucosal disease incidence in relation to known immunologic marker of HIV disease progression (CD4 lymphocyte count); and 2) assess the sensitivity and specificity of detecting oral mucosal lesions by visual inspection of the mouth by trained nurses in a family planning/gynecology clinic in the sub-Saharan African setting. To address these objectives, we will conduct follow-up oral examinations at 6-month intervals on 225 HIV-positive participants who are being recruited into our cross-sectional study from an ongoing parent cohort study. Each participant would be seen at 6-month intervals over a 3-year period as part of the proposed study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HOST AND VIRAL FACTORS IN SIV PNEUMONIA Principal Investigator & Institution: Zink, M C. Professor; Comparative Medicine; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001; Project Start 30-SEP-1997; Project End 31-AUG-2002 Summary: Tropism of HIV for macrophages contributes to primary HIV pneumonia whereas replication in lymphocytes leads to immunosuppression and secondary opportunistic infections. The two main forms of primary HIV-induced pneumonia are lymphocytic interstitial pneumonia (LIP) and diffuse infiltrative lymphocytosis syndrome (DILS), and individuals with these conditions survive longer and have fewer opportunistic infections than those who do not. Like HIV, SIV replicates in both CD4+ lymphocytes and monocytes/macrophages, but is mainly detected in cells of macrophage lineage in the lung. Specific strains of SIV cause lesions in the lungs of juvenile macaques that resemble HIV lymphoid interstitial pneumonia, and macaques with these lesions also survive longer. This application proposes a multidisciplinary approach to identify viral and host factors that contribute to pulmonary disease. The hypothesis to be tested in these studies is that while many viral strains enter the lung in infected blood, only certain macrophage-tropic strains establish themselves in

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pulmonary tissue, possibly related to expression of specific viral co-receptors in the lung. It also hypothesized that the lymphocytic pneumonia is indicative of effective immunologic restraint of macrophage-tropic viral burden and thus improved prognosis. For these studies, macaques will be inoculated with SIV and euthanized during the initial stage of viral replication (3 weeks p.i.), during the stage of clinical quiescence (3 months p.i.), and during terminal clinical diseases. 1) Pulmonary and systemic immune responses, pulmonary lesions, and viral load will be measured in these macaques to determine at what stage of infection lymphocytic interstitial pneumonia appears, whether lymphocytic interstitial pneumonia is indicative of effective pulmonary antiviral immune responses, and whether the effectiveness of pulmonary immune responses predicts outcome of infection. 2) The levels of expression of pro-inflammatory molecules (cell adhesion molecules, chemokine receptors, chemokines, and cytokines) in lung tissue and bronchoalveolar cells will be measured throughout SIV infection and correlated with pulmonary and peripheral viral load with host immune responses. 3) The viral strains and genotypes that replicate productively in lungs of animals infected with SIV will be identified to determine if specific virus strains are associated with the development of LIP. Replication of viruses isolated from the lung of infected macaques in primary cultures of peripheral blood-derived macrophages and alveolar macrophages will be measured. Virus isolates from lung will be characterized for co-receptor usage (chemokine receptors) to determine if differences exist between macrophage-tropic viruses isolated from the peripheral blood and the lung. 4) The cytokines, chemokines, and chemokine receptors that are expressed in alveolar macrophages and peripheral blood-derived macrophages infected with different strains of virus will be identified. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HOST CELL DETERMINANTS IN PSEUDOMONAS PNEUMONIA Principal Investigator & Institution: Mostov, Keith E. Professor; Anatomy; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001; Project Start 30-SEP-1995; Project End 31-MAR-2004 Summary: (Adapted from the Applicant's Abstract): In immunocompromised and other severely ill patients, Pseudomonas aeruginosa (PA) causes an acute pneumonitis, which has an extremely high fatality rate. Improved methods for prevention and therapy are urgently needed. An in vitro model of PA infection using polarized Madin-Darby canine kidney (MDCK) cells or cultured lung epithelial cells mimics many important features of in vivo pneumonia. Live Pseudomonas organisms added to the apical surface of these cultures attach to and kill the cells. These foci of infection spread centripetally. The current proposal will study the host cell factors that determine susceptibility to Pseudomonas pneumonia using these in vitro model systems. There are four aims in this study: to investigate how modification of cell polarity affects virulence; to identify the receptors for PA and how their regulation affects bacterial interaction; to determine the pathway for internalization of PA organisms; and to examine the role of the actin cytoskeleton in interaction of PA with cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HOST RESPONSE TO POST-OPERATIVE PNEUMONIA Principal Investigator & Institution: Knight, Paul R. Professor and Vice Chairman; Anesthesiology; State University of New York at Buffalo 402 Crofts Hall Buffalo, NY 14260 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 31-MAY-2006

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Summary: (Verbatim from the Applicant's Abstract): Anesthesia/surgery predisposes the patient to develop nosocomial pneumonia by mechanisms that are not completely defined. The presence of a viral respiratory tract infection (RTI) during anesthesia/surgery further complicates the host antibacterial response. Evidence from our laboratory has demonstrated anesthesia/surgery induces changes in cytokine response (e.g., TNFalpha, MIP-2, IFNgamma), leukocyte recruitment, and lung injury to influenza RTI. These responses are also critical to innate host defenses against bacterial pathogens. Our focus is to examine cellular mechanisms during a viral RTI that predispose the host to a post-surgical bacterial pneumonia. We hypothesize that anesthesia/surgery will change host responses differently during distinct periods in the course of a viral RTI by altering expression of pro- and antiinflammatory cytokines, thereby decreasing antibacterial defenses. Aim #1 will assess the effects of anesthesia/surgery during influenza on bacterial clearance, inflammatory cell influx, and cytokine expression an Escherichia coli challenge. We predict that laparotomy during influenza will promote the relative expression of MCP-1 and IL-10 over TNFalpha, MIP-2, and IFNgamma. Aim #2: will assess ex vivo the combined effect of laparotomy and influenza on a) LPS stimulated aMphi cytokine expression and phagocytic activity, and b) the ability of in vitro antiMCP-1, antiIL-10, or IFNgamma administration to improve M dysfunction. We postulate that laparotomy during influenza will alter aMphi regulatory functions and decrease effector functions as a result of selective enhancement of expression anti-compared to proinflammatory cytokines. Finally, in Aim #3, we will examine the contribution of endogenous cytokines in the suppression of antibacterial defenses following laparotomy during influenza by selective cytokine manipulations. Bacterial clearance, inflammatory cell influx, and cytokine levels will be assessed. We anticipate that neutralization of IL-10 or MCP-1, administration of IFNgamma, or increased TNFalphaexpression will improve antibacterial host defenses following laparotomy during physical signs of influenza. These studies will examine mechanisms that lead to alterations in bacterial clearance post-surgically following a viral RTI, assess the pathogenesis of post-surgical pneumonia in general, and suggest immune adjuvant strategies to prevent this complication. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HOST VIRUS INTERACTION AND GENE EXPRESSION Principal Investigator & Institution: Banerjee, Amiya K. Chairman; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, OH 44195 Timing: Fiscal Year 2002; Project Start 01-FEB-1992; Project End 31-MAY-2007 Summary: (provided by applicant): The long term goal of this renewal grant application is to understand the molecular mechanism of host-virus interactions and gene expression of human parainfluenza virus, type 3 (HPIV3), an important human pathogen which targets lung epithelial cells of the respiratory tract of infants and children leading to acute bronchiolitis, pneumonia and croup. Effective vaccines or antivirals to combat HPIV3 infection are currently unavailable. Our primary goal is to gain insight into some specific host-virus interactive processes which include, (b) identification and characterization of the cell surface receptors of epithelial cells (a) the role of actin binding protein, beta catenin in the transcription ability of HPIV3 ribonucleoprotein (RNP) complex and (c) regulation of expression of major histocompatibility complex II induced by HPIV3 which may play an important role in cellular immunity leading to infection-related damage to lung epithelium. We also propose to continue our studies in understanding the structure and function of the RNA

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polymerase, L and P proteins, of HPIV3, especially with regard to the role of phosphorylation of P protein and identification and characterization of the functional domains of L and P proteins. Finally, we wish to exploit reverse genetics using the infectious cDNA of HPIV3 constructed in our laboratory to study phenotypic characteristics of some distinctive cis-regulatory mutants. The studies proposed in this application have the potential to gain deeper insight to various host-virus interactive pathways, which may eventually lead to rational designing of antivirals, vaccines, and expression vectors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HOW CD2 AND CD28 DETERMINE SUSCEPTIBILITY TO P. CARINII Principal Investigator & Institution: Green, Jonathan M. Assistant Professor; Internal Medicine; Washington University Lindell and Skinker Blvd St. Louis, MO 63130 Timing: Fiscal Year 2002; Project Start 15-MAY-2002; Project End 30-APR-2004 Summary: (Provided by the applicant): Loss of CD4+ T cell number or function may render individuals susceptible to opportunistic infection such as P. carinii pneumonia (PCP). This is exemplified by Human Immunodeficiency Virus infection, but also complicates other diseases in which normal immune cell function is perturbed. Although both observational and experimental data indicate that the CD4+ T cell is a critical determinant of the outcome of infection with Pneumocystis, the precise manner in which this effect is exerted is less clear. In addition to direct effector function, CD4+ T cells influence the function of other cells such as B cells, macrophages and cytolytic T cells through both soluble mediators as well as via direct intercellular interactions. Derangement in any of these elements of the immune response may lead to increased susceptibility to opportunistic infection. T cell activation is determined not only by engagement of the T cell antigen receptor, but also by theengagement of other receptors, termed costimulatory receptors. CD2 and CD28 are two well-described costimulatory molecules. Mice deficient in CD2 have little discernible phenotype on examination of T cell function. T cells from CD28-deficient mice have reduced proliferative responses and cytokine secretion. as well as impaired survival, but previously have not been noted to be susceptible to opportunistic infection. We have generated mice deficient in both CD2 and CD28. These mice have a profound defect in T cell activation despite normal lymphocyte numbers and distribution. Furthermore, the CD2/CD28 double deficient mice spontaneously develop and succumb to infection with P. carinii. Mice deficient only in CD28 do not develop P. carinii following co-housing with infected animals, yet are susceptible if inoculated intratracheally. The defined genetic defect that results in defective T cell function despite normal T cell number provides us with a novel opportunity to examine the role of T cells response to P. carinii. Furthermore, the differential susceptibility of CD28-deficient mice to naturally acquired infection vs direct inoculation allows us to examine how route of infection influences the host response. To address this, we propose the following two specific aims: 1 ) Characterize the response of costimulation deficient mice to infection with Pneumocystis carinii. The experiments proposed in this aim will provide quantitative data defining the susceptibility of the costimulation deficient mice and the characteristics of the immune response mounted against them. 2) Determine if reconstitution of specific cellular elements enable clearance of P. carinii infection in costimulation deficient mice. In this aim we will restore specific aspects of the host response by adoptive transfer into the costimulation deficient mice to dissect what required elements of the host response are lacking in the costimulation deficient mice. Although the observation of severe P. carirzii pneumonia in the double knockout mice was unexpected, these mice provide us with a powerful tool to examine

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the role of costimulatory molecules in defense against this important opportunistic pathogen. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IDENTIFICATION OF S. PNEUMONIAE VIRULENCE FACTORS Principal Investigator & Institution: Joyce, Elizabeth A. Microbiology and Immunology; Stanford University Stanford, CA 94305 Timing: Fiscal Year 2002; Project Start 01-SEP-2002 Summary: (provided by applicant): Streptococcus pneumoniae, is the primary cause of invasive bacterial disease in children and the elderly. This organism infects the lung with devastating consequences. Worldwide, over 5 million children under the age of 5 die of S. pneumoniae-acquired pneumonia each year. S. pneumoniae is also responsible for more than 12 million cases of middle ear and sinus infections annually. Given its impact on public health, surprisingly few virulence determinants have been described, and little is known about how these factors are regulated in pneumococci. There is a growing body of evidence suggesting that the regulation of a number of virulence factors depends on the cell density of the pneumococci (Quorum Sensing; QS). Using microarray analysis, I will investigate, on a genome-wide scale, the role of QS regulation in S. pneumoniae pathogenicity under conditions of in vitro broth culture, in vitro cell culture, and ultimately in two pneumococcal animal models of infection. I hope the results of this approach will contribute to a much more comprehensive molecular description of S. pneumonia/host relationship and the diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IL-17 AND KLEBSIELLA PNEUMONIA Principal Investigator & Institution: Shellito, Judd E. Professor; Medicine; Louisiana State Univ Hsc New Orleans New Orleans, LA 70112 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2007 Summary: The long-term objective of this project is to understand interactions between cellular and soluble factors in host defense against bacterial pneumonia. Preliminary data from our laboratory indicate that deposition of bacteria (Klebsiella pneumoniae) into the lungs of mice stimulates the release of one such soluble factor- the lymphocytederived cytokine, Interleukin-17 (IL-17). Additional experiments in IL- 17 receptor "knock-out" mice show increased mortality and impaired neutrophil recruitment after K. Pneumoniae challenge. In this project, we will test the experimental hypothesis that IL17 released from lung T-lymphocytes amplifies the host response to bacterial infection through stimulated release of C-X-C chemokines for neutrophils and enhanced release of other proinflammatory cytokines. In Specific Aim 1, we will localize IL-17 to CD4+ and CD8+ T- lymphocytes in the interstitium or alveolar space at serial intervals after bacterial challenge using flow cytometry and laser capture microdissection. In Specific Aim 2, we will show that IL-17 enhances host release of CXC chemokines and recruitment of neutrophils in response to K. Pneumoniae. We will utilize IL-17 receptor knock-out mice and mice administered a neutralizing IL-17 receptor/FC fusion construct by gene transfer. In Specific Aim 3, we will investigate the interactions between IL-17 and other pro-inflammatory and anti-inflammatory cytokines released into lung tissue in response to K. Pneumoniae. These experiments will focus on TNFalpha, IL-12, IFN-gamma, and IL-10. In Specific Aim 4, we will upregulate IL-17 in lung tissue with gene transfer of the murine IL-17 gene using an adenoviral vector and demonstrate increased bacterial clearance and enhanced recruitment of neutrophils. The

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results of these experiments will provide new information on how IL-17 participates in host defense against bacterial pneumonia and may lead to novel approaches to augment immune function in the immunocompromised host. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNE RESPONSES DURING MEASLES VIRUS INFECTION Principal Investigator & Institution: Griffin, Diane E. Professor & Chair; Molecular Microbiol and Immun; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2003; Project Start 01-DEC-1985; Project End 31-DEC-2007 Summary: (provided by applicant): Measles remains a major cause of morbidity and mortality worldwide due to problems with delivery, acceptance and timing of measles immunization. An additional contributor to the continued failure of measles control may be the epidemic of human immunodeficiency virus (HIV) in developing countries, particularly sub-Saharan Africa, where many of the measles deaths occur. The primary complications of measles are pneumonia, otitis media, diarrhea and post-infectious encephalomyelitis and the effect of measles virus (MV) on the immune system is important in the development of these complications. Delayed type hypersensitivity skin test responses, natural killer cell activity and mitogen-induced proliferative responses are depressed and plasma IgE is increased for weeks after infection. At the same time, the immune response is effective in clearing virus from tissue and in establishing lifelong immunity to reinfection. Our studies of measles in the US and Peru have determined: (i) that monocytes, epithelial cells and endothelial cells are the primary sites of MV replication in vivo; (ii) that there is immune system activation during the period of "immune suppression"; and (iii) that type 2 cytokines are the predominant T cell cytokines expressed late in the response to MV. In vitro studies have shown that MV interaction with CD46 suppresses production of IL-12 by macrophages and that MV infection of B cells synergizes with IL-4 to induce IgE class switching. Recent studies in Zambian children have shown that concurrent HIV infection slows clearance of MV, that many children have baseline skewing of cytokine responses toward production of IL-5, and that measles transiently, but profoundly, suppresses HIV replication. To define the role of host immune responses during measles and the effect of concurrent HIV infection on these responses, we propose the fol]owing specific aims: 1. To determine the effects of MV infection on antigen presenting cells in vivo and in vitro and the consequences of these effects for the immune response. 2. To determine the role of CD8 T cells in MV clearance and the effect of concurrent HIV infection on this role. 3. To determine the roles of different CD4 and CD8 T cell populations in production of cytokines at various times during measles and the effect of concurrent HIV infection on these roles. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMMUNOLOGY OF BACTERIAL PNEUMONIA IN HTLV-II INFECTION Principal Investigator & Institution: Jarvis, Gary A.; Northern California Institute Res & Educ San Francisco, CA 941211545 Timing: Fiscal Year 2001; Project Start 01-MAR-2000; Project End 28-FEB-2003 Summary: (Adapted from the Applicant's Abstract): This projects seeks to understand the immunologic basis for the epidemiological outcome observation of an increased incidence of bacterial pneumonia in HTLV-II-infected blood donors. In a study of

70 Pneumonia

persons with both HTLV-II seropositivity and intravenous drug use, an increased risk for bacterial pneumonia compared to patients with neither risk was found. A similar finding of increased risk for bacterial pneumonia in HTLV-II-infected individuals was observed in a clinical outcome analysis of blood donors who participated in a Retroviral Epidemiological Donors Study. Since the cell tropism of HTLV-II infection includes CD4+ and CD8+ T cells, B cells and monocytes, the investigators will determine whether HTLV-II infection predisposes to bacterial pneumonia by creating immune dysfunction in these cells which are known to be critical for natural protection against pneumococcal pneumonia, the most common cause of bacterial pneumonia in individuals with immune dysfunction. Studies planned for the next five years address the immune status of HTLV-II-infected persons. HTLV-II-infected and -uninfected individuals will be vaccinated with the pneumococcal 23-valent polysaccharide vaccine, and their qualitative and quantitative antibody responses will be investigated by determining the isotype and IgG subclass distribution, concentration, avidity and opsonic function of specific pneumococcal capsular antibodies. The same individuals will also be vaccinated with tetanus toxoid protein antigen as a control for antibody response to a separate class of antigen, and their antibody responses measured. The effect of HTLV-II infection of T cells on the proliferative and antibody-secreting functions of B lymphocytes will be tested. CD4+ and CD8+ T cells will be isolated from HTLV-II-infected persons using immunobeads, co-cultivated with normal B lymphocytes, and the functional activity of the B cells assessed using mitogen stimulation and ELISA antibody quantitation assays. Levels of B cell regulatory cytokines produced by infected and uninfected T cells will be measured by ELISA. Levels of immune response markers IL2 receptor on CD8+ T cells, and CD21 and CD35 on B cells will be determined by flow cytometry. The phagocytic and bactericidal function of PMN and of human macrophages derived from the monocytes from HTLV-II-infected individuals will be tested and compared to the function of those cells from uninfected persons. Human CD4+ and CD8+ T cells will be isolated using immunobeads and quantities of macrophage and PMN regulatory cytokines produced by HTLV-II-infected and -uninfected T Cells will be measured by ELISA. The effect of HTLV-II infection of human T cells on cytokine-dependent activation of macrophages and PMN will be studied using functional assays of pneumococcal phagocytic killing. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNOREACTIVE MACROMOLECULES OF COCCIDIOIDES CELL TYPES Principal Investigator & Institution: Cole, Garry T. Professor and Chairman; Microbiology and Immunology; Medical College of Ohio at Toledo Research & Grants Admin. Toledo, OH 436145804 Timing: Fiscal Year 2002; Project Start 01-SEP-1986; Project End 31-MAR-2007 Summary: (provided by applicant): Coccidioidomycosis is a fungal respiratory disease which is endemic to desert regions of the Southwestern U.S. The most common clinical presentation is self-limited pneumonia, although the fungus is also capable of establishing systemic infections in immunocompetent individuals. The pivotal arm of host defense against coccidioidal infection is T cell mediated immunity. The T helper 1 (Th1) subset of T cells secretes cytokines that activate macrophages which contribute to protection, while Th2 cells secrete cytokines that stimulate B cells to produce antibodies which seem to provide little protection against the mycosis. A correlation exists between resistance/susceptibility to Coccidioides immitis infection and the profile of cytokine response elicited in mice. It has been shown that administration of interleukin (IL-12) to

Studies 71

susceptible BALB/c mice either before or after intraperitoneal challenge promoted the production of interferon (IFN-gamma) and significantly reduced the fungal burden in these animals compared to controls. Evidence has also been presented that upregulation of IL-10 expression, which inhibits stimulation of the Th1 pathway of immune response, can exacerbate susceptibility to coccidioidal infection in certain strains of inbred mice. Our central hypothesis is that the virulence phenotype of C. immitis is the result of in vivo expression of multiple genes, the products of which contribute to colonization of host tissue, modulation of host immune response to the advantage of the pathogen, and maintenance of a persistent inflammatory response which can result in host tissue damage. The major goal of the proposed project is to develop a fundamental understanding of the influence of selected antigens of C. immitis upon the stimulation of innate immune cells and production of specific cytokines and chemokines that activate either a Th1 or Th2 immune response. The specific aims of the project are focused on studies of four C. immitis gene products, three of which appear to contribute to the initiation and metastasis of the infection, and one which stimulates host protection against coccidioidal infection. We have outlined a multifaceted approach to the evaluation of the impact of these four gene products on the course of disease development. We suggest that the results of these studies will significantly advance our understanding of the pathogenesis of C. immitis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNOSENESCENCE AND CHLAMYDIA PNEUMONIAE Principal Investigator & Institution: Fresa, Kerin L. Pathology, Microbio/Immunology; Philadelphia College of Osteopathic Med 4170 City Ave Philadelphia, PA 19131 Timing: Fiscal Year 2001; Project Start 01-MAY-2001; Project End 30-APR-2004 Summary: (the Applicant's Abstract): With increasing age, there is increased incidence and severity of infectious diseases, including pneumonia, meningitis and sepsis, as well as many non-infectious diseases including cancers, heart disease, Alzheimer' s disease and other dementias. The obligate intracellular bacterial parasite Chlamydia pneumoniae is an established pathogen for respiratory infection. Recent evidence from a number of laboratories suggests that C. pneumoniae may be a factor in the pathogenesis of a number of non-respiratory diseases including Alzheimer's disease and atherosclerosis. It has been repeatedly hypothesized that increased incidence of infectious and other diseases with age may be the result of age alterations in the immune system, particularly in cell mediated immune reactions. It is well established that T cell function, as measured in vivo by delayed type hypersensitivity reactions and in vitro as proliferative responses to antigenic or mitogenic stimulation, both decline with age. While infection with C. pneumoniae as well as other Chlamydial species induces production of antibodies, recent evidence suggests that cell mediated immune mechanisms play a key role in recovery from infection as well as immunopathology associated with Chlamydial infection. It has not been established whether old animals are able to clear infection by C. pneumoniae or remain chronically infected. It also remains unknown whether the immune response, particularly the cell-mediated immune response, to acute chlamydial infection is altered with age. Finally, the extent to which the cell-mediated immune response to Chlamydia, or lack thereof, contributes to the pathogenesis of diseases such as atherosclerosis or Alzheimer's disease is entirely speculative. We propose here to begin to address these issues in a mouse model. The working hypothesis is that the cellular immune response against C. pneumoniae declines with age. The Specific Aims of this project are: 1) To assess whether aging is associated with alterations in the clinical course of experimental intranasal infection of

72 Pneumonia

mice by C. pneumoniae; and 2) To assess whether there are age-associated changes in the immune response to C. pneumoniae. Specifically, we will examine proliferative responses, generation of cytotoxic T cells, and production of Th1 associated cytokines (IL-2 and IFN-g). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMPROVING ANTIBIOTIC USE IN ACUTE CARE SETTINGS Principal Investigator & Institution: Gonzales, Ralph; Assistant Professor; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2003; Project Start 07-AUG-2003; Project End 31-JUL-2007 Summary: (Provided by the Applicant) The emergence and rapid rise in antibiotic resistance among common bacteria are adversely affecting the clinical course and health care costs of community-acquired infections. Because antibiotic resistance patterns are strongly correlated with antibiotic use patterns, reductions in unnecessary antibiotic use are critical components of efforts to combat antibiotic resistance. Among humans, the vast majority of unnecessary antibiotic prescriptions are used to treat acute respiratory tract infections (ARIs) that have a viral etiology. Although the rate of antibiotic prescribing for ARIs by office-based physicians in the U.S. has decreased about 16% from its peak in 1997, the rate of antibiotic prescribing in acute care settings (e.g., emergency departments and urgent care centers), which account for 1 in 5 ambulatory antibiotic prescriptions in the U.S., has shown only a modest decline (6%) during this period. Translation of lessons from intervention studies in office-based practices is needed to improve antibiotic use in acute care settings. We propose to conduct a randomized controlled trial of a quality improvement program consisting of physician education (educational seminar, practice guidelines, performance feedback, and decision support tools) and patient education (waiting room print and audiovisual materials) in 8 VA hospital urgent care clinics and 8 non-VA hospital emergency departments. Non VA study sites will be identified from an existing research network of hospital emergency departments--EMNet. VA urgent care clinic sites will be selected among academically affiliated hub facilities. Preliminary studies suggest that a rapid, bedside c-reactive protein test on a fingerstick blood specimen can help classify adults at very low risk, and at high risk, for community-acquired pneumonia. In a second phase of the study, we propose to evaluate the incremental impact of a c-reactive proteinbased diagnostic algorithm to improve antibiotic prescribing behavior. Specific Aim 1: To evaluate the impact of a multidimensional (patient, system, clinician) intervention on appropriate antibiotic use for adults with acute respiratory tract infections-- identifying factors that influence successful translation across VA and non-VA hospital acute care settings. Specific Aim 2: To evaluate the impact of a rapid diagnostic test for c-reactive protein on antibiotic use for adults with acute cough illness when added to a multidimensional intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INFECTION AND CARDIOVASCULAR DISEASE Principal Investigator & Institution: Davidson, Michael; Medstar Research Institute Hyattsville, MD 20783 Timing: Fiscal Year 2001; Project Start 01-APR-1999; Project End 30-JUN-2003 Summary: Recent studies have associated evidence of Chlamydia pneumoniae infection with coronary and carotid atherosclerosis and evidence of increased infection with cytomegalovirus (CMV) in patients developing restenosis or with atherosclerosis.

Studies 73

Several other common pathogens have been less consistently associated with atherosclerosis. Altered parameters of inflammation and hemostasis have been identified as prognostic factors of myocardial infarction and have been linked as possible pathogenetic mechanisms. Recent studies have indicated that peripheral blood mononuclear cells (PBMC) from patients with coronary artery disease frequently called Chlamydia pneumoniae DNA and stimulation of PBMCs can reflect an unsuccessful host cellular immune response to CMV associated with elevated C-reactive protein (CRP). This proposed study is both a nested case-cohort study and a nested cohort analysis within the Strong Heart Study (SHS), an ongoing cohort study of 4,549 American Indians. This study will utilize previously collected specimens, baseline data, and the planned ultrasound measurement of carotid wall thickness (IMT) in SHS participants. Within the initial SHS cohort, 400 definite cases of incident myocardial infarction, coronary heart disease, and stroke will be compare with 400 control individuals with no such diagnoses and matched for age, gender, and residence. Their prior serum specimens will be analyzes for Chlamydia pneumoniae-specific IgG, IgM antibody, for cytomegalovirus-specific IgG antibody, and for CRP. In addition, assays will be performed for antibodies to Helicobacter pylori, hepatitis A virus, (HAV) and herpes simplex virus (HSV) type 1 and 2. Correlations will be made with baseline parameters of lipids, coagulation, and adjusted for potential confounding variables of tobacco use, pneumonia, and altered pulmonary function. An additional analysis of a subcohort, the above 400 controls, will be performed looking at the outcome of their carotid IMT, a parameter of subclinical atherosclerosis, in relation to serologic results indicating a prior exposure to CMV, Chlamydia pneumoniae, and/or other pathogens approximately 8 years preceding ultrasound testing. Both case-control and cohort analysis will be stratified by levels of hemostasis and inflammation, including CRP, fibrinogen, Lp(a), and plasminogen- activator inhibitor-1. A separate nested substudy performed on PBMCs, prospectively collected from 80 cases and 80 controls, will examine the host T-cell proliferative response to CMV and other pathogens in relation to disease and also search for a chronic persistent infection with Chlamydia pneumoniae evidence by DNA detection. Thus, this study will assemble a prognostic profile of infectious, inflammatory, and hemostatic factors and provide a foundation for possible future primary prevention trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INHALED PARTICLES AND HOST DEFENSE IN THE PRIMED LUNG Principal Investigator & Institution: Kobzik, Lester; Associate Professor; Environmental Health; Harvard University (Sch of Public Hlth) Public Health Campus Boston, MA 02460 Timing: Fiscal Year 2003; Project Start 07-JUL-2003; Project End 31-MAY-2008 Summary: (provided by applicant): The Problem: Hospital admissions for pneumonia are increased by elevated air particle levels. The mechanism(s) underlying particle effects on lung infection are unknown, but may reflect increased incidence of infection, increased severity of infection, or both. Hypothesis: The pathogenesis of the pneumococcal pneumonia (the most common variety and the disease we will study) suggests three possible mechanisms for particle effects: enhancement of lung cell 'receptors' used by bacteria for initial adhesion, damage to antimicrobial function of host cells (AMs and PMNs), and exaggerated inflammation in established infection leading to worse signs and symptoms. Hence, the central thesis of this research is that oxidant components of air particles mediate 1) dysfunction of host defenses against infection

74 Pneumonia

(incidence) and 2) increased inflammation in extant pneumonia (severity). Experimental Plan: Aim 1 will measure expression and function of pneumococcal 'receptors' (e.g., PAF receptor) used by pneumococcal for initial adhesion after exposure to concentrated ambient particles (CAPs) or control particles. Aim 2 will determine effects of air particles on pulmonary inflammation before and after onset of pneumococcal pneumonia. The hypothesis to be tested is that particles cause enhanced release of cytokine mediators by primed AMs, leading to increased inflammation and ultimately oxidant damage to both AM and PMN In vivo and in vitro studies will measure release of pro-inflammatory cytokines, cell influx and viability and severity of pneumonic inflammation. Aim 3 will test the hypothesis that particle exposure inhibits bacterial clearance via oxidantdependent damage of anti-microbial functions of AMs and PMNs. Component analysis will be performed using a panel of CAPs samples to provide links of particle constituents (e.g., metals, organics, endotoxin) with biologic effects. Rotated factor analysis will be used to correlate source types with CAPs toxicity. Specific intracellular oxidant pathways will be identified by measurement of oxidant production, intracellular levels of antioxidants, and the effect of a panel of anti-oxidants and other inhibitors. Significance: This research is relevant to the public health question of how inhaled particles cause pulmonary health effects and to the pathophysiology of lung host defense against environmental agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INNATE MECHANISMS OF MYCOPLASMAL KILLING BY ALVEOLAR MAC Principal Investigator & Institution: Hickman-Davis, Judy M. Anesthesiology; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2001; Project Start 01-JUL-1999; Project End 30-JUN-2004 Summary: I graduated from Emory University in 1987 and then spent 2 years as a research assistant in the Department of Pediatric Biochemistry at Emory Hospital. My research experience at Emory prompted me to study animal medicine and I received the D.V.M., cum laude from the University of GA in 1993. At UAB I have received excellent training in laboratory animal medicine, and molecular and Cellular Pathology (Ph.D. December 1998; mentor, Dr. Lindsey). My dissertation research has produced a number of important advances in understanding pulmonary antimycoplasmal defenses applicable to human disease. This SERCA provides the ideal setting for my desired maturation into an independent comparative medicine scientist. Mycoplasma pneumoniae is a leading cause of pneumonia and extrapulmonary disease in humans. C57BL mice are highly resistant and C3H mice are highly susceptible to Mycoplasma pulmonis and are excellent models of the human disease. I have shown that the alveolar macrophage (AM) is the key cell in resistance of C57BL mice, and surfactant protein A (SP-A) mediates the killing of mycoplasmas by C57BL AMs in vitro through the production of reactive oxygen-nitrogen species. Furthermore, my results suggest for the first time that AM nitric oxide derived species, but not reactive oxygen species, are essential for killing mycoplasmas in vivo and in vitro. My aims for the 01-03 years are: (1) Determine the molecular mechanism(s) responsible for SP-A mediate mycoplasmal killing by C57BL AMs in vivo and in vitro, and (2) Identify the mechanism responsible for the defect in SP-A mediated killing by susceptible C3H AMs in vivo and in vitro. My tentative plan for the 04-05 years is to investigate the mechanism by which reactive species damage and effect killing of mycoplasmas, and the pathophysiologic sequelae of mycoplasmal injury to alveolar epithelium in vivo. My career will emphasize the development of models and the investigation of immunologic mechanisms for

Studies 75

resistance/susceptibility to bacterial pneumonias, utilizing transgenic and other methodologies. Thus, I plan to perform experiments in vivo, to show the relevance of my findings in human disease, and in vitro to identify the basic mechanisms. This SERCA with Dr. Matalon (lung physiology, biochemistry) as advisor and Drs. Lindsey (mycoplasmal diseases, lung defenses) and Wood (molecular genetics, transgenics) as co-advisors provides a unique and extremely stimulating environment, ideal for my desired maturation into an independent scientist focused on the development of models for pneumonic processes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTERFERON-ALPHA/BETA PATHOGENESIS

IN

RESPIRATORY

VIRUS

Principal Investigator & Institution: Durbin, Joan E. Associate Professor; Children's Research Institute 700 Children's Dr Columbus, OH 43205 Timing: Fiscal Year 2001; Project Start 01-MAR-2001; Project End 28-FEB-2005 Summary: Respiratory syncytial virus (RSV) is a major cause of lower respiratory infections in infants and the elderly. Bronchiolitis and pneumonia caused by RSV are the primary reasons for the hospitalization of infants under 6 months of age. The initial infection often occurs in the presence of maternal antibodies and reinfections occur throughout life. To date, efforts to develop a safe and effective vaccine have failed. Progress in RSV vaccine development has been hampered by the legacy of enhanced, even fatal, illness in vaccinated children during trials of a formalin- inactivated, alumprecipitated whole virus vaccine in the mid 1960s. The lack of a clear understanding of vaccine-augmented RSV disease still stands in the way of clinical trials of new vaccines in RSV naive infants. Our laboratory has demonstrated enhanced RSV and influenza disease in strains of knockout mice that are unable to respond to IFN-alpha/beta (IFNalpha/beta Receptor-/-) or IFN-alpha/beta and IFN-gamma (Stat1-/- ). The pathology of primary virus infection in these mutant animals resembles that seen following RSV challenge of mice previously immunized with the formalin-inactivated whole virus vaccine (FI-RSV) with exacerbated, eosinophilic inflammation and a Th-2-like cytokine pattern. In this proposal we will test our hypothesis: that poor IFN- alpha/beta induction by RSV may help to explain the induction of Th-2 biased immunity by the FIRSV vaccine preparation. The specific aims of this proposal are: 1) Characterization of exacerbated disease in response to RSV infection in Stat1-/- mice. 2) Analysis of T cell lines derived from RSV immune WT and mutant animals. 3) Alteration of RSV pathology by priming in the presence of IFN- alpha/beta. 4) Development of a vaccine strategy promoting strong induction of IFN- alpha/beta. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTERSTITIAL TRANSPLANTATION

PNEUMONIA

AFTER

BONE

MARROW

Principal Investigator & Institution: Cohen, Donald A. Professor; Microbiology Immunology, and Molecular Genetics; University of Kentucky 109 Kinkead Hall Lexington, KY 40506 Timing: Fiscal Year 2001; Project Start 17-SEP-1999; Project End 31-JUL-2003 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INVASION GENE AND VIRULENCE OF LEGIONELLA Principal Investigator & Institution: Cirillo, Jeffrey D. Assistant Professor; Veterinary & Biomedical Scis; University of Nebraska Lincoln 14Th and R Sts Lincoln, NE 68588 Timing: Fiscal Year 2001; Project Start 01-JUL-1997; Project End 30-JUN-2002 Summary: (Adapted from the applicant's abstract): Legionella pneumophila causes the severe and sometimes lethal pneumonia termed Legionnaire's disease. Legionnaire's disease has been shown to arise in individuals that undergo prolonged exposure to aerosols from domestic water supplies that contain Legionella. The first evidence that air-handling devices were the source of infection stems from a confirmed Legionella epidemic in 1976. There have recently been a large number of infections that have arisen aboard cruise ships as well. Approximately 15% of all domestic water supplies are thought to contain Legionella. It has been found that Legionella replicates almost exclusively intracellularly during infection and in the environment. Thus, Legionella must enter a eukaryotic cell in order to survive and the genes involved in entry should be critical for production of disease. The investigator's recent data indicate that Legionella grown in an environmental host, the amoebae Acanthamoeba castellani, are approximately two to four logs more invasive for host cells than bacteria grown in the standard laboratory medium. Electron microscopic examination of entry has shown that a novel mechanism, termed "coiling phagocytosis", is responsible for bacterial uptake. This mechanism appears to result in enhanced survival of Legionella after entry into activated macrophages. Taken together, these studies indicate that a key factor in the production of virulent Legionella in water supplies is growth within the appropriate environmental host, without which the investigator hypothesizes that human infections will most likely not occur. The specific aims of the current proposal are to: 1) isolate and characterize the genes involved in invasion and 2) determine the involvement of these genes in virulence of Legionella. Through an examination of the mechanisms of entry and the factors that regulate it, the investigator hopes to further the understanding of how Legionella causes disease as well as provide insight into novel methods for disease prevention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INVASION OF THE ALVEOLAR EPITHELIUM BY PSEUDOMONAS Principal Investigator & Institution: Zaas, David W. Pathology; Duke University Durham, NC 27706 Timing: Fiscal Year 2003; Project Start 01-APR-2004 Summary: (provided by applicant): Pseudomonas aeruginosa (Pa) is a major cause of morbidity and mortality in patients with nosocomial pneumonia and patients with cystic fibrosis. Although usually considered an extracellular pathogen, Pa may be able to enter respiratory epithelial cells in order to avoid host defenses. Caveolae are lipid rich domains present on the plasma membranes of a wide range of cell types including the alveolar epithelium that can function as an alternative pathway of endocytosis. We hypothesize that the virulence of Pa may be in part due to its ability to live intracellularly within the alveolar epithelium. Pa may co-opt the pathway of caveolaemediated endocytosis as a mechanism invading type I pneumocytes. This work is important because interventions aimed at reducing the morbidity and mortality of Pa must be refined by a better knowledge of the mechanisms by which Pa avoids host defenses. Specific Aims: I) Expose primary cell cultures of rat type I-like pneumocytes to several strains of Pa to screen for the ability of Pa to invade the alveolar epithelium. 2) Determine the role of caveolae in the uptake of Pa by examining the cellular invasion of

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type I-like pneumocytes by previously identified invasive strains of Pa. 3) Examine the specific role of caveolin-I in the endocytosis of invasive strains of Pa. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IRAK FAMILY FUNCTION IN BACTERIAL INFECTION Principal Investigator & Institution: Thomas, James A. Pediatrics; University of Texas Sw Med Ctr/Dallas Dallas, TX 753909105 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2007 Summary: Infection represents one of the most fundamental threats to host integrity. When bacterial pathogens breach an epithelial barrier, the host innate immune system detects the attack and triggers a response to contain and eliminate the invader. Cellular sensors, such as macrophages and dendritic cells, detect pathogen through receptors that recognize bacterial macromolecules. These cells then mount a proinflammatory reaction that leads to cellular responses that contain and eliminate the infection. Thus, the innate immune response contains both afferent (pathogen-sensing) and efferent (proinflammatory) limbs. The Toll/IL-1 signal transduction pathway mediates both arms of this innate response to infection. This conserved signaling cascade consists of the proteins MyD88, the interleukin-1 receptor-associated kinase (IRAK) family of molecules (IRAK, IRAK2, and IRAK-M) and the tumor necrosis factor associated factor 6. It processes signals from at least 10 Toll-like receptors (TLRs) and three IL-1 receptor family members (IL-1, IL-18, and Ti/ST2), distributing them to multiple downstream targets, including NF-kB and several mitogen activated protein kinase cascades. We have genetically deleted IRAK, the primary proximal kinase in this pathway, in mice. IRAK-deficient animals and macrophages exhibit impaired responses to lipopolysachharide (LPS), peptidoglycan (PGN), lipotechoic acid (LTA), and CpG DNA, bacterial molecules that activate the afferent arm of innate immunity through TLR4 and TLR2. These mice also exhibit attenuated proinflammatory (efferent) responses due to disrupted IL-1 and IL-18 signaling. The overall objective of this proposal is to determine IRAK function in the host response to Gram-negative and Gram-positive infections. Aim 1 is to determine the role of IRAK in the acute inflammatory response to Gram-negative and Gram-positive infections. We will subject IRAK- deficient macrophages and mice to increasingly complex models of these infections, using toxin challenges, stimulation with nonreplicating bacteria, and Klesiella pneumoniae and Staphylococcus aureus pneumonia. Aim 2 is to isolate IRAK function genetically to either the TLR4 or IL1receptor pathway by generating IRAK/IL-121 and IRAK/TLR4 double knockout animals and comparing the responses of double and single KO macrophages and mice to LPS stimulation, nonreplicating K. pneumoniae, and K. pneumoniae pneumonia. Aim 3 is to determine the contributions of IRAK2 and IRAK-M to residual TLR signaling in IRAK-deficient cells, as deletion of IRAK impairs, but does not completely abrogate signaling. These studies should provide fundamental new information about the role of IRAK in the innate immune response to acute bacterial infection and may eventually lead to the development of strategies to modulate deleterious aspects of this response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ISOLATION AND CHARACTERIZATION OF GBS VIRULENCE GENES Principal Investigator & Institution: Clancy, Kathryn A.; Children's Hospital and Reg Medical Ctr Box 5371, 4800 Sand Point Way Ne, Ms 6D-1 Seattle, WA 98105 Timing: Fiscal Year 2001; Project Start 01-AUG-2001

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Summary: Group B streptococci (GBS) are the leading cause of human neonatal pneumonia, sepsis and meningitis in the United States. The high incidence of infant mortality associated with GBS infection has led to a significant research effort focused on GS pathogenesis and the identification of virulence-related factors. However, the characteristics of GBS that are critical to the virulence of this pathogen and disease progression largely remain unknown. The long-term goals of this proposal are to gain a better understanding of the molecular basis for BS virulence in the human host and to identify important protein targets for the development of preventative and therapeutic measures such as vaccines and novel antimicrobials. Specifically, the aims of this proposal are to isolate putative virulence proteins from GBS and investigate the role of these proteins in the disease process. Gene fusion technology using alkaline phosphatase as a reporter enzyme will be employed to isolate secreted proteins from GBS, which are thought to be enriched for factors that participate in bacterial-host cell interactions, and have been shown to contribute to bacterial virulence in other microbial systems. Bacterial strains deficient for the putative protein effectors will be constructed and examined in vivo animal sepsis and infection models, which, in concert with in vitro cell-culture adherence and invasion assays, will help to characterize the function of the identified proteins and their importance in disease. The isolation of putative protein effectors from GBS is hoped to help identify future targets for therapeutic studies and development to provide treatment and protection against GBS infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: JOHNS HOPKINS ADULT AIDS CLINICAL TRIALS UNIT Principal Investigator & Institution: Flexner, Charles W. Associate Professor; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001; Project Start 01-JAN-2000; Project End 31-DEC-2004 Summary: (adapted from applicant's abstract): Johns Hopkins University has had an ACTU since its inception in 1986. The Unit is administratively within the Division of Infectious Diseases as a component of the Johns Hopkins HIV Care Program, but it is configured to make maximum use of relevant institutional resources with investigators from multiple departments and divisions including Pharmacology, Neurology, Ophthalmology, Gynecology, Pathology and Internal Medicine. The Hopkins ACTU has provided leadership to the ACTG scientific agenda and has provided HIV clinical trials to Baltimore, a city that ranks ninth among metropolitan areas in AIDS rates. The performance record for the last grant cycle shows average enrollment, data performance and a rank of No. 3 in scientific contributions. Assets of this ACTU include leadership and scientific expertise in virology (B. Jackson), immunology (H. Lederman, T. Quinn, R. Bollinger), quality of life assessment (A. Wu), neurology (J. McArthur), pharmacology (C. Flexner), CMV retinitis (D. Jabs), and mycobacteriology (R. Chaisson). This unit has a subunit in the prison system, has developed an ACTG study of tuberculosis in Haiti and has high enrollment of injection drug users and African-Americans. This application proposes to continue a scientific portfolio that has depth and diversity to support the ACTG scientific agenda and a clinical trials program that includes good data performance and the enrollment of high priority participants. All current investigators will continue in their present roles as will the three advanced technology laboratories. Three new investigators, Dr. R. Siliciano (latent reservoirs of HIV), Dr. Richard Moore (HIV outcomes, cost and cost effectiveness), and Dr. David Thomas (hepatitis C coinfection) will be added. Preference will be given to protocols that reflect emphasis areas of the Hopkins ACTU, especially pharmacology, neurology, immunology, mycobacteriology, hepatitis C, long-term outcomes (quality of life and cost analyses)

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and simplified ART regimens (to better serve the patients). There will be emphasis on enhanced enrollment with a new peer recruiter and a new subunit to increase the catchment area. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LETHAL PNEUMOCOCCUS

SYNERGISM

BETWEEN

INFLUENZA

AND

Principal Investigator & Institution: Mccullers, Jonathan A. Assistant Member; St. Jude Children's Research Hospital Memphis, TN 381052794 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2004 Summary: (provided by applicant): The K08 Award will provide an opportunity for the applicant to extend his virology training in the area of viral-bacterial interactions and to develop new expertise in pneumococcal pathogenesis in the setting of prior viral infection. These skills will enable the applicant to achieve his long term career goals by becoming a fully independent research scientist who can translate observations made at the bench into therapeutics and interventions at the bedside. Epidemiologic evidence suggests that there is a lethal synergism between influenza A virus and Streptococcus pneumonias accounting for excess mortality (average 20,000 influenza-related deaths per year in the US) during influenza epidemics. However, the pathogenic mechanisms underlying this interaction are poorly understood, and the lack of a suitable animal model of pneumonia following infection with both organisms has hampered study. The goal of the proposed research plan is to determine the role of receptor alterations engendered by influenza virus infection in the pathogenesis of pneumococcal pneumonia. A newly developed murine model of dual infection will be used to examine the relationships of timing and of infectious doses of influenza virus and pneumococcus to morbidity and mortality. Influenza viruses with different pathogenic features in the mouse will be utilized to determine how cytokine expression varies with different viruses. Expression of receptors permissive for pneumococcal adherence and invasion will be examined in the context of cytokine expression following influenza virus infection, and a correlation to development of pneumonia and in the murine model of dual infection will be made. Identification of specific pneumococcal proteins involved in this synergistic interaction will provide drug and vaccine targets for future intervention in human disease and death caused by pneumococcal superinfection following influenza. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LINGUAL MECHANICAL FUNCTION DURING SWALLOWING Principal Investigator & Institution: Gilbert, Richard J. Mechanical Engineering; Massachusetts Institute of Technology Cambridge, MA 02139 Timing: Fiscal Year 2003; Project Start 12-SEP-2003; Project End 31-AUG-2006 Summary: (provided by applicant): The human tongue is an intricately configured muscular organ that plays a vital role during the physiological act of swallowing. During normal deglutition, the tongue first configures, then propels the ingested bolus from the oral cavity retrograde to the pharynx. From a clinical perspective, disorders of lingual function are exceedingly common in the elderly, in association with common neurological diseases, such as stroke, Parkinson's disease, and dementia, and are responsible for impaired nutrition and increased risk of aspiration pneumonia in these patient populations. Notwithstanding, there is minimal understanding of the way in which lingual muscular structure contributes to physiological function. The study of

80 Pneumonia

lingual mechanics has long been hampered by the complex myoarchitecture of the tissue and its material properties. As a result, mechanical function cannot be determined solely from global changes of shape, but necessitates the study of intramural dynamics. Our overall hypothesis is that the tongue functions as a muscular hydrostat, a unique structure in the human body, with the ability to both create motion and to provide the skeletal support for that motion. In order to test this hypothesis in the setting of human swallowing, we have considered the tongue from the perspective of a material continuum, and have thus depicted the tissue in terms of local fiber organization and strain. This project will study the quantitative relationship between three-dimensional myoarchitecture and regional mechanics during human swallowing. Our experimental approach uses non-invasive nuclear magnetic resonance imaging techniques to discern patterns of myoarchitecture and regional mechanics in vivo. In Specific Aim 1, the threedimensional myoarchitecture of the tongue will be studied through the depiction of the local second order diffusion tensor derived from magnetic resonance imaging. In Specific Aim 2, the quantitative relationship between muscle fiber architecture and regional strain in association with swallowing will be determined by linkage of the structural measures with tagged magnetization. In Specific Aim 3, the regional mechanical adaptation to varying bolus volume and viscosity will be studied through combined diffusion tensor and tagged magnetization imaging under varying load conditions. This project should result in an improved understanding of structurefunction relationships for the human tongue, and related human muscular hydrostats. It is anticipated that this understanding will result in novel hypotheses of pathological lingual function for patients with oropharyngeal dysphagia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIPOPEPTIDE VACCINE TO PREVENT HCMV INFECTION AFTER BMT Principal Investigator & Institution: Diamond, Don J. Professor and Head, Laboratory of Vaccin; City of Hope Helford Building Duarte, CA 910103000 Timing: Fiscal Year 2001; Project Start 01-APR-1998; Project End 31-JAN-2003 Summary: (Applicant's Abstract) A complication of the recovery phase after BMT is cytomegalovirus (HCMV) infection. Therapy using gancyclovir prophylaxis has decreased the mortality from HCMV infection in allogeneic BMT recipients. However side-effects which include delayed immune reconstitution limit its effectiveness in reducing overall mortality from BMT. Studies from several laboratories have indicated that control of CMV infection in BMT recipients is dependent on a strong cytotoxic T lymphocyte (CTL) response which is targeted mainly against the viral matrix protein pp65, and to a lesser degree against pp150. An adoptive immunotherapy strategy using CTL has proved successful but is impractical for general use in BMT centers. The applicant will develop an alternative strategy that uses small peptide fragments from the CTL viral target proteins pp65 and pp150 in the form of a vaccine as a means to simulate CTL in vivo. The vaccine is a peptide composed of a CTL epitope combined with a peptide which stimulates a T helper (TH) response and is lipidated on the amino terminus. He will first evaluate several different structural forms of the vaccine containing the HLA-A0201 restricted CTL epitope from pp65 and several different TH epitopes in a transgenic HLA-A2.1 mouse model. He will evaluate which of the vaccine molecules provide the strongest and longest-lived immunity by comparing the degree of lysis in vitro of human fibroblasts infected with HCMV mediated by murine splenic effector CTL. Based on the results of murine immunizations, a Phase I dose-escalating and safety trial will be conducted in asymptomatic HCMV seropositive human

Studies 81

volunteers with a lipidated HLA-A0201 restricted CTL vaccine. Additional vaccines including those with 2 or 3 CTL epitopes will also be evaluated in human volunteers in a Phase I trial. In order to test whether the vaccine, which enhances CTL against HCMV in healthy volunteers, is also capable of protecting against infection, a Phase II trial will be conducted in HCMV seropositive BMT donors and recipients. BMT donors will be vaccinated according to a protocol determined by the Phase I trial and their HLAmatched siblings who undergo BMT will be monitored for the ability to resist viremia and/or pneumonia brought about by HCMV infection. Success of this protocol will be determined by the avoidance of gancyclovir post-BMT and reduction of early and late HCMV infection in the BMT recipient. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LOS ANGELES PEDIATRIC AIDS CONSORTIUM Principal Investigator & Institution: Bryson, Yvonne J. Professor; Pediatrics; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, CA 90024 Timing: Fiscal Year 2001; Project Start 30-SEP-1988; Project End 28-FEB-2002 Summary: This is a renewal of the Pediatric ACTG unit for the Los Angeles area. The LAPAC consists of 7 clinical study sites (UCLA Med. Ctr., Childrens Hosp., of LA, Harbor-UCLA, Mem. Med. Ctr. Long Beach, Cedars-Sinai Med. Ctr., Martin Luther King Jr. Hosp., and Kaiser Perm. Med. Group). This consortium has successfully worked together for the past eight years and has enrolled a significant number of HIV infected women, children and adolescents representing 79% ethnic minorities and other disenfranchised populations into AGTG trials (n=336). UCLA is the main administrative data entry, coordinating and laboratory site with a well integrated network and infrastructure at our subsites. We have established effective liaisons with an LA County surveillance study, community health centers for HIV screening of pregnant women, a county- wide social service network for HIV+ children, community representatives and a pediatric Community Advisory Board. All centers provide primary care for HIV infected children and adolescents and three are also designated perinatal centers, which can enroll HIV+ pregnant women into clinical trials with liaisons for continued care and access to clinical trials. This consortium provides clinical care for 80% of the HIV exposed or infected children in LA (n=424) and is a catchment area for 75,000 of the deliveries. Our unit has made major scientific contributions both in the design and implementation of the overall pediatric/perinatal scientific agenda including studies to enhance the knowledge of pathogenesis and to significantly reduce perinatal transmission, to develop new methods of early diagnosis in infected infants, to provide insight into the actors associated with disease progression in infants and children and to improve the treatment and quality of lives of infected children and adolescents. We have a very strong record in advancing the science, providing leadership and also contributing to the productivity of the national pediatric effort. We plan to enroll a minimum of 50 patients/yr into clinical trials with an emphasis on perinatal and phase I/II studies, and to follow 87 continuing patents. We plan to enroll 28 new HIV infected pregnant women and/or newborns, 14 HIV infected children or adolescents into primary therapy and 8 into studies of opportunistic infections. Our goals are integrated into the scientific agenda and include the reduction of perinatal transmission to Th1 lymphocytes --> days 7-21 SA2: CXCR3 / IP-10 (CXCL10) and Mig (CXCL9) SA3: CCR2: / MCP-1 (CCL2) --> monocytes/macrophages -> days 14-28 SA4:CXCR2 / KC and MIP-2 (CXCL1) --> neutrophils --> days 21 to 42 Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF LUNG INJURY FOLLOWING AUTOLOGOUS BMT Principal Investigator & Institution: Folz, Rodney J. Associate Professor; Medicine; Duke University Durham, NC 27706

Studies 89

Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Lung toxicity following high dose chemotherapy (HDC) and bone marrow transplantation (BMT) or hematopoietic stem cell support develops in up to 70% of patients, with the most severe form of toxicity, termed idiopathic pneumonia syndrome (IPS), accounting for up to 40% of non-graft versus host disease related deaths. We have described a lung toxicity syndrome that occurs following HDC and autologous bone marrow transplant (autoBMT) that we termed delayed pulmonary toxicity syndrome (DPTS). DPTS may be an early form of IPS, is a risk factor for increased mortality, and manifests as an interstitial pneumonitis no sooner than 4 to 6 weeks following autoBMT (mean onset 11 weeks). To begin to better understand its pathogenesis, we developed a novel HDCIautoBMT mouse model of lung toxicity that shows remarkable similarity to the human condition. Based on clinical and bronchoalveolar lavage studies of patients undergoing HDC/autoBMT and our mouse model, we hypothesize three specific mechanisms the development of DPTS. First, HDC induces an intense oxidative stress resulting in both lung tissue injury and increases in monocyte chemo attractant protein-1 (MCP-1). Second, in response primarily to MCP-1 (and MIP-1a), pulmonary inflammatory cells are recruited into the lung, which possess antigen presenting cells (APC) features and may further stimulate a T cell lymphocyte response. Finally, fibroblast growth factors, like FGF-2, initiate a lung repair and fibrotic response. We plan to test these hypotheses by utilizing mouse strains that 1) overexpress and under express (knockout) antioxidant enzymes, 2) overexpress MCP-1, and 3) are deficient in CCR2. Additional studies designed to characterize the pulmonary inflammatory cells, determine their activation status, and their ability to stimulate T cells will be performed. Finally, we plan to identify BALF growth factors responsible for the development of restrictive lung. This proposal should provide new insights into the pathophysiology of lung injury following autologous bone marrow transplant and provide the basis for future clinical studies to prevent or treat this serious pulmonary complication. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MIAMI ADULT AIDS CLINICAL TRIALS GROUP, AACTG Principal Investigator & Institution: Fischl, Margaret A. Associate Professor; Medicine; University of Miami Box 016159 Miami, FL 33101 Timing: Fiscal Year 2001; Project Start 01-APR-1992; Project End 31-DEC-2004 Summary: (adapted from application's abstract): The Miami ACTU has been a member of the AACTG since its inception and has contributed to a number of AACTG studies that led to the approval of seven antiretroviral drugs and numerous HIV treatment strategies including lower and alternative dosing schedules for all three classes of antiretroviral agents, early treatment intervention, combination therapies with dual NRTIs and triple-drug therapy. The Miami ACTU has also actively participated in the Virology Laboratory Subcommittee working groups with an active role in the standardization of a PBMC culture assay for determining drug susceptibility, the assessment of interlaboratory concordance of DNA sequencing analysis of HIV RT, and the development of a consensus sequencing protocol to detect drug resistant mutations. This unit has also been involved with the Surrogate Markers Subcommittee with an active role in the assessment of plasma cytokines and soluble markers, cytotoxic Tlymphocyte activity, lymphocyte proliferation and advanced flow cytometry, and defining and validating immunologic markers as surrogate markers independent of CD4 and HIV RNA. Finally, this unit has contributed to the Pharmacology Committee with the evaluation of targeted- concentration control studies and the correlation of

90 Pneumonia

drug exposure with treatment response and failure parameters. The Miami ACTU will actively participate in HIV Disease RAC efforts and provide expertise to address study treatment strategies for initial therapy, treatment options for virologic failure and utilization of phenotypic and genotypic assessments to direct subsequent therapy and treatment intensification. The Miami ACTU will also bring expertise in the areas of hepatitis B and C pathogenesis and treatment, metabolic complications of HIV-1 protease inhibitor pathogenesis and treatment, HIV dementia pathogenesis and treatment and peripheral neuropathy pain assessment, Kaposi sarcoma (KS) pathogenesis, intensive immunologic monitoring and definition, and validation of immunologic determinants of treatment response. The Miami ACTU plans to enroll 100 subjects per year across AACTG studies and 70 patients into AACTG substudies, including but limited to Compartmental, Virology, Viral Dynamics, Pharmaceuticals, Metabolic, Neurologic, Women's Health and Adherence and Outcomes substudies. With a support system in place for the long-term follow-up of patients, the Miami ACTU anticipates to enroll approximately 80 patients into the ALLRT study (ACTG 5001) over a 2-year period. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MICROARRAY DETERMINANTS IN COMMUNITY-ACQUIRED PNEUMONIA Principal Investigator & Institution: Wood, Kelly; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2008 Summary: (provided by applicant): I am a junior faculty member in the Department of Critical Care Medicine at the University of Pittsburgh. I am trained in Pulmonary and Critical Care Medicine and have a Masters of Health Science degree in clinical research. My short-term goal is to become expertly trained in clinical research of the critically ill, specifically focusing on the integration of emerging knowledge of the biology of critical illness with advances in clinical research, biostatistics, and data management. My longterm goal is to bring a new level to critical care medicine where an individual's pathophysiologic response to illness is used to predict outcome and guide care. Under the tutelage and mentorship of Dr. Angus (sponsor) and key consultants, I have developed a set of formal coursework, directed reading and tutorials that will form the educational and training core necessary to achieve my goals. This training and education will take place in the Department of Critical Care Medicine, the Department of Biostatistics in the Graduate School of Public Health, the Center for Human Genetics and integrative Biology at the University of Pittsburgh Medical Center, and at the adjacent Carnegie Mellon University. My research project, "Microarray Determinants in Community-Acquired Pneumonia (CAP)" is designed to both provide important new information and provide an important educational opportunity complimenting the other components of my training and education. CAP is a major public health problem, frequently fatal in the elderly. The proposed study will perform a high throughput genetic analysis of elderly Caucasian males with pneumococcal CAP using microarray technology. Two substudies will occur. The first substudy is designed to develop a mortality risk prediction that distinguishes survivors and non-survivors, who are phenotypically similar, from a pre-existing database of stored whole blood samples (n=50). The second substudy involves the recruitment of a prospective inception cohort (n=50) of elderly white males with pneumococcal pneumonia. The value that provocation testing (with pneumococcal vaccine) has in providing additional information with regard to predicting clinical outcome will be explored. This second

Studies 91

substudy will also serve as a validation cohort for the model developed in the first substudy. This proposed study will generate a new predictive tool of clinical outcome based on gene expression analysis in the narrowly defined, homogeneous cohort of elderly Caucasian males with CAP and potentially identify genes not previously known to be involved in the immune response to infection. Information will also be generated regarding the pathophysiology of infection and possible points of early intervention with medical therapy that may alter the course of the disease process. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MIF AND THE HOST RESPONSE TO INFECTION Principal Investigator & Institution: Bucala, Richard J. Professor; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, CT 065208047 Timing: Fiscal Year 2003; Project Start 01-JUN-1998; Project End 31-JAN-2008 Summary: (provided by applicant): Overwhelming infection can lead to massive endorgan damage and death, which is a clinical condition known as septic shock. Current concepts of septic shock pathogenesis emphasize the role of innate immunity and excessive inflammatory cytokine production. Under normal circumstances, these responses are carefully regulated so that the infectious agent is eliminated without causing life-threatening tissue damage. Inhibition of inflammatory cytokines has been studied as a way to treat septic shock, however therapies directed at mediators such as TNF alpha and IL-I have not shown clinical benefit, and in fact have worsened outcome in some studies. We have discovered that macrophage migration inhibitory factor (MIF) is an important mediator of innate immunity and upstream regulator of inflammatory cytokine production. Anti-MIF protects from shock caused by live bacteria in the same models of infection that have demonstrated either a null or a detrimental effect of antiTNF alpha therapy. Interference with MIF action thus offers potential therapeutic advantages that have not been observed with previous anti-cytokine interventions. The objective of this application is to understand the mechanism by which MIF contributes to the overwhelming inflammatory response that produces shock. Our central hypothesis is that septic shock is the result of genetic predisposition to overproduction of MIF, coupled with M1F activation of cells by binding to the surface protein, CD74. We have formulated this hypothesis on the basis of our studies showing, first, that antiMIF prevents shock in relevant models of bacterial sepsis, second, that MIF is encoded by a functionally polymorphic gene, and third, that MIF initiates signal transduction by binding to CD74. The rationale for this proposed research is that once it is known how MIF expression leads to septic shock, then new and selective approaches for therapeutic intervention may be devised. We will test our hypothesis by pursuing the following three specific aims: 1) Define the Frequency of the Low and High Expression M/f Alleles in Patients with Pneumonia, and Determine if the High Expression Alleles are Associated with Septic Shock. Our working hypothesis is that high expression M/f alleles wilt be over-represented in patients with pneumonia who develop shock. 2) Define the Mechanism of MIF Signal Transduction. Our working hypothesis is that CD74 transduces MIF signals by recruiting an additional protein(s) into the signaling complex. 3) Determine the Biological Significance of the MIF-CD74 Interaction. Our working hypothesis is that anti-CD74 mAb and soluble CD74 protein (sCD74) will protect mice from lethal septic shock. The proposed research is innovative because it capitalizes on two recent and potentially unifying findings, a polymorphism in the M/fgene that affects its level of expression, and a cell surface protein (CD74) that mediates MIF signal transduction. These results will be significant because they will

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provide a better understanding of the molecular pathways responsible for the development of sepsis in susceptible individuals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MK-0826 VS CEFTRIAXONE FOR PNEUMONIA Principal Investigator & Institution: Dunbar, Lala; Tulane University of Louisiana New Orleans, LA 70118 Timing: Fiscal Year 2001 Summary: MKC-0826 is a recently developed investigational antibiotic drug that has been shown in laboratory tests to have a strong inhibitory effect on the growth of bacteria. Ceftriaxone sodium, a marketed drug has been approved by the Food and Drug Administration (FDA) for the treatment of complicated lower respiratory infections, including pneumonia. The purpose of this study is to determine whether MK-0826 is equivalent to ceftriaxone (an established cephalosporin with a prolonged serum half-life) for the treatment of community acquired pneumonia in adults with a positive Gram stain. The primary goal is comparison of clinical efficacy, secondary and tertiary goals are comparisons of safety and microbiologic effects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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MODIFIABLE

RISKS

FOR

NURSING

HOME

ACQUIRED

Principal Investigator & Institution: Quagliarello, Vincent J.; Yale University 47 College Street, Suite 203 New Haven, CT 065208047 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2003 Summary: (provided by applicant): The purpose of this pilot/exploratory study is to identify and validate modifiable risk factors for nursing home acquired pneumonia that are amenable to a targeted prevention strategy. The underlying premise is that nursing home acquired pneumonia is a multifactorial geriatric syndrome with modifiable risk factors amenable to prevention. Under the standard disease model of pneumonia, the invading infectious organism is the focus of diagnosis and treatment. However, under the multifactorial geriatric syndrome model, the invading organism is the precipitating event which is superimposed upon a set of modifiable predisposing factors that make the individual vulnerable to infection with the invading organism. The specific aims of this pilot/exploratory study are to identify modifiable risk factors for nursing home acquired pneumonia in a development cohort of elderly residents (age > 65 years) housed in three New Haven area nursing homes, and to test the validity of the identified risk factors in an independent cohort of elderly residents housed in two additional New Haven area nursing homes. To accomplish these aims, baseline demographic and clinical data are being collected from enrolled residents, and surveillance for the primary outcome (radiographically documented pneumonia) is conducted three times per week for 12 months following enrollment. Bivariate and multivariable Cox modeling will identify modifiable risk factors that have an independent association with the development of pneumonia. Pneumonia is the leading cause of death in elderly nursing home residents, and it results in considerable morbidity and healthcare expenditures since it is a major cause of transfer to acute care facilities. The long term implication of this study is that identification and validation of modifiable risk factors for nursing home acquired pneumonia will facilitate the development of a targeted prevention strategy that can be tested and ultimately placed

Studies 93

into practice to reduce the incidence of pneumonia in this vulnerable population of older Americans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MODULATION OF CYTOKINE NETWORKS IN MYCOPLASMA PNEUMONIA Principal Investigator & Institution: Simecka, Jerry W. Associate Professor; Molec Biology & Immuno; University of North Texas Hlth Sci Ctr Fort Worth, TX 761072699 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2005 Summary: (provided by applicant): The broad, long-term objective of the parent grant (5 R01 AI42075-04) and this project is to determine the immune and inflammatory responses that have an impact on the pathogenesis of and protection from mycoplasma respiratory disease. In the parent grant, the hypothesis is that T helper cells play a central role in determining the balance between helpful and harmful immunologic responses in murine mycoplasma respiratory disease. Furthermore, this balance is mediated by T cell subsets whose activity is modulated by regulatory cytokines, such as IL-4 and IFN-gamma. In fact, Th cells are proinflammatory while CD8+ T cells were found to unexpectedly dampen the inflammatory disease due to mycoplasma infection. In addition, the results demonstrate that IFN-gamma plays a novel but an important regulatory role in innate immunity against mycoplasma. These results indicate that the immune mechanisms involved in this disease are complex and require a broader understanding of the regulatory cytokines produced during disease pathogenesis and their regulation by T cells and cytokines. Thus, the current studies are proposed to establish whether a broader, more exploratory approach to analyze production of cytokines can facilitate our understanding their modulation and their potential role in mycoplasma respiratory disease. The Specific Aims address the following questions: 1) What cytokines are produced in lungs of normal or IFN-gamma deficient mice at different stages of mycoplasma disease?; and 2) What is the impact of CD4+ and CD8+ T cells on pulmonary cytokine production? The methods to be used in this exploratory approach are to first monitor cytokine mRNA production using array technology, and those cytokine mRNAs, shown modulated using arrays, will be further analyzed for their levels of expression and for experimental variations using real-time RT- PCR analysis. Furthermore, cytokine protein arrays will be developed to assess their production in a microarray format; once established tissue homogenates and cell culture supernatants to do this, we will develop assays using pre-existing antibodies to capture and detect cytokine protein in an array format. Thus, by analysis of a broad number of cytokines, clusters of cytokines with similar and/or contrasting regulatory properties should be identified that are associated with disease progression for further functional analysis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR AND FUNCTIONAL STUDIES OF H INFLUENZAE PILI Principal Investigator & Institution: Gilsdorf, Janet R. Professor of Pediatrics; Pediatrics & Communicable Dis; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2001; Project Start 01-JAN-1991; Project End 31-MAR-2003 Summary: (Adapted from the applicant's abstract): Haemophilus influenzae (Hi) are significant cause of respiratory tract infections, including sinusitis, otitis media,

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bronchitis, and pneumonia. The first step in the development of Hi infections is colonization of nasopharyngeal tissues, which depends on the ability of Hi to adhere to nasopharyngeal cells. To this end, Hi have evolved pili that bind to gangliosidecontaining receptors on epithelial cells and human red cells. Hi pili are complicated structures composed of at least three proteins, including HifA (the major pilus subunit), HifD (whose function is poorly defined), and HifE which contains the actual epithelial cell adhesin. The long-term goal of this project is to identify strategies to interfere with Hi adherence and, thus, prevent Hi infections. This goal will be met through understanding the underlying mechanisms by which the HifE adhesin of Hi mediates adherence to human tissue. Specific Aim I is designed to identify the receptor binding domain(s) of HifE through three approaches: 1. To analyze the amino acid sequences of HifE from Hi respiratory and invasive strains for conserved regions; 2. To identify epitopes defined by monoclonal antibodies that interfere with pilus mediated Hi binding to erythrocytes and epithelial cells; 3. To construct mutations in candidate receptor binding domain(s) by alanine-replacement and to test the function of the mutants in adherence assays. Specific Aim II is designed to compare the receptor binding domain(s) of Hi strains (biotype IV and biogroup aegyptius strains) that occupy unique niches within humans and may possess distinctive receptor binding domains. Specific Aim III is designed to identify tissue specificity of the receptor binding domain(s), by testing in competitive inhibition assays the binding of receptor binding domain mutants to a variety of human epithelial cells and by determining the role of the pilus stalk in binding specificity. Specific Aim IV is designed to identify the immunogenic potential of the receptor binding domain(s). Rabbit antisera will be raised to the domains and binding of the antibodies to HifE assessed by whole cell dot blot assays, Western blot assays, and immunoelectron microscopy. The receptor binding domain antibodies will be tested for their ability to interfere with the adherence of piliated Hi to human erythrocytes and respiratory cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •


MOLECULAR

EPIDEMIOLOGY

OF

HUMAN

P.

CARINII

Principal Investigator & Institution: Huang, Laurence; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2007 Summary: (provided by applicant): This is a resubmission of a K23 grant application that is designed to enable Dr. Laurence Huang to acquire additional clinical research training and to develop a research program that will allow him to become an independent and successful clinical investigator. The plan emphasizes didactic training in clinical epidemiology, molecular methods in clinical research, and advanced statistical analysis techniques, which he will gain through completion of a Master's Degree Program in Clinical Research. This didactic training will be coupled with the opportunity to spend time in the laboratories of his scientific collaborators so that he may gain practical insights into the new and highly promising molecular techniques he proposes to use to examine the epidemiology and transmission of human Pneumocystis carinii pneumonia. These studies will involve the close collaboration of scientists from the CDC, NIH, and several university-based laboratories. and will be conducted under the guidance of his two co-mentors: Philip Hopewell, MD, one of the world's foremost experts in the molecular epidemiology of tuberculosis, and Dennis Osmond, PhD, a leading HIV/AIDS epidemiologist and biostatistician. Although the transmission of Pneumocystis carinii between mammals of the same species has been convincingly

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demonstrated in the laboratory, it is unproven whether a similar clinical model exists for human disease. In addition, it is debated whether PCP in humans develops solely from reactivation or of a latent infection acquired early in childhood or also from acquisition of a new infection due to a recent exposure. The proposed research plan will determine whether P. carinii and immune responses to P. carinii can be detected in household and hospital contacts living with and caring for HIV-infected patients with PCP and, if P. carinii is detected, whether the P. carinii genetic sequence from a contact matches that from the patient with PCP. This information will be used to develop future studies to examine whether PCP can result from acquisition of a new infection. Since PCP remains a leading cause of the moribiity and mortality in HIV-infected and other immunocompromised persons, insights into its epidemiology and transmission may have profound implications for clinical management and disease prevention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR PATHOLOGY OF PNEUMOCYSTIS PNEUMONIA Principal Investigator & Institution: Lee, Chao-Hung; Professor; Pathology; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, IN 462025167 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2005 Summary: Alveolar macrophages from Pneumocystis carinii-infected hosts are defective in phagocytosis, and the expression of the transcription factor GATA-2 in these cells is severely down-regulated. Introduction of a GATA-2-specific antisense oligonuceotide into alveolar macrophages from normal uninfected animals also resulted in a decrease in the phagocytic activity of these cells. In this proposed study, experiments will be performed to further investigate the role of GATA-2 in alveolar macrophage phagocytosis. A GATA-2 expression vector will be introduced into alveolar macrophages from P. carinii-infected hosts to investigate whether GATA-2 overexpression could correct the defect. To further understand the involvement of GATA-2 in P. carinii pathogenesis, genes that are regulated by GATA-2 in monocytes will be identified. DNA microarrays will be probed with labeled cDNA from wild type and GATA-2 knockout monocytes. The hybridized microarrays will then be analyzed to determine which genes are regulated by GATA-2. Experiments will also be performed to determine whether genes such as those encoding MMR, MIP-1alpha, MCP-1, IL6 and TNF-alpha that are associated with functions of alveolar macrophages are regulated by GATA-2. The mechanisms by which P. carinii causes down regulation of GATA-2 in alveolar macrophages will be explored. Normal alveolar macrophages will be incubated directly or indirectly with live or dead P. carinii organisms to determine whether a P. carinii protein is responsible for down regulation of GATA-2 transcription leading to a reduction in the phagocytic activity of alveolar macrophages. Proteins such as vitronectin, fibronectin, surfactant proteins A and D, and P. carinii major surface glycoprotein, which are known to interact with alveolar macrophages during P. carinii infection, will also be examined. These proteins will be incubated either alone or in combination with normal macrophages to determine whether they have any effect on GATA-2 down regulation. Different fractions of bronchoalveolar lavage fluids from P. carinii-infected lung will also be tested. Any P. carinii or host protein that is found to have the ability to down regulate GATA-2 expression will be identified by sequencing a portion of the protein. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR PATHWAYS OF HOST SUSCEPTIBILITY TO LEGIONELLA Principal Investigator & Institution: Dietrich, William F. Assistant Professor; Genetics; Harvard University (Medical School) Medical School Campus Boston, MA 02115 Timing: Fiscal Year 2002; Project Start 15-FEB-2002; Project End 31-JAN-2007 Summary: Legionella pneumophila is a significant human lung pathogen that is responsible for many community- and hospital- acquired cases of pneumonia. An important part of the pathogenesis of Legionella infection is its ability to grow inside of macrophages. Interestingly, different inbred strains of mice exhibit differences in the permissiveness of their macrophages for the intracellular replication of Legionella, and these differences have been attributed to genetic differences in one of the mouse Neuronal Apoptosis Inhibitory Protein (Naip) genes. The goals of this project are to: Establish the identity of the Naip gene and its mutations that are responsible for the differences in Legionella permissiveness, and to study the function of the Naip proteins by identifying critical interacting proteins that participate in its molecular function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MUNC18 PROTEINS IN AIRWAY MUCUS HYPERSECRETION Principal Investigator & Institution: Dickey, Burton F. Professor and Chairman; Medicine; Baylor College of Medicine 1 Baylor Plaza Houston, TX 77030 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Airway mucus forms a protective layer against inhaled particles and pathogens. However, excessive mucus secretion in response to inflammatory stimuli can lead to airflow obstruction. Mucus hypersecretion can be divided into two distinct stages: metaplasia of an epithelial layer that consists predominantly of ciliated and Clara cells into a layer that consists predominantly of mucus-secreting goblet cells; this is followed by regulated secretion of mucus from the metaplastic epithelium. At a molecular level, secretory metaplasia involves expression of genes encoding three sets of proteins: secretory products; components of an exocytic machinery; and signal transduction pathways connecting extracellular secretory signals to exocytic membrane fusion. Secreted macromolecules and signal transduction pathways are subjects of intensive study, but little is known about the exocytic machinery. Munc18 proteins are ubiquitous components of the exocytic machinery of secretory cells. Their absence leads to a complete failure of secretion, and their overexpression also impairs secretion. Together, these data indicate the critical role played by Munc18 proteins and suggest that their expression is tightly regulated. We have found that Munc18B is highly upregulated in metaplastic airway epithelium of mice, and that its promoter region contains elements known to respond to inflammatory stimuli. We propose to suppress expression of Munc18B to test the protective and pathophysiologic roles of mucus secretion in models of allergic and infectious lung inflammation in mice, and to analyze the control of Munc18B expression in mice and humans to gain insight into the molecular pathogenesis of mucus metaplasia. Aim 1: Further characterize the cellular biology of Munc18 proteins in the regulation of airway mucus secretion in murine and human cells. Aim 2: Analyze the protective and pathophysiologic roles of mucus hypersecretion in murine models of allergic asthma and bacterial pneumonia by reducing the capability of airway goblet cells to secrete mucus through reduction of Munc18B expression. Aim 3: Identify critical cis-acting DNA elements and transcription factors that control expression of the Munc18B gene in metaplastic airway epithelium of mice. Aim 4: Confirm the importance of cis-acting

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DNA elements and transcription factors that control expression of the Munc18B gene in airway secretory metaplasia of humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MUTANTS FOR CELL ADHESION MOLECULES Principal Investigator & Institution: Beaudet, Arthur L. Professor and Chair; Molecular and Human Genetics; Baylor College of Medicine 1 Baylor Plaza Houston, TX 77030 Timing: Fiscal Year 2001; Project Start 01-JUL-1991; Project End 31-DEC-2001 Summary: (Adapted from the Investigator's Specific Aims): The overall goals of this project are to use genetic strategies to study the role of leukocyte and endothelial cell adhesion molecules in normal biology and in disease processes. Five Specific Aims are proposed: (1) Develop mutations in all three mouse selectin genes. (2) Perform phenotypic evaluation of knockout mice, including routine pathology, leukocyte counts, peritonitis, pneumonia, delayed type hypersensitivity reactions, and intravital microscopy. (3) Investigate the pathogenesis of psoriasis-like skin disease in CD18 deficient mice, specifically searching for a modifier gene or genes using a genomic-wide linkage strategy. (4) Develop cell-specific and inducible mutations using the loxP/Cre recombinase system, including an endothelial cell-specific mutation for VCAM-1 and an inducible mutations for ICAM-1. (5) Evaluate the role of adhesion molecules in the pathogenesis of atherosclerosis using apolipoprotein E-deficient mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MYCOPLASMA PNEUMONIAE - AIRWAY INTERPLAY Principal Investigator & Institution: Baseman, Joel B. Professor & Chair; Microbiology and Immunology; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, TX 78229 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: The epithelial lining of air spaces of the human respiratory system provides a crucial barrier between inspired gas and pulmonary blood flow. By virtue of its large surface area, delicate membranes and anatomic location, the epithelial barrier is vulnerable to damage by inhaled toxic substances and attack by infectious agents. The cell wall-less bacterium, Mycoplasma pneumoniae (whose genome is completely sequenced), is a common bacterial pathogen of the human respiratory tract. It causes a range of acute and chronic illnesses, including tracheobronchitis, pneumonia and other airway pathologies as well as extrapulmonary manifestations, such as joint, CNS and cardiovascular involvement. This microorganism exhibits a flask-like appearance and adheres to respiratory cell surfaces via a unique tip-like terminal organelle. In general, bacterial adherence is a complex process involving multiple interactions and molecular cross-talk between the microbe and target cell. We have been investigating mechanisms of cytadherence of M. pneumoniae and other mycoplasmas, and our recent studies indicate that various components in the airway microenvironment contribute to mycoplasma-respiratory cell interactions and subsequent tissue colonization. Delineating the role of such environmental components in the infectious process of mycoplasmas, particularly M. pneumoniae, is a major objective of this proposal. We will focus on understanding how fibronectin (FN) and surfactant protein A (SP-A) influence the mycoplasma-airway cell interplay, as these host proteins exist abundantly in the respiratory tract. These proteins play several roles including i) modulating alveolar macrophages in enhanced phagocytosis of invading bacteria; and ii) assisting bacteria (particularly FN) in binding to non-phagocytic cells. We have discovered the presence of

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FN- and SP-A binding proteins in M. pneumoniae, and we intend to clarify the role of these proteins as mediators of mycoplasma- airway cell interactions. Thus, the proposed study is expected to provide new insights concerning mycoplasma parasitic mechanisms which, together with the existing knowledge base concerning mycoplasma cytadherence, will broaden our overall understanding of mycoplasma pathogenesis and virulence determinants. Ultimately, these studies should identify new therapeutic strategies to control mycoplasma infections in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NATURAL CONTROL OF M AVIUM IN SAIDS Principal Investigator & Institution: Didier, Peter J.; Tulane University of Louisiana New Orleans, LA 70118 Timing: Fiscal Year 2001 Summary: The objectives of this pilot project are to establish the source of Mycobacterium avium infection in SIV-infected monkeys, characterize immune correlates of disease, and determine the feasibility of vaccination to prevent opportunistic infection of SAIDS animals with M. avium. The incidence of M. avium infection (MAI) in the SAIDS colony has increased from undetectable levels in 1988 to 18-25% in recent years. This opportunistic infection produces diarrhea, cachexia, and sometimes pneumonia in severely immunocompromized monkeys with remarkable similarity to MAI in children with AIDS. We detect M. avium by culture and PCR and characterize isolates from the environment (soil and water) and monkeys by molecular fingerprint analysis. To date, isolates from the environment rarely infect deep tissues of monkeys. In vitro testing of monkey macrophages demonstrates that cells co-infected with SIV and a common strain of pathogenic M. avium found in our monkey colony produces higher than expecte d levels of virus. Protein components of our pathogenic strain are being characterized. We have demonstrated that animals infected with SIV and severely immunodeficient can be infected with our pathogenic strain (MavK128) while inoculation with a human strain of M. avium (Serovar 4) fails to infect immunodeficient monkeys. In a pilot study vaccination of four animals with sonicated M. avium prior to SIV-infection failed to protect them from challenge with MavK128 but lesions contained more lymphocytes than expected. Future studies could look for promising formulations of M. avium and adjuvant that might provide protection against opportunistic infection. FUNDING Venture Research PUBLICATIONS Greenberg SS, Xie JM, Kolls J, Mason C, Didier P. Rapid induction of mRNA for nitric oxide synthase II in rat alveolar macrophages by intratracheal administration of Mycobacterium tuberculosis and Mycobacterium avium. Proc Soc Exp Bio Med, 209:46-53, 1995. Didier P, Ramesh G, Newman G, Maslow J. Detection of M. avium by PCR in rhesus monkeys. [Abstract #2486]. FASEB J, 10(6):A1431, 1996. Brar I, Didier P, Murphey-Corb M, Newman GW, Maslow JN. Prevalence of Mycobacterium avium complex (MAC) infection in SIV infected monkeys. [Abstract]. Infectious Diseases Society Meeting, September 1996, New Orleans, LA. Brar I, Didier P, Murphey-Corb M, Maslow JN. Epidemiology of Mycobacterium avium complex (MAC) infection in simian immunodeficiency virus (SIV) infected rhesus monkeys. [Abstract #655], p185, 4th Conference on Retroviruses and Opportunistic Infections, Washington, DC, January 2226, 1997. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEONATAL INHALED NITRIC OXIDE Principal Investigator & Institution: Ehrenkranz, Richard A.; Yale University 47 College Street, Suite 203 New Haven, CT 065208047 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEW AGENTS FOR PNEUMOCYSTIS CARINII PNEUMONIA Principal Investigator & Institution: Huang, Tien L.; Xavier University of Louisiana Box 121-C New Orleans, LA 70125 Timing: Fiscal Year 2001 Summary: Pneumocystis carinii pneumonia (PCP) is the most common serious opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS) and as a major cause of mortality in these patients. Pentamidine is one of the drugs of choice widely used for the treatment of AIDS-related PCR despite its high incidence of serious side effects. Therefore, the is a critical need for more effective and less toxic antiPCP agents. Pentamidine is a flexible molecule and can assume a number of interconvertible conformations. The precise mechanism of anti-PCP action of pentamidine is unknown. We hypothesize that the conformational flexibility of pentamidine allows it to bind to different macromolecules and this may account at least in part, for the therapeutic as well as toxic actions of the drug. It may therefore, be possible to separate these actions by a conformation-biological activity relationship study. To test these hypothesis, we propose to conduct the following studies: a) design and synthesize new conformationally restricted analogues related to pentamidine; b) determine the pKa values of the synthesized compounds; c) evaluate the compounds for in vitro anti-PCP activity and toxicity in an animal model of the disease; e) study the interactions of the proposed pentamidine analogues with DNA using molecular modeling techniques and by measuring thermal denaturation temperatures. The information gained will be valuable not only in determining the mechanism(s) of action of the pentamidine analogues, but may also result in the development of a more effective and safer anti-PCR agent. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NITROUS OXIDE AND WOUND INFECTIONS Principal Investigator & Institution: Sessler, Daniel I. None; University of Louisville University of Louisville Louisville, KY 40292 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2007 Summary: (provided by applicant): Nitrous oxide remains the most commonly used anesthetic and has been given to several billion patients. In vitro, even brief exposure to nitrous oxide inactivates methionine synthetase, which reduces induction of enzymes required for immune function. Nitrous oxide also reduces chemotactic migration by monocytes. However, nitrous oxide improves neutrophil chemotaxis and facilitates oxygen radical formation, and may therefore augment the efficacy of oxidative killing by neutrophils - the primary defense against pathogenic bacteria. Preliminary results in 200 patients suggest that the beneficial effects of nitrous oxide on wound healing outweigh its toxicities. We will thus test the hypothesis that the incidence of postoperative wound infection will be less in patients given 60% nitrous oxide than in those given 60% nitrogen during elective colon surgery. We propose to study up to 1000

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patients undergoing elective colon resection. Perioperative antibiotic, anesthetic, fluid, and oxygen management will be set by protocol. Patients will be anesthetized with isoflurane in 40% inspired oxygen, with the remaining ventilatory mixture randomly assigned as nitrous oxide or nitrogen. Surgical wounds will be evaluated daily by a physician blinded to group assignment. Wounds will be considered infected when they meet CDC criteria or pus is detected and they are culture-positive for pathogenic bacteria. As a secondary outcome, incidence of nosocomial pneumonia in the two groups will be determined. Results will be analyzed by Fisher Exact and unpaired, twotailed t-tests; P < 0.05 will be considered statistically significant. We anticipate showing that substituting nitrous oxide for nitrogen reduces the incidence of surgical wound infection. Confirming our hypothesis would thus allow clinicians to make a minor modification in anesthetic practice that might reduce the incidence of a complication responsible for considerable perioperative morbidity and cost. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NON CD4 HOST DEFENSE AGAINST P CARINII PNEUMONIA Principal Investigator & Institution: Kolls, Jay K. Professor of Pediatric; Medicine; Louisiana State Univ Hsc New Orleans New Orleans, LA 70112 Timing: Fiscal Year 2001; Project Start 01-JAN-1999; Project End 31-DEC-2002 Summary: Despite current strategies to treat HIV infection and its complications, Pneumocystis carinii pneumonia (PCP) remains a common clinical problem. Although there is a well-known relationship between CD4+ lymphocyte count and the risk of PC infection, the role of mononuclear phagocytes, CD8+ cells, NK cells, and their secreted cytokines in host defense against this infection are far less clear. As it is unknown at the present time, whether highly active antiretroviral therapy will result in long term immune reconstitution in patients with AIDS, understanding non-CD4+ T cell dependent host defense mechanisms operative in opportunistic infections may be critical. Among CD4+ T cell derived cytokines, interferon-gamma (IFN-g) is likely to play a key role in host defense against PC infection. Lymphocytes exposed to PC organisms or the major surface glycoprotein of PC in vitro elaborate IFN and lymphocytes recovered from HIV-infected individuals are deficient in IFN-g production. Preliminary studies from our laboratory demonstrate that overexpression of IFN-g in the lung, using adenoviral-mediated lung delivery of the murine IFN cDNA, (AdIFN) enhances clearance of PC in normal mice, and eradication of infection in mice depleted of CD4 lymphocytes, with a monoclonal antibody. Moreover, this augmented host response is associated with a significant increase in lung CD8+ T-cells. Furthermore, AdIFN fails to eradicate PC infection in scid mice which lack both T and B cells, suggesting that overexpression of IFN is not solely through macrophage activation and/or NK cells. We hypothesize that IFN is critical to host defense against PC and that overexpression of IFN in the lungs of mice depleted of CD4+ T cells will substitute for CD4+ T-lymphocytes, and mediate clearance of PC pneumonia through a CD8 T-celldependent mechanism. We will test this hypothesis with the following Specific Aims. Specific Aim 1. Our hypothesis predicts that overexpression of IFN-g will enhance recruitment of inflammatory cells and permit clearance of P. carinii in CD4-depleted mice. Specific Aim 2. Our hypothesis predicts that AdIFN induces the recruitment of CD8+ T cells, specifically of the Tc1-like phenotype, in CD4-depleted mice challenged with P. carinii. Specific Aim 3. To elucidate cytokine and cytotoxic mechanisms of CD8+ T cell mediated clearance of P. carinii in CD4-depleted mice. These studies will investigate non-CD4 dependent host defenses utilizing a novel form of immunotherapy against an important opportunistic pathogen. The results of these studies will not only

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aid us in further understanding lung host defenses, but also may lead to novel methods of therapy for opportunistic infections. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NOVEL ANTI-BACTERIAL THERAPY FOR GRAM NEGATIVE PNEUMONIA Principal Investigator & Institution: Murthy, Kanneganti; Director of Molecular Biology; Inotek Pharmaceuticals Corporation 100 Cummings Ctr, Ste 419E Beverly, MA 01915 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 28-FEB-2003 Summary: (provided by applicant):In spite of aggressive antibiotic therapy and supportive care, gram negative pneumonia remains a major cause of death and prolonged hospitalization. To address this unmet need, Inotek is developing an antibody-based strategy that targets flagellin, a critical virulence factor of motile gram negative pathogens. Flagella is required for effective bacterial invasion of epithelium. Moreover, flagellin is a highly potent trigger of NF-kappa B activation and proinflammatory gene expression, and thus may contribute to the excessive deleterious host response to regional infection. Both active and passive immunization strategies that target the N-terminal domain of flagellin reduce mortality in LD9O-100 murine models of Serratia marcescens induced acute pneumonia to less than 10 percent. This level of protection is associated with a 90 percent reduction in bacterial cfu in the lung, a 95 percent decrease in pulmonary neutrophil infiltration, and a 50 percent reduction in the incidence of bacteremia. Because the N-terminus is highly conserved, immune responses are cross-protective against a broad spectrum of gram negative pathogens. The central objective of the Phase I SBIR is to obtain proof of principle that anti-N-terminal flagellin mAb's are protective in vivo against a broad spectra of lethal infection.We will test the in vivo protective action of 14 proprietary murine mAb's in a murine model of acute gram negative bacterial pneumonia produced by intratracheal bacterial inoculation of E. coil. Specific outcome variables will include: 1) Pharmacodynamic profile; 2) Therapeutic window of opportunity; and 3) Spectrum of activity against Pseudomonas aeruginosa, Serratia marcescens, and Enterobacter cloacae. In a follow-on Phase II SBIR, we will use the peptide corresponding to the lead epitopes identified in Phase I in order to produce a human mAb.We will then advance the lead mAb technology towards commercialization by 1) optimizing in vitro yield and purity, 2) characterizing in vivo half-life, and 3) performing safety and tolerance studies in two species. These milestones will provide a foundation for IND submission and the first clinical trials of a human anti-flagellin broad-spectrum mAb. PROPOSED COMMERCIAL APPLICATION: Since there are no marketed anti-inflammatory agents that are safe and effective for the adjunctive therapy of gram negative pnenmocda, it is difficult to predict the future market size and trend. We anticipate, based upon the numbers of hospitalized patients with severe pneumonia, that the market exceeds that for sepsis. Thus, a very conservative estimate of the domestic market may be $200-400 million per annum. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NOVEL PRODRUGS FOR TREATMENT OF OPPORTUNISTIC INFECTIONS Principal Investigator & Institution: Allen, James L.; Immtech International, Inc. 150 Fairway Dr, Ste 150 Vernon Hills, IL 60061 Timing: Fiscal Year 2001; Project Start 30-SEP-1996; Project End 31-AUG-2002

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Summary: The long-range goal is to develop new drugs to treat important AIDS-related opportunistic infections and tropical parasitic diseases. STTR Phase I studies confirmed the hypothesis that diamidoxime prodrugs are readily absorbed after oral administration, then metabolized to active diamidines, with excellent antimicrobial activity and reduced host toxicity. Phase I research identified a lead candidate prodrug, DR 289 that is highly active orally in rodent models of P. carinii and African trypanosomiasis, with markedly reduced toxicity compared to pentamidine. The objective in Phase II is to synthesize sufficient quantities of DB289 to perform formal preclinical toxicity and further pharmacological studies required to support IND filing for Phase I clinical trials. The immediate goal is to apply for FDA approval to begin human clinical trials as an orally active agent to treat P. carinii pneumonia. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NUTRITION, IMMUNITY & HEALTH STATUS OF ELDERLY ECUADORA* Principal Investigator & Institution: Meydani, Simin N. Professor of Nutrition & Immunology; None; Tufts University Boston Boston, MA 02111 Timing: Fiscal Year 2002; Project Start 15-JUL-2002; Project End 30-JUN-2005 Summary: (provided by applicant)This research will be done primarily in Ecuador as an extension of NIA grant 1 R01 AG13975, May 1997- April 2003 "Vitamin E and Infection in the Elderly." The overall goal of the parent grant is to determine the role of nutrients on immune response and resistance to infectious diseases in the elderly. Specifically, the objectives include evaluations of the effect of one year supplementation with vitamin E on: 1) incidence of respiratory infections (RI), total number of sick days, and antibiotic use, 2) in vivo and in vitro indices of cell-mediated and humoral immune responses, and 3) incidence of other infections, hospitalization, transfer to skilled nursing home facilities, and death. We intend to expand the goals of this grant by determining the relationship between nutritional status, immune response and health status in Ecuadorian elderly. In so doing, we will in part utilize the infrastructure of a related NIH grant, 1 R01HD 38327-0 1 A1, "Vitamin A and Zinc: Prevention of Pneumonia (VAZPOP) Study, Jan 2000-Dec 2004. This latter project is studying the potential benefits of vitamin A and/or zinc for the prevention of pneumonia and diarrheal diseases in malnourished children in Ecuador. The number of elderly is increasing both in developed and developing countries. Age-associated physiological, psychological, social, and economic changes adversely affect the nutritional and immunological status of older individuals. These changes are often reflected in poor health and a reduced quality of life. Infections, particularly respiratory infections, are prevalent in the elderly, and contribute significantly to their morbidity and mortality as well as to the associated costs of heath care. Micronutrient supplementation has been proposed as a cost-effective intervention to improve immune response and reduce morbidity and mortality in the elderly. Because of the higher prevalence of nutritional deficiencies and infectious diseases in developing countries such as Ecuador, the interaction between nutrition, immune response, and infectious diseases can be more efficaciously determined in these countries. Such information would be of great value to developing countries, because, despite the increasing number of elderly in these countries, very little is known about the nutritional and immunological status of their elderly and their impact on the health of the older population. Thus the specific aim of this proposal is to determine the nutritional, immunological, and health status of the elderly population living in the VAZPOP study area (poor northwestern suburb) of Quito. Nutritional status will be

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assessed by obtaining dietary intake, selected nutrient analysis, and anthropometrics measurements. Immunological status will be assessed using delayed type hypersensitivity skin test (DTH), cellular profile, and a whole blood assay to determine lymphocyte proliferation and selected cytokine production. Health status will be determined using health questionnaires. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ORAL CARE AND RESPIRATORY PATHOGEN COLONIZATION Principal Investigator & Institution: Akca, Ozan; Anesthesiology; University of Louisville University of Louisville Louisville, KY 40292 Timing: Fiscal Year 2003; Project Start 15-JUL-2003; Project End 30-APR-2005 Summary: (provided by applicant): Ventilator-associated pneumonia (VAP) causes significant morbidity and increases health care cost. Identical bacteria have been cultured from the mouth and sputum of VAP patients suggesting that the oropharynx of critically ill patients becomes colonized with respiratory pathogens that are aspirated into the lungs. Antimicrobial rinsing reduces surface bacteria in the oropharynx, but does not remove plaque, which can serve as a reservoir of bacteria for recolonizing the entire oropharynx. Removing dental plaque may thus reduce recolonization following antibacterial rinse. A national survey of oral care practices in American intensive care units indicates that usual oral care consists primarily of swabbing the teeth and mouth with foam toothettes and rinsing with alcohol-free mouthwash. Foam swabbing is not effective in plaque removal and may not remove respiratory pathogens. Plaque removal with manual toothbrushing is effective but is performed once a day or less often by approximately 80% of ICU nurses. We will therefore test the hypothesis that mechanical removal of dental plaque combined with antimicrobial oral rinse significantly reduces respiratory pathogen colonization when compared usual to oral care plus swabbing with a placebo solution or the antimicrobial agent chlorhexidine. Seventy-five patients expected to be on a ventilator for more than 48 hours will be recruited for this study. Patients will be randomly assigned to: 1) Control: twice daily swabbing of the oropharynx with placebo in addition to usual oral care; 2) Chlorhexidine: twice daily swabbing of the oropharynx with chlorhexidine in addition to usual oral care; 3) Chlorhexidine/brushing: twice daily swabbing of the oropharynx with chlorhexidine followed by brushing of the teeth with a powered toothbrush with simultaneous suctioning and finally another swabbing with chlorhexidine. Research personnel who are unaware of patient assignment will collect plaque scores and microbial samples from all patients at baseline and every three days until extubation or day 15. The primary outcome will be the colonization by respiratory pathogens of microbiological samples taken from the teeth, mucosa, and sputum, Secondary outcomes will be dental plaque scores, endotracheal tube colonization and development of VAP. Data and confounding factors will be quantitatively analyzed. This study will serve as a basis for future multi-site clinical trials that will: 1) validate the effectiveness of dental hygiene as another measure to prevent VAP; 2) evaluate cost effectiveness; and 3) evaluate mortality. Reducing respiratory pathogen colonization in the mouth could significantly reduce the morbidity and cost of VAP. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ORAL CARE INTERVENTION IN MECHANICALLY VENTILATED ADULTS Principal Investigator & Institution: Munro, Cindy L. Adult Health Nursing; Virginia Commonwealth University Richmond, VA 232980568

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Timing: Fiscal Year 2002; Project Start 01-MAR-2002; Project End 28-FEB-2007 Summary: (provided by applicant) Pneumonia is the leading cause of death from nosocomial infections. Intubation and mechanical ventilation greatly increase the risk of bacterial ventilator-associated pneumonia (VAP). Growth of potentially pathogenic bacteria in dental plaque of critically ill patients provides a nidus of infection for microorganisms that have been shown to be responsible for the development of VAP. Since these organisms are concentrated in dental plaque, removal of organisms form the oral cavity by oral care interventions is a theoretically attractive method to reduce the risk of development of VAP. However, evidence-based protocols for oral care of mechanically ventilated patients are not available. Thus, we propose a prospective, randomized clinical trial to test the effects of three oral care interventions (mechanical, MECHI; pharmacologic, PHARMI; and combination, mechanical plus pharmacologic, COMBI) in reducing the risk of developing VAP. The primary aim of this study is to test the effects of mechanical, pharmacologic and combination (mechanical plus pharmacologic) oral care interventions on dental plaque, oral microbial flora and oral immunity in critically ill mechanically ventilated adults. Secondary aims are to1) examine the effects of mechanical, pharmacologic and combination (mechanical plus pharmacologic) oral care interventions on development of VAP in critically ill mechanically ventilated adults; and 2) describe any differential effects of mechanical and pharmacologic oral care interventions on the development of VAP in specific patient populations (medical, surgical, and neurologic critically ill patients). A total of 456 subjects will be randomly assigned to 4 groups (control, MECHI, PHARMI, COMBI) in order to attain an adequate sample size of 300 subjects. The effects of interventions will be examined using a between-subjects 22 factorial design. A two-factor analysis of variance will be used to conduct significance tests, including tests of the effect of each intervention (MECHI, PHARMI, and COMBI) on the outcomes of dental plaque (UMOHI score), oral immunity (salivary IgA and lactoferrin), oral flora (semi-quantitative culture), and development of VAP (CPIS score). Results of the study have the potential to positively affect patient well-being, morbidity, mortality and health care costs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: P CARINII PNEUMONIA--IMMUNOPATHOGENESIS OF LUNG INJURY Principal Investigator & Institution: Gigliotti, Francis; Professor; Pediatrics; University of Rochester Orpa - Rc Box 270140 Rochester, NY 14627 Timing: Fiscal Year 2001; Project Start 30-SEP-1997; Project End 31-AUG-2003 Summary: Pneumocystis carinii produces a life-threatening pneumonia in patients who are immunocompromised. It is especially prevalent among patients with AIDS. While the hallmark of P. carinii pneumonia (PCP) is hypoxia, the type and extent of lung injury produced by P. carinii has never been defined or characterized. The goal of this proposal is to define and begin to characterize the pulmonary insult resulting from PCP. This will be accomplished by completing the following specific aims: 1) to determine the extent and means by which P. carinii directly contributes to injury and altered lung function in the absence of a host immune response, i.e., in a SCID mouse; 2) to determine the extent and mechanism by which the host inflammatory response contributes to the pathophysiological changes that occur in PCP; and 3) to determine whether manipulation of the host inflammatory response can ameliorate the pathophysiological sequelae of PCP. Preliminary experiments show that the host inflammatory response itself contributes significantly to the overall pulmonary injury in a SCID mouse model of PCP. Using the most modem molecular/cellular and

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physiologic techniques, including assessment of lung compliance in a ventilated living mouse, this proposal will test the hypothesis that the pathogenesis of PCP is the result of both the direct effect of P. carinii on the lung and the effect of the P. carinii-driven host inflammatory response. This will be done by carefully manipulating various aspects of the inflammatory response to determine the effect on lung injury. If this hypothesis is proven correct, the information gained from the proposed studies can be utilized to develop new therapeutic modalities to improve the morbidity and mortality resulting from PCP. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: P INFLAMMATION

CARINII-EPITHELIAL

INTERACTIONS

MEDIATE

Principal Investigator & Institution: Wright, Terry W. Assistant Professor of Pediatrics; Pediatrics; University of Rochester Orpa - Rc Box 270140 Rochester, NY 14627 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: Pneumocystis carinii produces life-threatening pneumonia (PCP) in immunocompromised patients. Importantly, the clinical severity of PCP often correlates more closely with a patient's ability to mount an inflammatory response against P. carinii than with organism burdens. Alveolar epithelial cells (AECs) interact closely with P. carinii, and the important role of these cells in initiating inflammatory responses is becoming increasingly recognized. The hypothesis of this proposal is that AECs play a critical role in the initial detection and recognition of P. carinii in the alveolar compartment, and that the interaction of P. carinii with the alveolar epithelium stimulates chemokine secretion, and signals the recruitment of inflammatory cells specifically to sites of infection. When immune function is restored to P. carinii-infected SCID mice, T lymphocytes and macrophages are recruited only to sites of infection. In addition to clearing infection, this inflammatory response also results in "bystander" injury to the lung. Our preliminary data extends these observations by demonstrating that beta-chemokines and the beta-chemokine receptors CCR1 and CCR2 are highly expressed in vivo after reconstitution of infected SCID mice, and after inoculation of immunocompetent mice. In addition, we show that the specific attachment of P. carinii to AECs, in vitro, simulates the secretion of TNF-alpha and beta-chemokine gene expression. The specific aims of this proposal are designed to: 1) characterize the ability of P. carinii stimulated AECs to secrete chemokines, and induce the chemotaxis of CD4+ T cells. 2) determine whether CD4+ T cells are required for the early chemokine signals at the alveolar surface following in vivo exposure to P. carinii. 3) determine the role of beta-chemokines in cell recruitment and in resistance to P. carinii by utilizing CCR1 and 2 knockout mice. 4) determine the role of CCR1 and CCR2 in T cell recruitment, organism clearance, and lung injury in a well-characterized model of P. carinii-induced pulmonary inflammation. The goal of this proposal is to understand the inflammatory response to P. carinii so that strategies may be developed to circumvent the lung injury that results from the host response to P. carinii. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOGENESIS OF A NOVEL HANTAVIRUS FROM LABORATORY RATS Principal Investigator & Institution: Simmons, Joe H. Laboratory Animal Medicine; University of Missouri Columbia 310 Jesse Hall Columbia, MO 65211 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2006

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Summary: (Adapted from the applicant's abstract): Dr. Simmons, the candidate for this SERCA, is a highly qualified young investigator who has achieved a MS in chemistry, a DVM and residency certification in laboratory animal medicine. He is a candidate for a PhD in veterinary pathobiology with an expected graduation date of summer semester 2001. During the course of the SERCA, Dr. Simmons will obtain additional training that will allow him to develop into an independently funded research investigator. To develop his scientific skills, Dr. Simmons will participate in a variety of research training opportunities, including an in-depth research project, scientific meetings, seminars and journal clubs relevant to his area of research, and specialized topical courses at the Cold Spring Harbor Laboratory. Further, Dr. Simmons will receive additional training via collaboration with Dr. Connie Schmaljohn of the US Army Medical Research Institute of Infectious Diseases. He will present his research findings at national scientific meetings, and he will publish his findings in peer reviewed journals. Preliminary results from this SERCA will be used to pursue additional extramural grant funding during year 5 of the granting period. The focus of Dr. Simmons' research project is a novel hantavirus that was recently isolated from laboratory rats with interstitial pneumonia. Preliminary serologic analysis indicates that this novel hantavirus is widespread in laboratory rodents in North America and Europe with approximately 8% of rats infected. Further study of this novel agent is warranted because hantaviruses are potentially zoonotic, subclinical viral infections of laboratory rodents can invalidate research data, and infected rats may represent a critically needed animal model of human hantavirus diseases. The short-term goals of this grant application are to characterize this novel rat hantavirus (RRV), to initiate studies to determine its pathogenesis in rats and to describe the rat's inflammatory cell and cytokine responses to RRV. The long term goal is to develop the RRV-infected rat into a rodent model of human hantavirus diseases. Dr. Riley's laboratory provides a unique environment for this project as it is the only laboratory that has isolated and cultured this novel hantavirus. Further, the UM Research Animal Diagnostic and Investigative Laboratory is an internationally respected rodent diagnostic laboratory with specialized handling facilities and expertise in the infectious diseases of rodents necessary to complete this project. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOGENESIS OF KLEBSIELLA AIRWAY INFECTIONS Principal Investigator & Institution: Clegg, Steven; Professor; Microbiology; University of Iowa Iowa City, IA 52242 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): The opportunistic pathogen, Klebsiella pneumoniae, is responsible for a significant number of pulmonary infections in compromised individuals. The ubiquity of antibiotic resistant strains, particularly those producing extended-spectrum beta-lactamases, presents a serious clinical problem among groups such as hospitalized individuals and chronic alcoholics. The pathogenesis of Klebsiella airway infections has not been studied to any great extent and the investigation of the production of virulence determinants has essentially focused upon the role of capsules as antiphagocytic factors. The mouse has been extensively used as a model of airway infections due to K. pneumoniae primarily to investigate host cell responses. Also, epidemiologic observations suggest that specific capsular serotypes (e.g. K2) are most frequently associated with pulmonary infections. However, our preliminary data indicate that not all K2-positive isolates are virulent in the mouse model of infection. Therefore, although the capsule is most likely to be an antiphagocytic factor and prevent efficient killing of the bacteria in vivo, additional factors are necessary to establish

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airway infections with subsequent invasion of the bloodstream. We propose to identify and confirm the role of previously unknown virulence factors that mediate airway infections due to K. pneumoniae. Three techniques; signature-tagged mutagenesis, subtractive hybridization and in vivo gene expression technology will identify these determinants. The murine model of Klebsiella infection will be used to demonstrate the role of putative virulence factors during infection. The three approaches are complementary and have been used to investigate virulence in many different types of pathogens. Since very little is known about the virulence factors of K. pneumoniae, it is anticipated that these studies will provide information on new and novel virulence factors produced by these bacteria. Fundamental to devising new therapeutic approaches to opportunistic infections will be an understanding of the virulence factors produced by this group of organisms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOGENESIS OF LUNG INJURY IN LUNG AND PERITONEAL SEPSIS Principal Investigator & Institution: Martin, Thomas; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2001 Summary: Problem. This project will investigate the cellular and molecular events that link local infection in a primary body space with systemic consequences and injury to distant organs. The major hypothesis is that a three compartment model best explains the responses of humans to bacteria and their products. In this model, bacteria enter an initial compartment (e.g., lungs or abdominal cavity), and local interactions between bacteria and host effector systems govern whether bacteria are effectively eliminated. When first compartment responses are ineffective, responses occur in the second "systemic" compartment. When the second compartment responses are severe, responses occur in the third compartment (distant organs). In the lungs these responses include injury to the epithelial barrier and sustained loss of function. We will investigate important questions that relate to understanding this model. The major long-term goal is to understand how responses in the second and third compartments can be minimized without adversely affecting bacterial elimination in the first compartment. Specific Aims. 1) to investigate the "first compartment" responses in the lungs and the peritoneal cavity, in order to determine why the "first compartment" responses differ in each of these two sites; 2) to investigate the critical inter-relationships between the first compartment and the second compartment inflammatory responses; 3) to investigate the mechanisms by which injury occurs to the lung epithelium in the third compartment; 4) to investigate strategies that will protect the third compartment without adversely affecting antibacterial responses in the first compartment. Experimental approach. We will study rabbits with pneumonia or peritonitis due to E. coli, and follow them for up to 24 hours after infection. Responses in the first compartment will be compared with systemic physiologic and inflammatory response variables, and measurements of functional and anatomic integrity of the third compartment (lungs). New strategies to protect the third compartment without compromising antibacterial defenses in the first compartment will be investigated. Significance. These studies will provide information about the relationship between local and systemic responses and lung injury in sepsis, and will help to determine whether the best approach to prevention and treatment of septic complications is to focus on the specific organism (e.g., better antibiotics), or on interfering with the host response (e.g., better anti-inflammatory therapy), or both. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PATHOGENESIS OF VIRAL PROLIFERATIVE BRONCHIOLITIS Principal Investigator & Institution: London, Lucille; Associate Professor; Microbiology and Immunology; Medical University of South Carolina 171 Ashley Ave Charleston, SC 29425 Timing: Fiscal Year 2001; Project Start 01-JAN-1999; Project End 31-MAR-2003 Summary: (Adapted from the applicant's abstract): Bronchiolitis obliterans with organizing pneumonia (BOOP) is a term for a long observed, but unclassified pattern of acute lung injury. In humans, BOOP is characterized by fibrosis of small airways with fibrous extension into the alveolar spaces with preservation of alveolar ducts and walls. It is frequently associated with a peribronchiolar organizing pneumonia. The lesions may also be accompanied by lipid-laden foamy alveolar macrophages trapped in the air spaces by the fibrosis and by a T cell rich lymphocytic interstitial infiltrate in the regions of the lung directly affected by the lesion. Also, necrosis and sloughing of epithelial cells has been observed and is thought to result in the partial alveolar collapse seen in human BOOP. While BOOP can be associated with documented viral and bacterial infections, many cases are not associated with known causes and are thus classified as idiopathic. Little is known concerning the pathogenesis and treatment of BOOP since no animal models were available for this disorder. The investigators are the first to establish an experimental animal model for this disease. In this model, CBA/J mice infected with reovirus serotype 1/strain Lang develop BOOP lesions which closely resemble the histopathological picture of human BOOP. In addition, the development of BOOP lesions in CBA/J mice is virus strain specific. The central hypothesis of this proposal is that "Disruption of the epithelial basement membrane determines the susceptibility to fibrosis". The investigators propose to characterize the host and/or viral factors (both immune and non-immune cellular populations) that result in initiation of damage to the basement membrane and relate these finding to the development of fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PEDIATRIC AIDS CLINICAL TRIALS GROUP Principal Investigator & Institution: Flynn, Patricia M. Member, Dept of Infectious Diseases; St. Jude Children's Research Hospital Memphis, TN 381052794 Timing: Fiscal Year 2001; Project Start 01-MAR-1992; Project End 28-FEB-2002 Summary: A pediatric AIDS Clinical Trials Unit (PACTU) is proposed for St. Jude Children's Research Hospital with subunits at the University of Tennessee, (Le Bonheur Children's Medical Center and The Med), the Methodist Hospital and Vanderbilt University Medical center. The objective is to support the scientific agenda of the coordinating and Operations Center (CORC) proposed by Spector et al. and the NIAID) HIV/AIDS research agenda set forth in 1995. The team off the proposed PACTU includes well established academic specialists in pediatric and adult infectious diseases, immunology, pharmacology, virology, pharmaceutical science, pediatric neurology, psychology, neonatology, fetal and maternal medicine, vaccinology, oncology and gene transfer- based therapy. Each of the three children's hospitals have ongoing clinics for pediatric AIDS and the hospitals provide three separate obstetrical and neonatal programs with experience in maternal and infant AIDS. Over the past five years the St. Jude PACTU has demonstrated excellence as an innovative, productive, interactive site for the AUG program of the NIAID). We now plan to build on the existing program by addition of esteemed colleagues, state-of-the-art facilities and expanded clientele of HIV-infected infants, children and women at Vanderbilt University. This, in turn, provides access for all HIV- infected children throughout Tennessee and its seven

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bordering states to ACTG protocols and experimental drugs and vaccines. The high density population of African-Americans in the mid-South and the rapid increase of HIV infection in adolescents of this group assure an ample sample of HIV-infected pregnant women and their infants, as well as nonpregnant adolescents for study. Because of the strength of our experience in pharmacology, phrmacokinetics and new drug development we intend to take a major role in phase I and I/II studies of new compounds. A second major emphasis will be on HIV-infected adolescents because of unique features of these older pediatric patients, the prevalence of these individuals in our catchment area and our well established collaboration with specialists in internal medicine who share our, interest in AIDS research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PEDIATRIC AIDS CLINICAL TRIALS GROUP Principal Investigator & Institution: Gershon, Anne A. Professor; Pediatrics; Columbia University Health Sciences New York, NY 10032 Timing: Fiscal Year 2001; Project Start 01-SEP-1993; Project End 28-FEB-2002 Summary: This application is for continuation of a Pediatric AIDS Clinical Trials (ACTU) at Columbia University, for years 10-14 of the project. The Unit has two components, the main unit at Babies Hospital, in the Women and Children's Care Center (WCCC) and a subunit Incarnation Children's Center (ICC) a residential center that provides respite, hospice and clinical care for HIV infected children many of whom are in foster care. This ACTU is located is located in the Upper West Side of New York City in a geographic location of high prevalence of HIV infection, especially in women and children. The PIs and other researchers are seasoned investigators in AIDS clinical trials and each is a full time member of the faculty at Columbia University College of Physicians and Surgeons. There is a Pediatric HIV-certified ACTG virology laboratory on site. At Babies Hospital the interweaving of staff involved in NIH-supported HIV studies of viral transmission of HIV from women into their offspring (WITS) and ACTG clinical trials provides a unique opportunity for rollover of patients from one HIV study into another, thus resulting in a high level of access to women and children in ACTG protocols. The representative patient population served by the two institutions are largely impoverished, from minority groups, and socially disadvantaged. For the past five years, staff at the Babies Hospital and ICC have worked together synergistically to enroll a large number of patients into ACTG protocols. On average, we have enrolled 18 new HIV-infected children into protocols annually in the past. We have also enrolled many children into multiple protocols so that over the past 9 years our patient accrual has been more than 250 enrollments. In the current year we have already enrolled have more patients above out originally planned accrual. With the local presence of the WITS study and a newly forged relationship with Harlem Hospital Department of Obstetrics, we anticipate significantly greater enrollment of HIV-infected women into perinatal studies. Based on our past performance at what we believe has been an outstanding level of regarding accrual, data management, compliance with regulatory requirements, and significant contributions to the research agenda of the ACTG, we are respectfully requesting that our unit be funded in order to perform future research studies. Our plans for the future are to concentrate our efforts on perinatal studies and Phase 1 primary antiretroviral studies in women, infants and children. We further hope to establish a program for adolescents. We will also participate to the fullest of our resources in protocols that address means to prevent and treat opportunistic infections and to record information regarding long term outcomes of HIV-infected patients. We believe that our ACTU provides significant access to patients and in turn offers an

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outstanding an outstanding level of medical competence, an outstanding staff whose aim is not only to provide compassionate medical care to HIV-infected patients but also to perform meaningful and useful research on prevention and treatment of HIV. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PEDIATRIC AIDS CLINICAL TRIALS UNIT Principal Investigator & Institution: Borkowsky, William; Professor of Pediatrics; Pediatrics; New York University School of Medicine 550 1St Ave New York, NY 10016 Timing: Fiscal Year 2001; Project Start 30-SEP-1988; Project End 28-FEB-2003 Summary: The New York University Medical Center Department of Pediatrics plans to continue its goal o providing excellent care and perform outstanding research for children, adolescents, and pregnant women part of the AIDS Clinical Trials Group. This goal will he accomplished by contributing to the scientific agenda established by the Coordinating and Operations Center and utilizing a Statistical and Data Management Center to collect and analyze the data resulting from the proposed studies. We also plan to provide clinical and laboratory expertise which will help elucidate mechanisms of pathogenesis. Although he participation of Minority groups will be encouraged, this group currently comprises 80% of our ongoing patient base. It is our goal to perform studies to prevent perinatal transmission of HIV with antiretroviral drugs, immunebased therapies such as vaccines and passive immunotherapy, and newly formulated genetic therapies. We also expect to modify the HIV- related illnesses of those already infected with HIV by using emerging new antiretrovirals or by using established drugs in different combinations, performing pharmacokinetic analyses as required. In addition to interventions directed at the HIV agent itself, we expect to intervene with agents which may prevent the development of serious infections which result from the immunodeficient state of the child and adolescent or to modify the course of already ongoing disease with these or other agents, including vaccines. It is expected that these goals will be achieved from patient resources present in Bellevue Hospital well as through an already established Consortium of health care providers present in Lower Manhatten and in Staten Island. This effort will also be helped by established links to previously funded community resources, our community advisory board, and by our own local General Clinical Research Center. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PERCUTANEOUS RESPIRATORY ASSIST CATHETER Principal Investigator & Institution: Federspiel, William J. Associate Professor/Director; Chemical and Petroleum Engr; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: The objective of this proposal is to develop a percutaneous respiratory assist catheter (PRAC) that can be inserted into the venous system to provide supplemental breathing support, independent of the lungs, for patients requiring short- term (less than 1-2 weeks) respiratory assistance. The PRAC will be designed for percutaneous insertion into a peripheral vein and placement in the central venous system, where it will be exposed to all the blood returning to the heart. The PRAC will incorporate a cylindrical bundle of microporous hollow fiber membranes woven as a fabric that is wrapped around a balloon. The balloon is pulsed with helium and enhances gas exchange by pumping blood past the hollow fibers at velocities much greater than would otherwise exist in the vena cava. The specific aims of the project are to: 1. Fabricate candidate

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PRAC devices with insertional diameters of 25-28 Fr (8-9 mm) and evaluate the functional mass transfer characteristics in an in-vitro test loop. We will establish how the gas exchange performance of the PRAC depends on key operating and design parameters. 2. Evaluate and optimize balloon pulsation in the PRAC to improve gas exchange. We will principally explore changes in balloon geometry and balloon pulsation mode, and we will use flow visualization, local gas tension measurements, and computational simulations to help guide our design development. 3. Perform acute calf implants of the PRAC to assess the gas exchange functionality in-situ and any adverse anatomical, physiological and biocompatibility effects associated with shortterm implantation. We will also evaluate the hemolysis potential of candidate PRAC designs in-vitro using bovine blood in a bench flow loop. Our target is a percutaneous assist catheter that can provide 75- 85 ml/min of extrapulmonary CO2 removal at normocapnia and that could be used as an adjuvant or replacement to existing therapy for patients with acute lung failure (ARDS, pneumonia) or acute on chronic lung failure (COPD with exacerbation). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHARMACOKINETICS OF GREPAFLOXACIN & CIPROFLOXACIN IN LUNG Principal Investigator & Institution: Bascom, Rebecca; Pennsylvania State Univ Hershey Med Ctr 500 University Dr Hershey, PA 17033 Timing: Fiscal Year 2001 Summary: The purpose of this study is to determine the concentration of the antibiotic Grepafloxacin (Raxar) or Ciprofloxacin (Cipro) in the lung after taking a single dose. Both drugs are used for treating lung infections such as pneumonia and acute exacerbations of chronic bronchitis caused by bacteria that are resistant to many antibiotics. The greater the amount of antibiotic that is deposited at the site of the infection, the faster the bacteria is eliminated and the course of treatment is shorter. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PHEROMONE SIGNALING IN PNEUMOCYSTIS CARINII Principal Investigator & Institution: Thomas, Charles F.; Mayo Clinic Rochester 200 1St St Sw Rochester, MN 55905 Timing: Fiscal Year 2002; Project Start 01-MAR-2002; Project End 28-FEB-2005 Summary: (provided by applicant): Pneumocystis carinii is an opportunistic fungal pathogen which causes severe pneumonia in patients with impaired immunity such as patients with AIDS. The life cycle of P. carinii is poorly understood. In fungi related to P. carinii, nutrient deprivation and dessication are the major stimuli for the release of pheromone mating factors which activate a mitogen-activated protein kinase (MAPK), resulting in mitotic cell cycle arrest, conjugation and meiosis, and increased pathogenicity. MAPK is the essential molecule in the pheromone-induced signal transduction cascade which controls these events. As an essential molecule regulating an organism's life cycle, MAPK activity is highly regulated. Dual phosphorylations are requiring for activation, and variable MAPK activity and expression are restricted to certain life cycle forms. Our initial studies indicate that P. carinii possesses a MAPK which is closely related to fungal pheromone-induced MAPKs. We hypothesize that the pheromone-induced mitogen-activated protein kinase (MAPK) signal transduction cascade regulates cellular differentiation and proliferation of P. carinii organisms. As an essential component in the life cycle of fungi, investigation of the P. carinii MAPK will

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result in an enhanced understanding of the P. carinii life cycle, pathogenicity, and lead to development of novel therapeutic agents to treat P. carinii pneumonia. To evaluate these hypotheses, we will undertake several parallel investigations. MAPK activity and expression in separated life cycle forms will be accessed to determine whether P. carinii MAPK is differentially regulated over the P. carinii life cycle. We will identify and characterize the P. carinii pheromone receptors and separate P. carinii mating types by FACS. We will access whether nutrient deprivation, hypoxia, or temperature changes results in mitotic cell cycle arrest leading to meiosis and formation of the cyst, and whether inhibitors of the MAPK cascade block these effects. We will also investigate if isolated mating types undergo haploid mitosis or if mixing of mating types is essential for meiosis and formation of the cyst. Through these investigations, we hope to gain important insights into the life cycle regulation and pathogenicity ofP. carinii. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PLATELET CELL ADHESION MOLECULES Principal Investigator & Institution: Furie, Bruce; Chief, Coagulation Unit; Beth Israel Deaconess Medical Center St 1005 Boston, MA 02215 Timing: Fiscal Year 2001; Project Start 01-DEC-1994; Project End 30-NOV-2003 Summary: P-selectin is a cell adhesion molecule that resides in the storage granules of platelets and endothelial cells. Upon cell stimulation, the protein is translocated to the plasma membrane where it functions as a leukocyte receptor for PSGL-1 on neutrophils and monocytes. The current application represents a continuation of studies of the biology of P-selectin and PSGL-1. Since PSGL-1 has been shown to bind to all selectins, the kinetic and equilibrium binding of soluble PSGL-1 to soluble P-selectin, E-selectin and L-selectin will be analyzed by fluorescence spectroscopy. During the past grant period, we have prepared a PSGL-1 deficient mouse by homologous recombination and have completed the initial characterization. Cells from this mouse will be used to establish the physiologic role of PSGL-1 in selectin function by comparing the interaction of PSGL-1 (-/-), (+/-) and (+/+) leukocytes with P-selectin, E- selectin and Lselectin under rolling conditions in a parallel plate ex vivo assay using neutrophils and T lymphocytes. The PSGL-1 deficient mouse and double knockout mice including PSGL1 null/P-selectin null mice, PSGL-1 null/E-selectin null mice and PSGL-1 null/Lselectin null mice will be employed in model systems to determine the physiologic function of PSGL-1. Pathologic processes to be studied include models of non- immune mediated and T-cell mediated skin inflammation, leukocyte rolling following trauma and TNF, experimental glomerulonephritis, chemical peritonitis, bacterial pneumonitis, thrombosis, atherosclerosis, wound healing and platelet rolling. To understand the molecular basis of signal transduction and effector function induced by platelet activation or P-selectin binding to the P-selectin ligand on leukocytes, the induction of Ca2+ flux in platelets by PSGL-1 via P-selectin will be analyzed. Furthermore, binding of cytoplasmic tails of P-selectin and PSGL-1 to cytoplasmic signalling proteins in platelets and monocytes respectively will be examined using dimer constructs of cytoplasmic tails. If these studies indicate that PSGL-1 and ESL-1 are not physiologically critical counterreceptors for E-selectin or that there is evidence for another P- selectin ligand, we propose to expression clone a novel E-selectin ligand from a leukocyte library prepared from WEHI cells and a novel P-selectin ligand from a library prepared from neutrophils isolated from the PSGL-1 null mouse. The putative ligands will undergo characterization of their full length cDNAs and comparison of their predicted amino acid sequences with that of the PSGL-1, ESL-1 and GlyCAM-1. These studies will

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contribute to our understanding of the physiologically relevant receptors and counterreceptors that define cell-cell interaction during inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PNEUMOCYSTIS CARINII IN CONTINOUS AXENIC CULTURE Principal Investigator & Institution: Clarkson, Allen B. Associate Professor; Medical/Molecular Parasitology; New York University School of Medicine 550 1St Ave New York, NY 10016 Timing: Fiscal Year 2001; Project Start 01-JUN-1999; Project End 31-MAY-2004 Summary: (Adapted from Investigator's Abstract) Pneumocystis carinii is also a very poorly understood fungal pathogen and P. carinii pneumonia (PcP) remains one of the most common opportunistic infections associated with AIDS despite effective antiretroviral therapy, improved PcP treatment protocols and widespread PcP prophylaxis. The greatest obstacle in P. carinii research has been the inability to culture this organism other than in short term systems, generally with a co-cultured mammalian cell line. This laboratory has obtained continuous axenic growth of both rat- and human-derived P. carinii.The overall goal of this project is to develop this culture system further and use it to study P. carinii. Conditions will be established allowing for optimal growth in culture. Temperature and pH optima will be determined. Validation will be sought for the supplements now added to the culture medium and other supplements will be tested. Supplement concentrations will be optimized. Minimum medium exchange rates for optimal growth will be determined. A method of growing a P. carinii culture from a single cell will be developed. Cultured P. carinii will be characterized with reference to morphology, movement, and aspects of cell physiology such as respiration and polyamine metabolism. A library of 50 isolates of human-derived P. carinii will be obtained using bronchoalveolar lavage fluid from patients with P. carinii pneumonia. These isolates will be studied in vitro for sensitivity to the combination of trimethoprim + sulfamethoxazole (the mainstay for both treatment of and prophylaxis against P. carinii pneumonia) and to atovaquone (a commonly used alternative drug). In these isolates, we will determine critical sequences in the sulfamethoxazole target enzyme (dihydropteroate synthase) gene and the atovaquone target enzyme (cytochrome b) gene. An attempt will be made to correlate drug sensitivity, gene sequence and patient response to determine if there is resistance to this drug combination in human P. carinii. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PNEUMOCYSTIS CARINII PNEUMONIA MODEL IN RHESUS MACAQUES Principal Investigator & Institution: Norris, Karen A. Associate Professor; Molecular Genetics & Biochem; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2003 Summary: Pneumocystis carinii pneumonia is a primary cause of morbidity and mortality in immunocompromised patients, with particularly high infection rates in patients with acquired immunodeficiency syndrome (AIDS). Studies of the pathophysiology of Pneumocystis carinii pneumonia (PCP), host immune responses, and molecular characterizations of the organism have relied on animal models because of the lack of continuous in vitro culture systems. Although these animal models have been useful in producing information regarding the nature of the organism and the complex host-parasite interaction, the relevance to human PCP has been questioned

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since they generally involve broadly immunosuppressed animals. In addition, much evidence has been accumulated that demonstrates host species specific phenotypic and genotypic variation. For these reasons, the development of a reproducible, nonhuman primate model of PCP which mimics the disease seen in AIDS would provide several advantages for studying the pathogenesis of PCP and the molecular aspects of host species variations in a model most closely related to humans. Simian immunodeficiency virus (SIV) infected rhesus macaques develop spontaneous PCP, and preliminary evidence suggests that this occurs when peripheral CD4+ T cells counts falls below approximately 30 percent of the total T cells. The occurrence of PCP in SIV infected animals is not predictable due to individual host variability, environmental factors, and the variability in the course of the SIV infection. The primary goals of this study are to develop a reproducible PCP infection in immunocompromised, SIV infected rhesus macaques and to use this model to characterized the phenotypic and genotypic variation of simian derived P. carinii. It is our hypothesis that this model will most closely resemble PCP in AIDS and that the simian P. carinii will be most closely related to human P. carinii at the molecular level. To test these hypotheses, we propose to develop a PCP model by initiating a P. carinii infection in SIV infected rhesus macaques. The P. carinii infection will be initiated in monkeys when the SIV -induced decline in peripheral CD4+ T cells reaches 30 percent of the total peripheral blood T cells. Various manifestations of the disease progression will be monitored and simian P. carinii will be recovered for molecular and antigenic characterizations. These studies will address the question of similarities between simian and human P. carinii and determine the relevance of the nonhuman primate model, thus providing the means to study many aspects of PCP previously unapproachable due to the limitations of other animal models. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PNEUMOCYSTIS ACTIVATION

CARINII:

MACROPHAGE

&

EPITHELIAL

Principal Investigator & Institution: Limper, Andrew H. Professor; Mayo Clinic Rochester 200 1St St Sw Rochester, MN 55905 Timing: Fiscal Year 2003; Project Start 10-JUL-1993; Project End 30-JUN-2008 Summary: (provided by applicant): Pneumocystis carinii pneumonia remains a significant cause of mortality and morbidity in immune compromised patients, particularly those with AIDS, malignancy, and organ transplantation. Our investigations demonstrate that respiratory impairment during PC pneumonia is more closely related to exuberant pulmonary inflammation than to toxic effects of the organism. Adjunctive anti-inflammatory corticosteroid therapy (given in addition to antibiotics) improves outcome in this infection. Our studies demonstrate that cell wall beta-glucans of Pneumocystis (PCBG) specifically interact with alveolar macrophages to trigger inflammatory activation through NF-kappaB translocation, stimulating release of TNFalpha and chemokines that promote neutrophil recruitment in the lungs. Additional investigations demonstrate that alveolar epithelial cells also interact with PC betaglucans and are potently activated to release chemokines including MIP-2, which further promote lung inflammation. Epithelial responses are robust and of magnitude comparable or greater than those elicited by macrophages. The mechanisms of activation of alveolar macrophages and epithelial cells by PCBG involve multiple distinct receptor systems. In the current proposal, we hypothesize that alveolar macrophages and epithelial cells are activated by PCBG through distinct receptor systems involving CD11b/CD18 in macrophages and lactosylceramide in epithelial cells

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resulting in NF-kappaB-based activation. These concepts will be addressed through four independent but interrelated specific aims. In Aim 1, we will assess the roles of CD11b/CD18 integrins and TLR-2 (toll like) co-receptors in initiating NF-kappaB mediated inflammatory responses in macrophages. In Aim 2, the mechanisms through which lactosylceramide initiates inflammatory activation of epithelial cells will be determined. Aim 3 will evaluate the mechanisms of PCBG internalization in macrophage and epithelial cell inflammatory activation. Finally, Aim 4 will utilize mice deficient in CD11b or TLR2, and inhibitors of lactosylceramide, to study the roles of these lung responses during development of PC pneumonia in the intact host. Organisms burden and associated measures of lung inflammation will be studied during the course of PC pneumonia in these animals. Better understanding of the interactions of PC beta-glucans with host alveolar macrophages and epithelial cells will assist in the development of novel adjuvant anti-inflammatory. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: POST BMT LUNG INJURY PATHOPHYSIOLOGY Principal Investigator & Institution: Blazar, Bruce R. Director; Pediatrics; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, MN 554552070 Timing: Fiscal Year 2001; Project Start 15-SEP-1995; Project End 30-NOV-2004 Summary: (Applicant's abstract) Idiopathic pneumonia syndrome (IPS), formerly known as interstitial pneumonitis, accounts for up to 40% of non-GVHD deaths in allogeneic BMT patients. The pathophysiological mechanism(s) responsible for generating IPS are unknown. The applicants' laboratory has established a new murine IPS model which closely simulates the human condition. The severest form of IPS injury in humans occurs with the infusion of allogeneic T cells into recipients of cyclophosphamide (Cy) and total body irradiation (TBI). Therefore, they have constructed a murine model in which Cy/TBI conditioning and allogeneic T cells are used to generate IPS injury and mortality. Their central hypothesis is that these early peri-BMT inflammatory events establish an ideal environment for IPS injury as host MHC class II positive monocytes first are recruited into the lung (day 3), following which donor CD4+ and CD8+ T cells encounter these activated monocytes (Day 7). They will focus upon the early events that initiate lung injury. With respect to the T cell destructive component of IPS, they will determine whether donor T cells cause IPS injury via perforin or cause apoptotic injury via Fas ligand. The induction of endogenous IL-13 is associated with decreased IPS injury will be investigated. The role of IL-13 in downregulating IPS injury by donor T cells. They will explore two roles for these monocytes as: 1. facilitators of cytolytic T lymphocyte generation; 2. effector cells mediating tissue injury. B7 ligand expression is upregulated on host monocytes during IPS injury. Thus, they will use B7 ligand knockout (ko) mice to explore the requirement for B7 ligand expression in the lung for facilitating IPS injury. Their collaborator has shown that monocytes/macrophage secrete macrophage mealloelastase (MME) resulting in the destruction of essential matrix proteins leading to alveolar airspace destruction. They will determine whether MME is upregulated during IPS injury and if so, they will use MME ko recipients to determine whether MME is essential for IPS injury. Chemokines regulate cellular recruitment into damaged tissues. They will explore the critical role of chemokines known to regulate monocyte (MCP-1) and CD8+ T cell (MIP-1 alpha) recruitment in vivo; we will assess the role of proinflammatory Thelper type 1 (CCR5) and anti-inflammatory T-helper type 2 (CCR4) cell recruitment on IPS injury by infusing CC chemokine receptor (CCR) ko donor cells. Because adhesion molecules such as ICAM-1 are known to be critical in recruiting cells in the lung during

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TBI injury, they will determine whether ICAM-1 is responsible for residual cellular infiltration in the lung when chemokine/receptor interactions described above do not occur. This proposal will provide important new data as to the pathophysiology of IPS injury and may be useful in designing future clinical studies to prevent IPS injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PPARGAMMA IN SEPSIS-INDUCED IMMUNOSUPPRESSION Principal Investigator & Institution: Reddy, Raju C. Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Patients with sepsis are highly susceptible to the development of nosocomial infection, particularly bacterial infection of the lung. While the exact mechanism(s) that contribute to sepsis-mediated immunosuppression remains unclear, dysregulation of monocyte/macrophage function is believed to play an important role in these phenomena. Recently, peroxisome proliferator-activated receptor-gamma (PPARy), a member of the nuclear receptor superfamily of liganddependent transcription factors, has been shown to inhibit the expression of inflammatory mediators from monocytes/macrophages and other leukocyte populations. The hypothesis of this proposal is that sepsis induced immunosuppression is mediated, in part, by PPARy. Furthermore, we postulate that inhibition of this ligand dependent transcription factor will reverse sepsis-induced changes in alveolar macrophage function, resulting in augmented lung antibacterial host defense. A murine model of cecal ligation and puncture (resulting in an abdominal sepsis syndrome) will be utilized to assess the following Specific Aims: I) to determine the time course and magnitude of PPARy expression in lung during the evolution of murine abdominal sepsis; II) to determine the functional significance of PPARy activation on effector cell functions of primary murine alveolar macrophages or murine alveolar macrophage cell lines; III) to identify the endogenous signals that regulate PPARy expression during the evolution of murine abdominal sepsis; and IV) to determine the effect of inhibition of PPARy on sepsis- induced alterations in alveolar macrophage function ex-vivo and susceptibility to Pseudomonas pneumonia in-vivo. Performance of the studies outlined will help define the role of PPARy as a mediator of sepsis-induced alveolar macrophage dysfunction, and may lead to the development of novel therapies to be employed in the treatment of patients with sepsis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PRECLINICAL DEVELOP. OF A NEW DRUG FOR PCP AND MALARIA Principal Investigator & Institution: Elsohly, Mahmoud A. President; Elsohly Laboratories, Inc. 5 Industrial Park Dr Oxford, MS 38655 Timing: Fiscal Year 2001; Project Start 15-SEP-2000; Project End 31-DEC-2002 Summary: (Adapted from the application): The overall objective of this Phase II STTR application is to complete the preclinical studies for NPC 1161B, a promising new drug candidate for the treatment and prophylaxis of malaria. The drug is also very effective in animal models for the treatment or prevention of Pneumonocysis carinii (PCP) and leshmaniasis. This project is the continuation of the STTR Phase I project and a continuing collaborative effort between Elsohly Laboratories Inc., Oxford MS and The National Center for Natural Products Research of the University of MS (UM). In this Phase II application, these studies will be extended to complete the package of

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information necessary for the filing of the Investigational New Drug application. The objective will be accomplished through a plan of work to achieve the following specific aims: 1) Determine the physiochemical characteristics purity and stability of the GMP drug substance NPC1161B, assess compatibility of the drug with commonly used capsule formation excipients; 2) Evaluate the stereoisomers of NPC1161 (NCP1161A and NCP1161B) in primate models for relative antimalarial efficacy, toxicity, and metabolism/kinetics; 3) Develop analytical methods and a formulation of NCP1161B for clinical studies (drug product) and conduct accelerated stability studies; 4) Prepare and submit IND application. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREDICTING HOSPITALIZATION

PEDIATRIC

RISK

OF

DEATH

AFTER

Principal Investigator & Institution: Feudtner, John C.; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, PA 19104 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2006 Summary: (provided by applicant): The prospective identification of dying children is an essential task that must be accomplished in order to improve the beneficial impact of palliative, end-of-life, and bereavement (P-EOL-B) services on dying children and their families, since this prospective identification is essential if effective individual-level interventions are to be employed in a timely manner. We hypothesize that using administrative health service utilization data, one can prospectively identify with reasonable accuracy a substantial proportion of children who die from complex chronic conditions, and that proactive identification can improve the delivery of P-EOL-B care to these children and their families. We therefore aim to: 1. Develop a method of prognostication that would use administrative health utilization data to triage patients into low, medium-low, medium-high, and high risk groups for subsequent 1-year mortality. 2. Develop collaborative relationships and plan a larger replication study using data from other contexts, in order to validate techniques that would enable the recreation of this prognostication algorithm in the context of local and evolving systems of pediatric health care services. The algorithm will be developed using logistic regression and recursive partitioning, which will model the probability of dying 365 days after hospitalization among children age. We will utilize administrative hospital discharge data contained in the Pennsylvania Health Care Cost Commission database, linked to vital statistics records. With this innovative mortality risk prediction system in hand, we postulate that P-EOL-B and pastoral care teams in hospitals and health care programs would be able to identify individual patients or classes of patients (eg, those with cerebral palsy and the first or second hospitalization for an aspiration pneumonia) suitable for quality of care assessment and improvement, with targeted intensive care coordination to introduce P-EOL-B care earlier into these patients' and families' comprehensive package of care. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREDICTORS AND OUTCOMES OF PNEUMONIA AFTER STROKE Principal Investigator & Institution: Katzan, Irene L. Epidemiology and Biostatistics; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008

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Summary: (provided by applicant): The candidate's long-term goals are to become an independent clinical researcher and make significant contributions to the study of stroke management and outcomes. To fulfill these goals, the candidate proposes a 5-year plan to learn research methodologies related to assessing and analyzing stroke management in the community setting. This will involve formal training as well as comprehensive research on pneumonia as a complication of acute stroke. Pneumonia is a frequent and serious complication occurring after stroke, yet the predictors and preventability of pneumonia, and its effect on outcomes after stroke, are poorly known. The Aims of the proposed study are to use a large community-based cohort of Medicare patients hospitalized for acute stroke to: 1) Evaluate the effect of pneumonia on length of stay, rate of discharge to home, and 30-day readmissions. 2) Determine the effect of pneumonia on hospital costs. 3) Evaluate the effect of process of care measures on occurrence of pneumonia. 4) Develop a clinically useful prediction rule to identify patients most likely to benefit from preventive interventions. A retrospective cohort will be used to evaluate Primary Aims 1 and 2 and nested case-control studies will be performed to evaluate Primary Aims 3 and 4. For the first two Aims, the independent effect of pneumonia on outcomes and costs will be determined using data on 11, 286 stroke patients hospitalized in the Cleveland region from 1991-1997. Regression analyses will be performed with adjustments for both susceptibility and selection bias. To evaluate Primary Aims 3 and 4, a supplemental chart review will be performed for each case and control in the 2 nested case-control studies. Patients with pneumonia (n = 400) in a subset of 19 hospitals will serve as cases for both. For Aim 3, to isolate the effect of process of care measures, controls for Aim 3 will be selected using multivariate matching to cases on patient characteristics correlated with their propensity for pneumonia. For Aim 4, a random sample of patients will serve as controls. Products of this investigation will fill important gaps in knowledge about a serious compilation of stroke and guide further research and patient care to prevent stroke-related pneumonia. Combined with rigorous coursework in research methods, this body of work will establish a solid foundation for the candidate's long-term goals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREDICTORS OF POSTOPERATIVE ATELECTASIS PNEUMONIA Principal Investigator & Institution: Brooks-Brunn, Jo A. Assoc Scientist, Sch of Nursing; Medicine; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, IN 462025167 Timing: Fiscal Year 2001; Project Start 15-JAN-1997; Project End 31-DEC-2001 Summary: (Adapted from investigator's abstract) Postoperative pulmonary complications (PPCs) are frequent and associated with increased morbidity, mortality, hospital length of stay and resource utilization. Atelectasis and pneumonia account for >80% of reported PPCs. The objective of this study is to develop predictive models for stratifying the risk of clinically significant atelectasis and/or pneumonia using readily accessible or existing clinical data in an adult abdominal and cardiothoracic surgical population. The long term goal is to develop predictive model(s) for use in the clinical setting to guide preoperative and postoperative pulmonary care. The primary aim of this study is to develop, compare and validate models to predict the risk of clinically significant atelectasis and/or pneumonia following abdominal or cardiothoracic procedures by assessing combinations of risk factors available at differing time periods during the surgical episode of care. Secondary aims are to compare the incidence of clinically significant atelectasis and/or pneumonia following abdominal and cardiothoracic procedures and postoperative length of stay between patients who

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develop these complications and those who do not. Four institutions will be utilized for data collection and the target population is adults who are undergoing elective abdominal or cardiothoracic procedures with general anesthesia. The target sample size is 1500 subjects over a three year period. Multi-criteria definitions will be used to measure the outcomes of clinically significant atelectasis and pneumonia as not to overestimate the incidence. The risk factors of interest are: increased age, impaired preoperative level of cognitive function, history of chronic lung disease, preexisting comorbid diseases, low or high body mass index (BMI), increased preoperative length of stay, smoking history, absence of preoperative respiratory education, high anesthesia physical risk status (ASA), increased duration of anesthesia, type and location of surgical procedure, incision direction and length, duration of intubation/mechanical ventilation in the postanesthesia period, pain management, postoperative mobility, administration of H2 blockers/antacids and presence of a nasogastric tube. Data will be collected on each subject prior to surgery and on a daily basis until hospital discharge. Logistic regression analysis will be used to examine the risk factors for univariate effects on clinically significant atelectasis and pneumonia and to develop and compare the multivariate models. Models will be evaluated for utility and goodness-of-fit. A splitsample technique will be used for model validation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •


PROGNOSTICATION

IN

IDIOPATHIC

INTERSTITIAL

Principal Investigator & Institution: Flaherty, Kevin R. Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2002; Project Start 19-DEC-2001; Project End 30-NOV-2006 Summary: (provided by applicant): It has been proposed that idiopathic interstitial pneumonia (IIP) be divided into histopathologic categories. The overall prognosis differs between histopathologic categories; however, individual patients within categories can have an unpredictable response to therapy and survival. The potential for disease progression despite therapy often leads to the early listing of patients for lung transplantation as the mean time on the waiting list is 2-3 years. There is a shortage of donor lungs and this approach can lead to overpopulation of the waiting list and has the potential of preventing allocation of organs to the patients with the greatest need. This project will examine prognostic factors in patients with IIP and use these factors to develop a model that predicts survival. This model will help patients and physicians decide on optimal timing for lung transplantation. The histologic type of IIP is the most important, although not exclusive, factor influencing survival. Determination of histologic type requires a surgical biopsy which is not possible in all patients. Semiquantitative high resolution CT (HRCT) scoring for the amount of fibrosis also gives prognostic information. A drawback of this technique is observer variability, which could limit widespread utilization. We will collaborate with the University of Iowa to utilize a computerized quantitative scoring system which quantifies HRCT patterns (ground glass, fibrosis) present in the lungs of patients with IIP. We hypothesize that a computerized technique to determine the baseline and serial change in the amount of fibrosis will provide key prognostic information for patients with IIP. It has been suggested that radiologists can accurately diagnose categories of IIP. We will utilize survival analyses to compare the impact of a histologic diagnosis compared to a HRCT diagnosis for patients with IIP. We hypothesize that radiologists will have moderate accuracy in the diagnosis of IIP and that a HRCT diagnosis will provide more prognostic information when compared to a surgically obtained histopathologic

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diagnosis. The change in a clinical, radiographic, and physiologic (CRP) scoring system after three months of treatment also influences prognosis. A drawback is the requirement of a cardiopulmonary exercise test. We hypothesize that a scoring system utilizing the change in oxygen saturation during a six-minute hall walk will provide equal information without the need for a cardiopulmonary exercise test. During the past 10 years patients undergoing CRP testing have also performed a six-minute walk test. This information will be utilized to develop a new exercise component for a modified CRP scoring system. We will utilize survival analysis to define the patient population most likely to have improved survival through lung transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROPHYLAXIS FOR MAC, PNEUMONIA, AND HIV INFECTION Principal Investigator & Institution: Muschatt, David M.; Tulane University of Louisiana New Orleans, LA 70118 Timing: Fiscal Year 2001 Summary: Recent short-term studies have reported significant decreases in viral load and increases in CD4+ cell counts in people with HIV infection treated with combinations of antiretroviral agents. These changes in immunologic and virologic parameters have been shown to correlate with a decreased risk for development of AIDS-associated opportunistic infections (OIs). The question of whether there is a need to continue MAC prophylaxis in people who have had such responses to antiretroviral therapy is important in view of the toxicities, drug interactions, and complexity of drug regimens used to treat HIV infection and its complications. Deferred prophylaxis for MAC may be a reasonable option, provided this can be done without an unacceptably increased risk. The strategy of deferred prophylaxis may allow patients to avoid adverse side effects, the development of resistant organisms, and the extra pills and costs that are required to maintain a MAC prophylaxis regimen. Finally, the disadvantages associated with continued prophylaxis may outweigh the advantages in the context of a diminished risk of DMAC. This study will assess the impact of a strategy of prophylaxis versus deferred prophylaxis for MAC. It will evaluate the effect of azithromycin versus deferred azithromycin on the combined endpoint of DMAC and bacterial pneumonia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PROTECTIVE IMMUNITY TO VARICELLA ZOSTER VIRUS AFTER BONE MARROW TRANSPLANTATION Principal Investigator & Institution: Arvin, Ann M. Professor of Microbiology and Immunology; Stanford University Stanford, CA 94305 Timing: Fiscal Year 2002; Project Start 11-JUL-2002; Project End 28-FEB-2007 Summary: Reactivation of varicella-zoster virus (VZV) causes herpes zoster, which is common after bone marrow transplantation and is associated with considerable morbidity and even with life-threatening infection in some patients. The goals are to investigate the immunologic correlates of protection against VZV reactivation after hematopoietic cell transplantation (HCT), the role of viral tropism for human T cells in the pathogenesis of recurrent VZV infections, and the contributions of two novel VZV glycoproteins, gM and gN, to infectivity for T cells and skin. We propose to continue our studies of the reconstitution of VZV immunity by administration of inactivated varicella vaccine in a placebo controlled trial that incorporates a focus on refined analysis of the possible mechanisms and immunologic correlates of protection. The vaccine preparation to be tested will also be of higher initial virus content. The evidence from our current

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studies is that the inactivated vaccine accelerates reconstitution of VZV specific CD4 T cells in autologous HCT recipients who are vaccinated before as well as after transplant. We will continue to evaluate VZV immune reconstitution using novel assays to quantitate the CD8 as well as CD4 T cell responses in vaccine recipients. Immunologic correlates of protection will be defined by prospective monitoring for VZV-specific memory T cell recovery, and for the occurrence of herpes zoster as well as subclinical VZV reactivations documented by real time polymerase chain reaction (PCR). VZV infects human CD4 and CD8 T cells, which allows transport of the virus to visceral organs; this lymphotropism is an important event in the pathogenesis of VZV infections after HCT since it is responsible for the most serious complications of herpes zoster, such as pneumonia and encephalitis. In viral pathogenesis experiments, we plan to continue our focus on the contributions of VZV glycoproteins. The objective is to use our cosmid approach to generate recombinant VZV strains with modifications or deletions of the newly identified VZV glycoprotein genes, gM and gN. These genes are likely to be dispensable in vitro, but may be manipulated to reduce VZV virulence in vivo, providing a new approach for VZV attenuation. VZV recombinants that have deletions or selected mutations in gM and gN will be evaluated for changes in skin and T cell tropism in vivo in the SCID-hu model. A comprehensive assessment of immunologic correlates of protection from herpes zoster after immunization with inactivated varicella vaccine should suggest ways to enhance the control of VZV reactivation after HCT through targeting restoration of particular host responses; this work should have direct relevance to strategies for optimal reconstitution of host responses to other viral pathogens in high risk patients who have impaired immune function. Better understanding of VZV tropism for T cells and skin, and the contributions of the viral glycoprotein genes to virulence will provide basic information that may allow the design of live attenuated VZV vaccines which are safe and immunogenic in immunocompromised patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROTOCOL TO DEVELOP MODEL OF PNEUMOCYSTIS CARINII PNEUMONIA IN RHESUS MONKEY Principal Investigator & Institution: Rudolf P Bohm, Jr; Tulane University of Louisiana New Orleans, LA 70118 Timing: Fiscal Year 2001 Summary: This study is a continuation of previously reported work to develop a rhesus monkey model of Pneumocystis carinii pneumonia (PCP). This model will be important to study the pathogenesis and novel drug compounds that may be used to treat PCP. Four rhesus monkeys were chosen for this pilot study. Three animals received alternate day dosing of prednisone and cyclophosphamide to induce immunosuppression. The fourth animal was used as a non-immunosuppressed control. Bronchoalveolar lavage (BAL) was performed one week prior to immunosuppression and weekly thereafter. All four animals were inoculated via a bronchoscope with a homogenate from P. carinii frozen lung tissue derived from three SIV infected animals. Viability was assessed prior to the time of inoculation. Five ml of homogenate (2.8 x 106 organisms/ml) was inoculated in the right caudal lung lobe of each animal. Followup included BAL, silver stain, PCR, bacterial culture, complete blood counts, serum chemistries, chest radiographs, and physical examinations performed at weekly intervals. Total lymphocyte counts in peripheral blood as well as CD4+ And CD8+ subsets decreased to a nadir by day 21. The lung homogenate was positive by DNA PCR for SIV at the time of inoculation. All four animals became positive by DNA PCR for SIV by 14 days post

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inoculation. BAL samples were negtive for P. carinii by PCR and by Giemsa stain evaluation at all time points. Silver stains of cytospin samples from BAL were also negative. Thoracic radiographs were normal throughout the study period. Future experiments will involve timing of inoculation at the nadir of the CD4+ lymphocyte count and inoculation of SIV-negative lung homogenate. FUNDING Base Grant PUBLICATIONS None Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PSEUDOMONAS AERUGINOSA LPS CORE AND PATHOGENESIS Principal Investigator & Institution: Goldberg, Joanna B. Professor; Microbiology; University of Virginia Charlottesville Box 400195 Charlottesville, VA 22904 Timing: Fiscal Year 2001; Project Start 30-SEP-1997; Project End 31-AUG-2003 Summary: (Adapted from the applicant's abstract): Chronic lung infections with the opportunistic pathogen Pseudomonas aeruginosa remain the major cause of morbidity and mortality in patients with cystic fibrosis (CF). Initially P. aeruginosa strains that infect CF patients have a nonmucoid and smooth lipopolysaccharide (LPS) phenotype, typical of those found in the environment. As the clinical course of CF progresses, typical P. aeruginosa strains that are mucoid and have a rough LPS phenotype become predominant. The long-term objective of this proposal is to determine the bacterial and host factors responsible for the hypersusceptibility of CF patients to this infection. In vitro studies from the investigators' laboratory have shown that P. aeruginosa is internalized by human airway epithelial cells expressing wild-type CF transconductance membrane regulator (CFTR) significantly better than by epithelial cells that express the F508 mutant CFTR. Using structurally defined P. aeruginosa LPS mutants, we have identified the outer portion of the LPS core as an important ligand for this interaction. This ligand inhibited uptake of P. aeruginosa by the human airway epithelial cells and inhibited clearance of P. aeruginosa in vivo using a neonatal mouse model of pneumonia. The investigators suggest that the internalization of P. aeruginosa into normal airway epithelial cells represents an under-appreciated host defense mechanism that promotes desquamation and subsequent clearance. Further, this defense mechanism is ineffective in CF patient; thus, P. aeruginosa remains in the mucus layer and can cause a chronic infection. P. aeruginosa exacerbates this situation and evades the residual uptake mechanism of the CF cells by converting to an LPS-rough form that is even more poorly internalized. The specific aims of this proposal attempt to further define the P. aeruginosa LPS core structures involved in the interaction with human airway epithelial cells. The investigators will test structurally defined LPS core mutants for uptake by human airway epithelial cells. They will clone and sequence the P. aeruginosa LPS core genes encoding the proteins responsible for the synthesis of this ligand. This analysis will allow them to construct and characterize genetically defined LPS core mutants of P. aeruginosa and verify that the ligand is required for internalization. They will also determine the structure of the LPS core of three different P. aeruginosa CF isolates, since poor internalization of these strains suggests a defect in LPS core. The information derived from these studies may allow the investigators to devise a strategy to increase P. aeruginosa elimination by CF airway epithelial cells, and thereby inhibit the infection caused by this opportunistic pathogen. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PSEUDOMONAS PRODUCTS, OXYGEN RADICALS, AND LUNG INJURY Principal Investigator & Institution: Britigan, Bradley E. Professor; Internal Medicine; University of Iowa Iowa City, IA 52242 Timing: Fiscal Year 2001; Project Start 01-DEC-1993; Project End 30-NOV-2003 Summary: Pseudomonas aeruginosa causes acute nosocomial pneumonia as well as chronic lung infections in cystic fibrosis patients. The mechanisms responsible for the resulting lung injury remain unclear. Formation of oxidant species such as superoxide and hydrogen peroxide are associated with many forms of lung injury. During the initial funding period of this program, we obtained evidence that three compounds actively secreted by P. aeruginosa damage pulmonary epithelial and endothelial cells via oxidant production. In the next funding period we will define the cellular mechanisms of action of redox cycling. This results in superoxide and hydrogen peroxide generation. Pyocyanin causes a host of deleterious effects on cellular functions both in vitro and in vivo. In spite of this, there is only limited data on the cellular events by cells. Furthermore, the site(s), mechanism(s), and nature of the oxidants produced by pyocyanin, as well as the cellular targets are also poorly understood. We hypothesize that the complex series of effects mediated by pyocyanin occur through its ability to induce site specific oxidant production which leads to the disruption of cellular energy generation and activation of oxidant sensitive signaling pathways. To test this hypothesis three specific aims will be accomplished. Aim 1 is to identify the mechanism(s) of epithelial cell acquisition, cellular trafficking, and metabolism of pyocyanin under in vitro conditions. Aim 2 is to determine how pyocyanin deplete epithelial cells of ATP and cAMP by defining the effects of pyocyanin on oxidative phosphorylation and glycolysis. This aim will also address if pyocyanin acts on oxidantregulated signaling pathways, IL-8 expression will serve as a model system. The first two aims will use an in vitro system of polarized epithelial cell monolayers using normal and CF cells. Aim 3 will examine the extent to which the in vitro effects of pyocyanin are observed occur under in vivo conditions. This work will focus on IL-8 release and utilize xenografts of human respiratory epithelial cells in SCID mice. These studies will use state of the art technique of cell biology and oxidant chemistry to define novel and previously unexplored mechanisms whereby P. aeruginosa may contribute to acute and/or chronic lung injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PULMONARY DIAGNOSIS BY MULTICHANNEL LUNG SOUND ANALYZER Principal Investigator & Institution: Murphy, Raymond L.; Stethographics, Inc. 38 Cypress Rd Wellesley Hills, MA 02481 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 31-OCT-2002 Summary: (Applicant's abstract): Medical personnel routinely use the acoustic stethoscope to listen to lung sounds because the sounds provide important clinical information. These sounds are complex signals that reflect the underlying pulmonary pathophysiology. Unfortunately, studies of auscultation of the chest consistently show significant observer variability casting doubt on its clinical reliability. We developed user friendly, practical computerized technologies to obtain the important information provided by the sounds. Our results have been validated, patented, presented at scientific meetings and published in prominent journals. Our method provides objective, reliable information not previously possible to obtain with the human ear. It

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can be used even in severely ill patients. We are confident that automated lung sound analysis will replace the acoustic stethoscope in many of its current applications and become the new standard. In Phase I, we plan to determine whether our preliminary observations are correct that the acoustic patterns found in patients with heart failure are significantly different than those found in pneumonia. As a treatment of these very common disorders are different, more accurate diagnosis can have significant clinical and monetary benefit. In Phase II we will optimize our methods and demonstrate the value of automated lung sound analysis in broader clinical trials. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PULMONARY IMMUNE DEFENCES AGAINST M. BOVIS-BCG INFECTION Principal Investigator & Institution: Fulton, Scott A. Medicine; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-JUL-2005 Summary: Dr. Fulton is an Instructor at Case Western Reserve University School of Medicine in the Division of Infectious Diseases. As a fellow, Dr. Fulton was supported by an institutional training grant supported by the NIAID and a training grant from the American Lung Association. He has been responsible for setting up a new animal model to study the immune response to tuberculosis and chosen to continue studying tuberculosis at CWRU because of its long and productive interest in in immunity to tuberculosis. The scholarly environment was initiated by Dr. J. Ellner who is the current PI for a multi-center collaborative Tuberculosis Research Unit. Dr. Fulton's mentors, Drs. W. H. Boom and F. P. Heinzel are interested in cellular immune responses to complex intracellular pathogens and have had significant success in training physician scientists. Other members include Dr. Z. Toossi, Dr. R. Wallis, Dr. C. Hirsch and Dr. R. Silver who contribute to the intellectual environment. Additional formal and informal interactions with scientists in Geographic Medicine (Dr. J. Kazura, Dr. C. King, Dr. E. Pearlman) will foster Dr. Fulton's training environment. Dr. Fulton now proposes addditional specialized training with the goal of becoming an independent physician scientist. He has set up a mouse model of aerogenic M. bovis-BCG infection as a model of human disease since M. bovis-BCG grows in the lung and elicits protective T cell responses that eradicate 99 percent of the bacteria. 1 percent of bacteria persist in a steady state infection characterized by granuloma formation and immune surveillance. In contrast, viulent M. tuberculosis leads to progressive infection. Since human pulmonary immune responses can be only partially and indirectly studied, animal models have provided a means for studying the unique susceptibilty of the lung. To analyze immune responses that characterize the susceptibility of the lung to mycobacteria, three aims are proposed: Aim 1. To characterize the expression of chemokines and cytokines within the bronchoalveolar and lung microenvironments during early, maximal, and late immune activation phases of aerogenic M. bovis-BCG and M. tuberculosis infection. Aim 2. To characterize mycobacterial antigen presentation and T cell activation within the bronchoalveolar and lung microenvironments during early, maximal and late immune activation phases of aerogenic M. bovis-BCG and M. tuberculosis infection. Aim 3. To characterize the early pulmonary immune responses to aerogenic M. bovis-BCG and M. tuberculosis during local and systemic immunomodulation of cytokine and chemokine expression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PULMONARY PATHOGEN DEFENSE MECHANISMS Principal Investigator & Institution: Boom, W Henry. Professor of Medicine; Pediatrics; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2003; Project Start 01-JUL-1998; Project End 30-JUN-2008 Summary: (provided by applicant): This competitive renewal application for a postdoctoral training program in pulmonary host defenses to microbial pathogens (HL07889) at Case Western Reserve University (CWRU) seeks renewal funding for a research training program for M.D.,M.D.-Ph.D. and Ph.D. scientists. Funding for this novel training program was awarded in7/1998 on the strength of there search programs at CWRU in programmatic are as of tuberculosis, HIV and complications of cystic fibrosis. Research in pulmonary host defenses at CWRU has remained an institutional strength, with internationally recognized faculty with research programs on major pulmonary pathogens such as M. tuberculosis, HIV-1, Streptococcus pneumonia and Pseudomonas aeruginosa. Interdisciplinary approaches to study of host defenses to these bacterial and viral pulmonary pathogens involve faculty across basic and clinical departments and include immunology, molecular biology, biochemistry, genetics and cell biology. The interdisciplinary collaborations at CWRU in the area of pulmonary host defenses against microbial pathogens are greatly facilitated by the infrastructures of the Tuberculosis Research Unit (TBRU), the Center for AIDS Research (CFAR), the AIDS Clinical Trails Unit (ACTU), the Cystic Fibrosis Center and the NIH-funded Clinical Research Center (GCRC). In addition, strong basic research programs in the Departments of Pediatrics and Medicine in close proximity to and collaboration with clinical scientists has created a rich environment allowing trainees to learn how basic research translates into clinical investigation. The goals of the research training program are: 1. To provide rigorous training for promising M.D., M.D.-Ph.D. and Ph.D. postdoctoral fellows in the application of the tools of immunology, molecular biology or biochemistry to pulmonary host defenses to pathogens such as M. tuberculosis and HIV-I. 2. To assume an active role in career development by training and assisting trainees in securing funding either for additional postdoctoral training or for faculty development depending on their level of training at entree into the program and development in the training program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RECEPTOR-MEDIATED PNEUMOPHILA

ENDOCYTOSIS

OF

LEGIONELLA

Principal Investigator & Institution: Abu Kwaik, Yousef; Associate Professor; Microbiology Immunology, and Molecular Genetics; University of Kentucky 109 Kinkead Hall Lexington, KY 40506 Timing: Fiscal Year 2001; Project Start 15-JUL-2000; Project End 30-JUN-2005 Summary: Description (Adapted from applicant's abstract): The ability of Legionella pneumophila (Lpn) to cause pneumonia is dependent on intracellular replication within pulmonary phagocytic and epithelial cells. In the environment, the bacteria are ubiquitous where they multiply intracellularly with amoebae. Invasion and intracellular replication within protozoa play major factors in the amplification and dissemination of Lpn in the environment and in transmission and infectivity to humans. We have recently shown that uptake of Lpn by the protozoan Hartmannella vermiformis is mediated by bacterial attachment to a b2 integrin-like Galactose/N-acetyl-galactosamine lectin on the protozoan surface. Bacterial attachment to the lectin is associated with induction of protozoan gene expression and with tyrosine dephosphorylation of the

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lectin and several cytoskeletal proteins including actin, focal adhesion kinase, paxillin, and vinculin. Our data suggested a cytoskeletal disruption in the protozoan host upon bacterial attachment. Transmission electron microscopy showed that these bacterialinduced manipulations of cell processes in the protozoan host are associated with entry of the majority of the bacteria through a cup shape-like invagination that resemble receptor-mediated endocytosis, but some bacteria are internalized by coiling phagocytosis. Our preliminary data suggest that the mechanism of entry of Lpn is novel, which may contribute to its subsequent intracellular fate. Our hypothesis is that the lectin is a protozoan receptor involved in uptake of Lpn, and is dissociated from the cytoskeleton upon bacterial attachment and invasion. Our specific aims are, 1) to clone the lectin encoding gene and examine its regulation of expression; 2) to clone and characterize the bacterial ligand that binds the lectin receptor and the mode of ligandreceptor interaction; 3) to determine cellular distribution of the lectin receptor and its subsequent fate after internalization; and 4) to evaluate the interaction of the receptor with the cytoskeleton. The results derived for the proposed studies will uncover new paradigms of uptake of intracellular pathogens and will contribute to our understanding of targeting of molecules into a "protected vacuole" inside eukaryotic cells. Our proposed studies may also facilitate the design of future preventive strategies to control the amplification and spread of Lpn in the aquatic environment, which is the only source of bacterial transmission to humans. Our studies may uncover potential pathogenic evolution of Lpn to invade the more evolved mammalian cells, and may contribute to the understanding of invasion of protozoa by Mycobacterium and Chlamydia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RE-EXPLORING RACIAL DISPARITIES IN HOSPITAL CARE Principal Investigator & Institution: Shen, Jay J. Health Services Administration; Governors State University University Park, IL 60466 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 29-SEP-2003 Summary: Eliminating racial disparities in health care is a national priority. Although many studies have examined racial differences in aspects of hospital care such as severity of illness, care-seeking patterns, use of clinical procedures, use of resources, and outcome, no published research has integrated and examined these aspects simultaneously. Moreover, while many studies have reported racial disparities in hospital care only a few of them have examined the interactive effects between race and other factors on hospital care. Finally, while most of race-related studies on hospital care have focused on comparisons between one minority and non-Hispanic Caucasians, very few studies have examined health outcomes among the three largest racial groups (nonHispanic Caucasians, African-Americans, and Hispanic-Americans) simultaneously, let alone other ethnic groups. The proposed study forms an integrated conceptual framework, based on the concept of episode of care, the behavioral framework of health care use, and the structure-process-outcome triad, to examine the relationships between race and hospital care, in a systemic and comprehensive manner. The episode of hospital care, from the patient?s perspective, can be described by five dimensions: severity of illness, care-seeking patterns, process or receiving treatment, economic outcome, and clinical outcome. The study, with the inclusion of patients from all ethnic groups, focuses on four major diseases (heart attack, congestive heart failure, pneumonia, and stroke), extracts data from the 1995, 1997, 1999 National Inpatient Sample (NIS) datasets collected by the Hospital Cost and Utilization Project (HCUP), adopts validated administrative data based, risk adjustment methods, conducts

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multivariate analysis to control for potential confounding factors. This allows systemic exploration of the relationships between race and the five episode of hospital care dimensions and, in particular, to examines the interactive effects between race and other factors on outcome that are measured by the in-hospital mortality risk. Findings from this research will furnish information to help public and private sectors decision-makers better understand the racial gaps in hospital care in a more systemic way. It will also elucidate key factors that result in gaps in service to vulnerable populations. This will aid public policy development of effective interventions to improve health care deliverywith regard to eliminating racial disparities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COLLECTINS

REGULATION

OF

INFLAMMATION

BY

PULMONARY

Principal Investigator & Institution: Greene, Kelly E.; National Jewish Medical & Res Ctr and Research Center Denver, CO 80206 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 30-JUN-2003 Summary: (provided by applicant): Every day we breathe more than 7,000 liters of air, loaded with inorganic and organic particles and array of microbes. We all aspirate grampositive and gram-negative microorganisms and their products every night during sleep yet, most normal humans rarely develop pneumonia. This is due to highly effective host defenses that have evolved to protect the lung. Understanding the mechanisms that keep the pulmonary immune system and the associated inflammatory response in check and yet prepared to respond quickly to potentially deadly or disease-causing materials is crucial in developing approaches to intervene in many pulmonary diseases. Pulmonary surfactant, a complex mixture of lipids and proteins within the alveolar compartment, is the first biological interface encountered by airborne microorganisms and inflammatory mediators and is uniquely situated to play a role in host defense and modulation of inflammation. Surfactant-associated proteins A and D (SP-A and SP-D) are both members of the C-type lectin superfamily and have been shown in recent in vivo studies to recognize a significant number of microorganisms and play a role in their clearance. On the other hand, they also appear to be important in regulating the degree of lung inflammation. In this proposal we will address the mechanisms that allow the pulmonary collectins to serve this dual discriminatory role in the lung. We hypothesize that in the resting alveolus SP-A and SP-D provide an anti-inflammatory screen to prevent casual activation of macrophages and other inflammatory cells. We will 1) determine the characteristics and mechanisms of the anti-inflammatory effect in vivo as well as 2) examine the effect of pulmonary collectins on inflammatory mediator production from macrophages and neutrophils. Next we will 3) examine the mechanisms by which lung collectins inhibit proinflammatory signal pathways, focusing on CD45 as a potential cell surface ligand that delivers anti-inflammatory signals to the cell via inhibition of the src family kinases (specifically Lyn) and preventing activation of P38MAPKinase. Finally we will determine the mechanisms involved in the role of SP-A and -D as "defense collagens," which is in complete contrast to their anti-inflammatory role. We will 4) show that attachment and aggregation of pulmonary collectins to particles or organisms such that they are presented to macrophages via their collagenous tails, leads to proinflammatory effects. We propose that caireticulin is important for this effect. The challenge remaining in acute lung injury is to unravel at the cellular and molecular level the complexities of the inflammatory response in order to target therapeutic interventions so that they will lessen the injurious consequences of inflammation while leaving the beneficial effects intact.

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Gaining an understanding of the mechanisms by which pulmonary collectins inhibit or stimulate lung inflammation will be critical to this process. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RESEARCH PROGRAM TO IMPROVE QUALITY CARE FOR PNEUMONIA Principal Investigator & Institution: Fine, Michael J. Professor of Medicine; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-AUG-2005 Summary: (adapted from application abstract): This is a K24 application from Michael Fine, M.D., M.Sc. Dr. Fine is an Associate Professor in the Division of General Medicine at the University of Pittsburgh. His intermediate career objectives are (1) to further establish himself as a leading national authority on the quality and cost-efficiency of medical care for patients with community-acquired pneumonia (CAP), and (2) to serve as a mentor for medical trainees and junior faculty member pursuing patient- oriented research careers. His long-term objectives are (1) to apply the expertise in quality improvement developed throughout his systematic study of CAP to other clinical research areas of high priority to NIAID, and (2) to actively participate in the institutional commitment to promote patient- oriented research at the University of Pittsburgh. The candidate's patient- oriented research will be conducted in two phases. In phase I (years 1-3), he will direct a randomized clinical trial to assess the effectiveness of two medical practice guideline implementation strategies in improving the quality of medical care for patients with CAP. This trial will be supported by an RO1. In phase II (years 4 and 5), he will expand his research to the quality improvement of other clinical domains of high priority to NIAID. In both phases, medical trainees and junior faculty mentored by the candidate will be integral participants in his research activities. Over the course of the award, the candidate will mentor 5 medical students and residents, 6 clinical research fellows, and 4 junior faculty members in patient-oriented research. The candidate has already identified 2 of the clinical fellows and 1 junior faculty that he will mentor. Research training and education experiences, tailored to the level of the menthe, will include a mentored patient-oriented research project, participation in a weekly journal club, weekly research seminars, and year-round graduate-level coursework. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RESPIRATORY FAILURE IN A MODEL OF P. CARINII PNEUMONIA Principal Investigator & Institution: Paine, Robert; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2001; Project Start 01-JUL-2000; Project End 30-JUN-2005 Summary: (from applicant's abstract): It is hypothesized that infection with P. carinii renders the alveolar epithelium more susceptible to secondary insults, particularly hyperoxia, leading to respiratory failure in patients with PCP. To evaluate this hypothesis, the investigators will utilize a well-established CD4 depleted mouse model of P. carinii pneumonia, which is subsequently exposed to hyperoxia as a prototypical stress for alveolar wall injury. They propose that P. carinii infected mice will develop more severe lung injury following exposure to hyperoxia. They also postulate that GMCSF, a potent cytokine generated by alveolar epithelial cells and macrophages, is critical in ameliorating this response. GM-CSF expression induced in response to P. carinii infection exerts a protective effect to limit lung injury. They postulate that inhibition of lung GM-CSF expression as a result of hyperoxia is a critical event promoting lung

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injury and respiratory failure. Four specific aims will be undertaken. Initially they will characterize the response of P. carinii infected mice to hyperoxia. Next, they will determine the expression of GM-CSF in this animal infection model and in mice that genetically lack GM-CSF following exposure to PCP and hyperoxic conditions. They will further determine whether direct interaction of P. carinii and alveolar epithelial cells through integrins induces GM-CSF expression. Finally, they will evaluate the protective effect of GM-CSF in P. carinii pneumonia and in subsequent progression of lung injury following hyperoxia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RESPIRATORY IMMUNIZATION

SYNCYTIAL

VIRUS

ESCAPE

FROM

Principal Investigator & Institution: Sullender, Wayne M. Associate Professor; Pediatrics; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2001; Project Start 01-FEB-2001; Project End 31-JAN-2005 Summary: (Adapted from Applicant's Abstract) Respiratory syncytial virus (RSV) is the most common viral agent of lower respiratory tract infections of infants and causes repeat infections throughout life. RSV antigenic variability may contribute to the ability of RSV to cause repeated infections. RSV is also a cause of significant morbidity and mortality in bone marrow transplant (BTM) patients. Neutralizing antibodies to RSV may be pre-existing in and/or may be passively administered to BMT patients. It is hypothesized that due to selective pressure by antibody RSV will accumulate changes in the F and G proteins during prolonged replication in immunocompromised patients. Sequential RSV isolates from BMT patients will be monitored for the development of F and/or G protein genetic changes that are associated with resistance to antibody may result in impaired fitness for replication. Therefore the antibody resistant viruses will be characterized as to their fitness for replication in cell culture and in animals (Aim 2). The ability of the mutant viruses to evade passive immunity in animals will also be determined (Aim 3). In a clinical trial BMT patients with RSV pneumonia will receive therapy with a humanized F monoclonal antibody (palivizumab). This will result in the replication of RSV in the presence of an antibody that is known to select for escape mutants. Thus, palivizumab escape mutants will be selected in cell culture (Aim 4) and characterized as to fitness and capacity to evade passive immunity in the manner described for the human derived viruses. These experiments will define the extent to which RSV becomes resistant to antibodies during prolonged replication in immunocompromised host. In addition, the likelihood that resistant viruses derived in cell culture will maintain normal fitness for replication and escape passive immunity in animals will be determined. These studies will provide evidence from humans and from animals as to the clinical challenges that antibody resistant viruses may pose to the current passive immunization approaches against RSV. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RESPIRATORY VIRUS NEUTRALIZATION BY INTRACELLULAR AB Principal Investigator & Institution: Crowe, James E. Associate Professor of Pediatrics; Pediatrics; Vanderbilt University 3319 West End Ave. Nashville, TN 372036917 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2003 Summary: (Adapted from applicant's abstract): Respiratory Syncytial virus (RSV) is the leading cause of pneumonia and bronchiolitis in infants and children. The immune mediators of resistance to infection with RSV are still under investigation. In previous

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work the Principal Investigator generated large panels of live attenuated RSV viruses and performed the preclinical testing of these viruses in rodents and chimpanzees. New data from the applicant s clinical trials with these vaccines suggest that an IgA response correlates with protection against reinfection even in the absence of an IgG or neutralizing antibody response in the nasopharyngeal secretions or serum. The investigator's observations led to the hypothesis that IgA is indeed the principal mediator of protection against RSV reinfection in neonates. The question is: how do IgA antibodies that do not exhibit neutralizing activity protect against RSV? The hypothesis to be tested is that polymeric IgA (pIgAs) antibodies mediate intracellular neutralization of RSV. IgA transcytosis mediated by the polymeric immunoglobulin receptor (pIgR) was thought to be simply a mechanism for delivering high concentrations of antibodies to repertory secretions. Recent studies with several viruses, including Sendai virus, influenza virus, murine rotavirus, and HIV-1 suggest that IgA antibodies may neutralize viruses inside infected cells as the antibodies traverse the cell. The Principal Investigator will test this hypothesis using polarized epithelial cell cultures that express human or mouse pIgR. The Principal Investigator has developed panels of murine hybridoma lines secreting anti-RSV antibodies to either surface or internal proteins. The panels contain matched pairs of hybridoma lines that are identical except they are of the IgG or IgA isotype. The Principal Investigator will determine if murine PIgA binds to RSV inside polarized epithelial cells expressing the mouse pIgR and neutralizes RSV inside the cell. The applicants also will demonstrate this mechanism of virus inhibition in a cell line expressing human pIgR using pIgA purified from secretions of RSV vaccinees. Next, they will test the hypothesis that the compartment in which IgA complexes with RSV surface proteins is the apical recycling endosome, a site in which 80% of the intracellular IgA normally resides. Finally, the investigators will develop novel recombinant bi- specific antibodies that bind to both RSV and human pIgR. The Principal Investigator proposes that such novel antibody fragments will mimic the ability of IgA to enter cells and neutralize RSV, but will be vastly more potent in vivo due to their smaller size and hence better ability to exit the intravascular space following parenteral administration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RISK FACTORS FOR DRUG RESISTANT PNEUMOCOCCAL PNEUMONIA Principal Investigator & Institution: Metlay, Joshua P. Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: Adapted from the Applicant's Abstract): The emergence of antimicrobial drug resistance among isolates of S. pneumoniae threatens to have a major impact on the management of patients with community-acquired pneumonia (CAP). S. pneumoniae is the most common cause of CAP and adequate pneumococcal coverage is at the center of empirical guidelines for the management of this disease. Yet, risk factors for infection with drug-resistant vs. drug-susceptible S. pneumoniae are controversial and the clinical impact of in vitro levels of resistance is poorly understood. This study will focus on resistance to penicillin because penicillin and related ,8-lactam antimicrobials are a major component of current empirical treatment options for patients with CAP. Thus, understanding the risk factors for penicillin resistance can make a major contribution to the empirical management of these patients. The primary aim of this study is to identify risk factors for penicillin drug resistance in patients with bacteremic pneumococcal pneumonia. The primary study hypothesis is that both

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individual and community risk factors independently predict infection with penicillin resistant S. pneumoniae in patients with bacteremic pneumococcal pneumonia. A secondary hypothesis is that the duration of prior antibiotic use is a strong independent predictor of penicillin resistance in these patients. The secondary aims of this study are (1) to develop a prediction rule for penicillin resistance in patients with bacteremic pneumococcal pneumonia and (2) to measure the impact of different levels of penicillin resistance on medical outcomes in these patients. The hypotheses for these secondary aims are that (1) a prediction rule can be developed which accurately categorizes patients into high and low risk groups in order to improve the empirical selection of antimicrobial therapy for patients with CAP and (2) the in vitro level of penicillin resistance, alone, is a poor predictor of medical outcomes, but categorization of the adequacy of antimicrobial drug coverage, based on drug susceptibility profiles and pharmacodynamic drug considerations, will be a strong predictor of medical outcomes. This study is a population-based, case-control study, enrolling all hospitalized patients diagnosed with bacteremic pneumococcal pneumonia within the Pennsylvania Delaware Valley. Risk factors will be identified through patient interview and outpatient and inpatient medical record review. Pneumococcal drug resistance will be categorized at our microbiology laboratory with standardized susceptibility testing of all pneumococcal blood isolates. Finally, a cohort study will be completed within the study design, by examining outcomes for all patients, stratifying by pneumococcal drug susceptibility and adequacy of antimicrobial drug coverage. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF B CELLS IN RESOLUTION OF P CARINII PNEUMONIA Principal Investigator & Institution: Garvy, Beth A. Assistant Professor; Medicine; University of Kentucky 109 Kinkead Hall Lexington, KY 40506 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: Pneumocystis carinii (PC) pneumonia is a significant problem in immunocompromised patients, particularly those with HIV. It has been well documented that the presence of CD4+ T cells is required for resolution PC infections. In addition, it has recently been reported that mice that are deficient in B cells are susceptible to PC (4,9). This is important because AIDS patients have been shown to have B cell defects that may also render them susceptible to PC. Until recently, there have not been good animal models for studying the role of B cells in host defense to infectious diseases. Although B cell deficient mice have proven to be useful, it is not possible to determine whether susceptibility to PC in these mice is due to a lack of natural antibody, PC-specific antibody, or B cell effector functions such as antigen presentation, costimulation of T cells, or cytokine production. The goal of this proposal is to test the hypothesis that B cells play multiple roles in the resolution of PC including activating CD4+ cells through antigen presentation, producing protective antibody, and producing cytokines that lead to resolution of PC pneumonia (PCP). We will utilize existing mice that are transgenic for the B cell receptor as well as generate new murine models including 1) making mixed chimeric mice whose B cells are defective in expression of cytokines or costimulatory molecules and 2) generating new transgenic mice whose B cells express the Herpes Simplex Virus thymidine kinase gene. These new mice will have B cells that are susceptible to killing by ganciclovir. With these murine models we will address the following specific aims: 1) to determine whether B cell-T cell interactions are required for resolution of PCP; 2) to determine whether B cell-produced cytokines are required for the resolution of PC; 3) to determine whether protection against PCP is dependent on specific recognition of PC antigens by the B cells; 4) to

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determine whether natural antibody is required for resolution of PCP; and 5) To determine the kinetic requirements for B cell function in PC infection. Understanding host defense to PC is critical for developing vaccines or efficient therapies for preventing this potentially fatal infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE INFLAMMATION

OF

ENDOTHELIAL

DUFFY

ANTIGEN

IN

LUNG

Principal Investigator & Institution: Lee, Janet S. Medicine; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2007 Summary: (provided by applicant): The major goal of this proposal is to determine the role of Duffy Antigen/ Receptor for Chemokines (DARC) in endothelial cells during lung inflammation. DARC binds multiple CXC and CC chemokines and is expressed on post-capillary venular endothelial cells, the site where leukocytes traverse the endothelium in response to inflammatory signals released from a site of tissue injury. Although endothelial DARC is upregulated during inflammation, its biological function remains unknown. It's focal location at the site of leukocyte emigration, its upregulation during inflammation, and preservation of expression on endothelial cells in all individuals suggest that it may participate in the regulation of inflammatory cell recruitment at the bloodtissue interface. The specific aims will explore the following : (1)endothelial DARC's role in chemokine transport, (2) its ability to modify neutrophil transendothelial migration, (3) its in vivo expression in the lung during suppurative pneumonia, (4) and DARC's contribution to neutrophil recruitment in a mouse model of pneumonia. A human endothelial cell line stably expressing DARC cDNA has been developed to study its ability to modify the biological activity of chemokines in vitro. Immunohistochemical analysis of human lungs will define the expression pattern of endothelial DARC during suppurative pneumonia. Finally, DARC's role will be examined in an animal model of bacterial pneumonia using DARC knockout mice. These studies are important, as they will determine endothelial DARC's contribution to the pulmonary recruitment of neutrophils during lung inflammation. Understanding endothelial DARC's function may provide novel strategies in modifying the inflammatory component of specific diseases such as bacterial pneumonia. These studies will further the candidate's research training in cell and molecular biology and provide the foundation for a career as a physicianscientist. The proposed studies will be conducted at the Pulmonary VA Research laboratories under the guidance of the sponsor and co-sponsor. Interactions with consultants throughout the University of Washington research community will enrich the candidate's training and ensure the success of the proposal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF LYSOZYME IN AIRWAYS HOST DEFENSE Principal Investigator & Institution: Akinbi, Henry T.; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, OH 45229 Timing: Fiscal Year 2002; Project Start 15-FEB-2002; Project End 31-JAN-2007 Summary: Lysozyme is a cationic protein of 146 amino acid residues (Mr approximately 14k) that is bactericidal against multiple gram-positive bacteria in vitro. Although lysozyme is the most abundant antimicrobial protein in airway surface fluid (ASL), its role in protecting the airways against infection, chronic colonization, and inflammation

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in vivo remains unproven. The results of preliminary studies reported in this application demonstrate a dose-dependent relationship between the level of lysozyme activity in bronchoalveolar lavage fluid and the rate of bacterial killing, of both gram positive and negative organisms, in acutely infected transgenic mice that overexpress lysozyme. Studies proposed in this application will test the central hypothesis that lysozyme is a critical component of airway host defense in vivo. Pathogen killing will be assessed in lysozyme (-/-) mice and lysozyme overexpressing mice following acute and chronic lung infection. The antimicrobial spectrum and potency of exogenouslyadministered recombinant lysozyme protein will also be assessed. These studies will provide insight into the role of lysozyme in airway host defense and provide a preliminary assessment of the therapeutic potential of exogenously administered lysozyme. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF SP-A IN INFLAMMATION AFTER ALLOGENEIC BMT Principal Investigator & Institution: Haddad, Imad Y. Associate Professor of Pediatrics; Pediatrics; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, MN 554552070 Timing: Fiscal Year 2001; Project Start 01-MAY-2001; Project End 30-APR-2005 Summary: (Applicant's Abstract): In addition to innate host-defense functions, surfactant protein A (SP-A) suppresses T cell-immune responses in vitro, and may be responsible for the hyporesponsive state of lung lymphocytes in vivo. Recent evidence indicate that donor T cells play a major role in the pathogenesis of non-infectious lung dysfunction after allogeneic bone marrow transplantation (BMT), also referred to as idiopathic pneumonia syndrome (IPS). IPS accounts for up to 40 percent of non-GVHD deaths in allogeneic BMT patients. In a murine IPS model that simulates the human condition, lung dysfunction is dependent on infusion of allogeneic T cells. The most severe lung injury is observed during the generation of severe oxidative/nitrative stress in BMT mice given both allogeneic T cells and cyclophosphamide, a commonly used conditioning drug known to deplete antioxidant defenses. Oxidative/nitrative stress inhibits SP-A production, and can damage SP-A structure and function. Keratinocyte growth factor (KGF), a mediator of epithelial cell-proliferation, enhances SP-A expression and prevents experimental lung injury, but the protective mechanisms are incompletely understood. The role of SP-A and KGF-derived SP-A and the effects of reactive oxygen/nitrogen species on T cell-dependent inflammation and IPS injury in vivo have not been thoroughly investigated. We hypothesize that SP-A protects the lung in vivo from IPS injury by inhibiting allogeneic donor T cell-immune responses. We further hypothesize that injection of cyclophosphamide into T cell-recipient mice injures SP-A-producing cells and prevents upregulation of SP-A expression by the generation of peroxynitrite (ONOO), a potent oxidant and nitrating species. Our hypothesis has been formulated based on strong preliminary data showing that exogenous SP-A downregulates alveolar inflammation in vivo. The rationale for the proposed research is that, once the role of SP-A in T cell-dependent inflammation and repair is established, new and innovative anti-inflammatory and antioxidant approaches to limit IPS injury can be developed. Using our BMT model in normal and gene targeted irradiated mice infused with donor T cells from normal and knockout mice, our hypothesis will be tested by completing the following specific aims: 1. Establish the role and mechanism of SP-A in regulation of alveolar inflammation and IPS injury; 2. Determine the mechanism by which allogeneic T cells and cyclophosphamide increase oxidative/nitrative stress; 3. Define the role of SP-A and oxidative/nitrative stress in the immuno-modulatory effects

134 Pneumonia

of keratinocyte growth factor after allogeneic marrow transplantation. Completion of aims will establish whether exogenous SP-A and upregulation of endogenous SP-A may be utilized as therapeutic options for the treatment of IPS and, potentially, other lifethreatening inflammatory lung diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SCCOR IN TRANSLATIONAL RESEARCH IN ACUTE LUNG INJURY Principal Investigator & Institution: Matthay, Michael A. Professor; Cardiovascular Research Institute; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2008 Summary: (provided by applicant): This is an Acute Lung Injury SCCOR application designed to study the pathogenesis and treatment of early acute lung injury. Although considerable progress has been made in selected areas of research and treatment of clinical acute lung injury, the pathogenesis of clinical lung injury is incompletely understood and mortality remains too high. Clinical and basic research is needed to provide new knowledge regarding fundamental mechanisms of lung injury as well as to test new therapies for acute lung injury (ALl), an important cause of acute respiratory failure in critically ill patients. Project 1 proposes a randomized, double-blind, phase II clinical trial to evaluate the potential efficacy of activated protein C (APC) for the treatment of acute lung injury. This project will also explore mechanistically the contribution of coagulation and inflammation dependent mechanisms to clinical lung injury. Project 2 is a clinical project to investigate the interactions among human genetics, bacterial genetics, and host events in the development of acute lung injury from bacterial pneumonia. This project will test the potential contribution of Mannose Binding Lectin genetic abnormalities as a cause of severe pneumonia and acute lung injury. This project will also test the hypothesis that P.aeruginosa colonization transforms to lung infection (ventilator-associated pneumonia) when the P.aeruginosa strains express type III virulence genes. Project 3 will examine the contribution of coagulation dependent mechanisms in experimental lung injury in mice by studying genetically modified mice as well as testing the impact of recombinant mouse AP C as therapy for experimental lung injury. Project 4 will examine the role of transforming growth factor-beta1 as a pathogenetic mechanism for early experimental acute lung injury, evaluating the mechanisms for TGF-beta1 activation, and also will identify the mechanisms for responsible for the TGF-beta1 induced alterations in alveolar epithelial fluid transport. The administrative and clinical cores (Cores A & B) will support the scientific objective of the projects. The proteomics core (Core C) will provide innovative methods for identifying novel proteins in the bronchoalveolar lavage fluid from patients and animals with acute lung injury, both before and after several treatment strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SEVERE ASTHMA FROM RESPIRATORY INFECTIONS Principal Investigator & Institution: Busse, William W. Professor of Medicine; Medicine; University of Wisconsin Madison 750 University Ave Madison, WI 53706 Timing: Fiscal Year 2001; Project Start 20-SEP-2001; Project End 30-JUN-2006 Summary: (provided by applicant): Chronic severe asthma affects only a subsegment of patients with asthma and is characterized, in part, by persistent airflow obstruction and symptoms despite ongoing treatment. Because of the severity of their disease, this population of asthmatic patients has the greatest morbidity and health care costs. At

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present, the mechanisms that cause severe asthma are not fully established. The overall goal of this research project is to define the features of severe asthma, identify the mechanisms that lead to this phenotype and discover possible inroads for new and more effective therapies. Based upon existing evidence and preliminary data, it is the hypothesis of this research project that severe asthma is caused, in some patients, by a persistent respiratory infection by viruses (i.e. rhinovirus, respiratory syncytial virus, or adenovirus), Mycoplasma pneumonia, or Chlamydia pneumonia. It is further proposed that these agents infect lower airway epithelium and macrophages to enhance the production of inflammatory cytokines/chemokines (i.e. IL-8) and recruitment of inflammatory cells, particularly neutrophils, to further airway injury and airflow obstruction. To accomplish these goals, subjects with severe asthma (i.e. FEV1 or = 75 yrs. Author(s): Lim WS, Macfarlane JT. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2001 February; 17(2): 200-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11334120&dopt=Abstract

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Defining severe community-acquired pneumonia. Author(s): Neuhaus T, Ewig S. Source: The Medical Clinics of North America. 2001 November; 85(6): 1413-25. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11680110&dopt=Abstract

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Defining the potential impact of conjugate bacterial polysaccharide-protein vaccines in reducing the burden of pneumonia in human immunodeficiency virus type 1infected and -uninfected children. Author(s): Madhi SA, Cumin E, Klugman KP. Source: The Pediatric Infectious Disease Journal. 2002 May; 21(5): 393-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12150175&dopt=Abstract

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Deletion allele of the angiotensin-converting enzyme gene as a risk factor for pneumonia in elderly patients. Author(s): Morimoto S, Okaishi K, Onishi M, Katsuya T, Yang J, Okuro M, Sakurai S, Onishi T, Ogihara T. Source: The American Journal of Medicine. 2002 February 1; 112(2): 89-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11835945&dopt=Abstract

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Demystifying idiopathic interstitial pneumonia. Author(s): Collard HR, King TE Jr. Source: Archives of Internal Medicine. 2003 January 13; 163(1): 17-29. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12523913&dopt=Abstract

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Detection and quantification of human herpesvirus 6 genomes using bronchoalveolar lavage fluid in immunocompromised patients with interstitial pneumonia. Author(s): Nagate A, Ohyashiki JH, Kasuga I, Minemura K, Abe K, Yamamoto K, Ohyashiki K. Source: International Journal of Molecular Medicine. 2001 October; 8(4): 379-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11562775&dopt=Abstract

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Detection of antivimentin antibody in sera of patients with idiopathic pulmonary fibrosis and non-specific interstitial pneumonia. Author(s): Yang Y, Fujita J, Bandoh S, Ohtsuki Y, Yamadori I, Yoshinouchi T, Ishida T. Source: Clinical and Experimental Immunology. 2002 April; 128(1): 169-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11982605&dopt=Abstract

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Detection of bronchial breathing caused by pneumonia. Author(s): Gross V, Fachinger P, Penzel T, Koehler U, von Wichert P, Vogelmeier C. Source: Biomed Tech (Berl). 2002 June; 47(6): 146-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12149800&dopt=Abstract

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Detection of Pneumocystis DNA in samples from patients suspected of bacterial pneumonia--a case-control study. Author(s): Helweg-Larsen J, Jensen JS, Dohn B, Benfield TL, Lundgren B. Source: Bmc Infectious Diseases [electronic Resource]. 2002 November 25; 2(1): 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12445330&dopt=Abstract

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Determinants of adult influenza and pneumonia immunization rates. Author(s): Kamal KM, Madhavan SS, Amonkar MM. Source: J Am Pharm Assoc (Wash Dc). 2003 May-June; 43(3): 403-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12836791&dopt=Abstract

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Development and evaluation of a quantitative, touch-down, real-time PCR assay for diagnosing Pneumocystis carinii pneumonia. Author(s): Larsen HH, Masur H, Kovacs JA, Gill VJ, Silcott VA, Kogulan P, Maenza J, Smith M, Lucey DR, Fischer SH. Source: Journal of Clinical Microbiology. 2002 February; 40(2): 490-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11825961&dopt=Abstract

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Development and validation of a multifactorial risk index for predicting postoperative pneumonia after major noncardiac surgery. Author(s): Arozullah AM, Khuri SF, Henderson WG, Daley J; Participants in the National Veterans Affairs Surgical Quality Improvement Program. Source: Annals of Internal Medicine. 2001 November 20; 135(10): 847-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11712875&dopt=Abstract

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Diabetes and rapidly advancing pneumonia. Author(s): Bhansali A, Suresh V, Chaudhry D, Vaiphei K, Dash RJ, Kotwal N. Source: Postgraduate Medical Journal. 2001 November; 77(913): 734-5, 740-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11677289&dopt=Abstract

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Diagnosing and treating atypical pneumonia. Author(s): Smith G, Hosker H. Source: Practitioner. 2001 September; 245(1626): 736-40, 742, 746. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11584587&dopt=Abstract

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Diagnosing pneumonia during mechanical ventilation: the clinical pulmonary infection score revisited. Author(s): Fartoukh M, Maitre B, Honore S, Cerf C, Zahar JR, Brun-Buisson C. Source: American Journal of Respiratory and Critical Care Medicine. 2003 July 15; 168(2): 173-9. Epub 2003 May 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12738607&dopt=Abstract

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Diagnosis and management of pneumonia in the intensive care unit. Author(s): Cardenas VJ Jr. Source: Chest Surg Clin N Am. 2002 May; 12(2): 379-95. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12122830&dopt=Abstract

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Diagnosis of ambulatory community-acquired pneumonia. Comparison of clinical assessment versus chest X-ray. Author(s): Lieberman D, Shvartzman P, Korsonsky I, Lieberman D. Source: Scandinavian Journal of Primary Health Care. 2003 March; 21(1): 57-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12718463&dopt=Abstract

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Diagnosis of gram negative, ventilator associated pneumonia by assaying endotoxin in bronchial lavage fluid. Author(s): Flanagan PG, Jackson SK, Findlay G. Source: Journal of Clinical Pathology. 2001 February; 54(2): 107-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11215277&dopt=Abstract

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Diagnosis of legionellaceae as a cause of community-acquired pneumonia- “. continue to treat first and not bother to ask questions later”--not a good idea. Author(s): Marrie TJ. Source: The American Journal of Medicine. 2001 January; 110(1): 73-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11152873&dopt=Abstract

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Diagnosis of nosocomial pneumonia in medical ward: repeatability of the protected specimen brush. Author(s): Herer B, Fuhrman C, Demontrond D, Gazevic Z, Housset B, Chouaid C. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2001 July; 18(1): 157-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11510788&dopt=Abstract

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Diagnosis of pneumococcal pneumonia by psaA PCR analysis of lung aspirates from adult patients in Kenya. Author(s): Scott JA, Marston EL, Hall AJ, Marsh K. Source: Journal of Clinical Microbiology. 2003 June; 41(6): 2554-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791880&dopt=Abstract

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Diagnosis of pneumococcal pneumonia. Author(s): Leinonen M, Makela PH. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2001 October 15; 33(8): 1440-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11565089&dopt=Abstract

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Diagnosis of pneumonia by community health volunteers: experience of BRAC, Bangladesh. Author(s): Hadi A. Source: Trop Doct. 2001 April; 31(2): 75-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11321276&dopt=Abstract

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Diagnostic and therapeutic management of nosocomial pneumonia in surgical patients: results of the Eole study. Author(s): Montravers P, Veber B, Auboyer C, Dupont H, Gauzit R, Korinek AM, Malledant Y, Martin C, Moine P, Pourriat JL. Source: Critical Care Medicine. 2002 February; 30(2): 368-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11889312&dopt=Abstract

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Diagnostic investigation of ventilator-associated pneumonia using bronchoalveolar lavage: comparative study with a postmortem lung biopsy. Author(s): Balthazar AB, Von Nowakonski A, De Capitani EM, Bottini PV, Terzi RG, Araujo S. Source: Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas / Sociedade Brasileira De Biofisica. [et Al.]. 2001 August; 34(8): 993-1001. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11471037&dopt=Abstract

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Diagnostic value of D dimer in pulmonary embolism and pneumonia. Author(s): Castro DJ, Perez-Rodriguez E, Montaner L, Flores J, Nuevo GD. Source: Respiration; International Review of Thoracic Diseases. 2001; 68(4): 371-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11464083&dopt=Abstract

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Differences in mortality among patients with community-acquired pneumonia in California by ethnicity and hospital characteristics. Author(s): Haas JS, Dean ML, Hung Y, Rennie DJ. Source: The American Journal of Medicine. 2003 June 1; 114(8): 660-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12798454&dopt=Abstract

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Differential role for T cells in the development of fibrotic lesions associated with reovirus 1/L-induced bronchiolitis obliterans organizing pneumonia versus Acute Respiratory Distress Syndrome. Author(s): Majeski EI, Harley RA, Bellum SC, London SD, London L. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 February; 28(2): 208-17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12540488&dopt=Abstract

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Differentiation of bacterial and viral pneumonia in children. Author(s): Virkki R, Juven T, Rikalainen H, Svedstrom E, Mertsola J, Ruuskanen O. Source: Thorax. 2002 May; 57(5): 438-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11978922&dopt=Abstract

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Discontinuation of primary prophylaxis in HIV-infected patients at high risk of Pneumocystis carinii pneumonia: prospective multicentre study. Author(s): Furrer H, Opravil M, Rossi M, Bernasconi E, Telenti A, Bucher H, Schiffer V, Boggian K, Rickenbach M, Flepp M, Egger M; Swiss HIV Cohort Study. Source: Aids (London, England). 2001 March 9; 15(4): 501-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11242147&dopt=Abstract

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Discontinuation of secondary prophylaxis against Pneumocystis carinii pneumonia in patients with HIV infection who have a response to antiretroviral therapy. Eight European Study Groups. Author(s): Ledergerber B, Mocroft A, Reiss P, Furrer H, Kirk O, Bickel M, Uberti-Foppa C, Pradier C, D'Arminio Monforte A, Schneider MM, Lundgren JD; Eight European Study Groups. Source: The New England Journal of Medicine. 2001 January 18; 344(3): 168-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11188837&dopt=Abstract

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Discontinuation of secondary prophylaxis and the risk of Pneumocystis carinii pneumonia. Author(s): Miguez-Burbano MJ, Archer H, Rodriguez M, Shor-Posner G. Source: Aids (London, England). 2003 January 3; 17(1): 140-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12478087&dopt=Abstract

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Discontinuation of secondary prophylaxis for Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients: a randomized trial by the CIOP Study Group. Author(s): Mussini C, Pezzotti P, Antinori A, Borghi V, Monforte A, Govoni A, De Luca A, Ammassari A, Mongiardo N, Cerri MC, Bedini A, Beltrami C, Ursitti MA, Bini T, Cossarizza A, Esposito R; Changes in Opportunistic Prophylaxis (CIOP) Study Group. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 March 1; 36(5): 645-51. Epub 2003 February 12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12594647&dopt=Abstract

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Discontinuing prophylaxis against Pneumocystis carinii pneumonia. Author(s): Le Moal G, Breux JP, Roblot F. Source: The New England Journal of Medicine. 2001 May 24; 344(21): 1639-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11374363&dopt=Abstract

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Discontinuing prophylaxis against Pneumocystis carinii pneumonia. Author(s): Bender MA, Sax PE. Source: The New England Journal of Medicine. 2001 May 24; 344(21): 1639; Author Reply 1640-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11374364&dopt=Abstract

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Disseminated Pseudomonas aeruginosa and necrotizing pneumonia with complete recovery. Author(s): Kumar PD, Ravakhah K, West BC. Source: Southern Medical Journal. 2001 February; 94(2): 229-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11235039&dopt=Abstract

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Distribution of Pneumocystis carinii f. sp. hominis types in the lung of a child dying of Pneumocystis pneumonia. Author(s): Ambrose HE, Ponce CA, Wakefield AE, Miller RF, Vargas SL. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2001 November 1; 33(9): E100-2. Epub 2001 September 24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11568852&dopt=Abstract

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Disturbed surface properties in preterm infants with pneumonia. Author(s): Rudiger M, Friedrich W, Rustow B, Schmalisch G, Wauer R. Source: Biology of the Neonate. 2001 February; 79(2): 73-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11223646&dopt=Abstract

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Do guidelines for community-acquired pneumonia improve the cost-effectiveness of hospital care? Author(s): Nathwani D, Rubinstein E, Barlow G, Davey P. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2001 March 1; 32(5): 728-41. Epub 2001 February 28. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11229840&dopt=Abstract

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Do published guidelines predict pneumonia in children presenting to an urban ED? Author(s): Rothrock SG, Green SM, Fanelli JM, Cruzen E, Costanzo KA, Pagane J. Source: Pediatric Emergency Care. 2001 August; 17(4): 240-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11493820&dopt=Abstract

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Do viridans streptococci cause pneumonia in children? Author(s): Nascimento-Carvalho CM, Brandileone MC, Guerra ML, Di Fabio JL. Source: The Pediatric Infectious Disease Journal. 2001 July; 20(7): 726-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11465856&dopt=Abstract

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Does bronchoalveolar lavage enhance our ability to treat ventilator-associated pneumonia in a trauma-burn intensive care unit? Author(s): Wahl WL, Franklin GA, Brandt MM, Sturm L, Ahrns KS, Hemmila MR, Arbabi S. Source: The Journal of Trauma. 2003 April; 54(4): 633-8; Discussion 638-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12707523&dopt=Abstract

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Does smoking contribute to community acquired pneumonia? Author(s): Peach H, Barnett N. Source: Aust Fam Physician. 2001 January; 30(1): 10. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11211703&dopt=Abstract

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Does the use of fluoroquinolones for the empiric treatment of pneumonia delay initiation of treatment of tuberculosis? Author(s): Abiad H. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 December 15; 35(12): 1572; Author Reply 1572-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12471582&dopt=Abstract

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Dollars and sense in the intensive care unit: the costs of ventilator-associated pneumonia. Author(s): Shorr AF, Wunderink RG. Source: Critical Care Medicine. 2003 May; 31(5): 1582-3. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12771639&dopt=Abstract

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Doppler echocardiographic evaluation of pulmonary artery pressure in children with acute pneumonia. Author(s): Uner A, Caksen H, Arslan S, Abuhandan M, Oner AF, Odabas D. Source: Acta Paediatr Taiwan. 2002 January-February; 43(1): 10-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11890220&dopt=Abstract

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Doxycycline for treatment of community-acquired pneumonia. Author(s): Johnson JR. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 September 1; 35(5): 632; Author Reply 632-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12173142&dopt=Abstract

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Duration of antimicrobial therapy for nosocomial pneumonia: possible strategies for minimizing antimicrobial use in intensive care units. Author(s): Dugan HA, MacLaren R, Jung R. Source: Journal of Clinical Pharmacy and Therapeutics. 2003 April; 28(2): 123-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12713609&dopt=Abstract

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Dying from or with a nosocomial pneumonia in the intensive care unit? Author(s): Carlet J. Source: Critical Care Medicine. 2001 December; 29(12): 2392-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11801851&dopt=Abstract

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Dynamics of cytokines and role of immunocorrection in nosocomial pneumonia. Author(s): Kuznetsov VP, Markelova EV, Silich EV, Belyaev DL, Babayants AA, Kuznetsova SY. Source: Russ J Immunol. 2002 July; 7(2): 151-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12687258&dopt=Abstract

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Early IL-6 plasma concentrations correlate with severity of brain injury and pneumonia in brain-injured patients. Author(s): Woiciechowsky C, Schoning B, Cobanov J, Lanksch WR, Volk HD, Docke WD. Source: The Journal of Trauma. 2002 February; 52(2): 339-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11834998&dopt=Abstract

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Early switch and early discharge strategies in patients with community-acquired pneumonia: a meta-analysis. Author(s): Rhew DC, Tu GS, Ofman J, Henning JM, Richards MS, Weingarten SR. Source: Archives of Internal Medicine. 2001 March 12; 161(5): 722-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11231705&dopt=Abstract

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Early switch from intravenous to oral antibiotics in hospitalized patients with bacteremic community-acquired Streptococcus pneumoniae pneumonia. Author(s): Ramirez JA, Bordon J. Source: Archives of Internal Medicine. 2001 March 26; 161(6): 848-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11268227&dopt=Abstract

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Early trauma polymorphonuclear neutrophil responses to chemokines are associated with development of sepsis, pneumonia, and organ failure. Author(s): Adams JM, Hauser CJ, Livingston DH, Lavery RF, Fekete Z, Deitch EA. Source: The Journal of Trauma. 2001 September; 51(3): 452-6; Discussion 456-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11535890&dopt=Abstract

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Early-onset Pneumocystis carinii pneumonia complicating Norwood II operation in a 3-month-old patient. Author(s): Dittrich S, Grollmuss O, Kruger M, Hentschel R, Mehwald P, Schlensak C, Kececioglu D. Source: Intensive Care Medicine. 2002 November; 28(11): 1685-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12583383&dopt=Abstract

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Eccentric mitral regurgitation can imitate a diagnosis of pneumonia. Author(s): Orgus T, Altinmakus S, Bilgen F. Source: International Journal of Cardiology. 2001 February; 77(2-3): 307-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11393134&dopt=Abstract

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Effect of an education program aimed at reducing the occurrence of ventilatorassociated pneumonia. Author(s): Zack JE, Garrison T, Trovillion E, Clinkscale D, Coopersmith CM, Fraser VJ, Kollef MH. Source: Critical Care Medicine. 2002 November; 30(11): 2407-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12441746&dopt=Abstract

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Effect of continuous lateral rotational therapy on the prevalence of ventilatorassociated pneumonia in patients requiring long-term ventilatory care. Author(s): Kirschenbaum L, Azzi E, Sfeir T, Tietjen P, Astiz M. Source: Critical Care Medicine. 2002 September; 30(9): 1983-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12352030&dopt=Abstract

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Effect of design-related bias in studies of diagnostic tests for ventilator-associated pneumonia. Author(s): Michaud S, Suzuki S, Harbarth S. Source: American Journal of Respiratory and Critical Care Medicine. 2002 November 15; 166(10): 1320-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12421741&dopt=Abstract

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Effect of enriched thioglycolate on direct examination of respiratory specimens and guiding initial empirical therapy in intubated patients with pneumonia: a prospective, randomized study. Author(s): Rello J, Mariscal D, Gallego M, Valles J. Source: Critical Care Medicine. 2002 February; 30(2): 311-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11889300&dopt=Abstract

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Effect of maclorides on duration and resolution of symptoms and complication of pneumonia in children with influenza. Author(s): Ninomiya K, Fukui T, Imai T, Matsui M, Matsuoka K. Source: Journal of Nippon Medical School = Nihon Ika Daigaku Zasshi. 2002 February; 69(1): 53-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11847511&dopt=Abstract

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Effect of pneumonia case management on mortality in neonates, infants, and preschool children: a meta-analysis of community-based trials. Author(s): Sazawal S, Black RE; Pneumonia Case Management Trials Group. Source: The Lancet Infectious Diseases. 2003 September; 3(9): 547-56. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12954560&dopt=Abstract

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Effect of step-down therapy of ceftriaxone plus loracarbef versus parenteral therapy of ceftriaxone on the intestinal microflora in patients with community-acquired pneumonia. Author(s): Vogel F, Ochs HR, Wettich K, Kalich S, Nilsson-Ehle I, Odenholt I, Nord CE. Source: Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 2001 July; 7(7): 376-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11531985&dopt=Abstract

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Effectiveness of 0.12% chlorhexidine gluconate oral rinse in reducing prevalence of nosocomial pneumonia in patients undergoing heart surgery. Author(s): Houston S, Hougland P, Anderson JJ, LaRocco M, Kennedy V, Gentry LO. Source: American Journal of Critical Care : an Official Publication, American Association of Critical-Care Nurses. 2002 November; 11(6): 567-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12425407&dopt=Abstract

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Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia. Author(s): Black SB, Shinefield HR, Ling S, Hansen J, Fireman B, Spring D, Noyes J, Lewis E, Ray P, Lee J, Hackell J. Source: The Pediatric Infectious Disease Journal. 2002 September; 21(9): 810-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12352800&dopt=Abstract

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Effectiveness of oral moxifloxacin in standard first-line therapy in communityacquired pneumonia. Author(s): Torres A, Muir JF, Corris P, Kubin R, Duprat-Lomon I, Sagnier PP, Hoffken G. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2003 January; 21(1): 135-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12570122&dopt=Abstract

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Effectiveness of twice-weekly pyrimethamine-sulfadoxine as primary prophylaxis of Pneumocystis carinii pneumonia and toxoplasmic encephalitis in patients with advanced HIV infection. Author(s): Schurmann D, Bergmann F, Albrecht H, Padberg J, Wunsche T, Grunewald T, Schurmann M, Grobusch M, Vallee M, Ruf B, Suttorp N. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2002 May; 21(5): 353-61. Epub 2002 May 18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12072919&dopt=Abstract

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Effectiveness, safety and tolerability of gatifloxacin, a new 8methoxyfluoroquinolone, in the treatment of outpatients with community-acquired pneumonia: a Brazilian study. Author(s): Franca SA, Carvalho CR. Source: The Brazilian Journal of Infectious Diseases : an Official Publication of the Brazilian Society of Infectious Diseases. 2002 August; 6(4): 157-63. Epub 2003 April 01. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12204182&dopt=Abstract

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Effects of a practice guideline for community-acquired pneumonia in an outpatient setting. Author(s): Suchyta MR, Dean NC, Narus S, Hadlock CJ. Source: The American Journal of Medicine. 2001 March; 110(4): 306-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11239849&dopt=Abstract

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Effects of antibiotics on protected specimen brush sampling in ventilator-associated pneumonia. Author(s): Prats E, Dorca J, Pujol M, Garcia L, Barreiro B, Verdaguer R, Gudiol F, Manresa F. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 May; 19(5): 944-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12030737&dopt=Abstract

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Efficacy and pharmacodynamics of simulated human-like treatment with levofloxacin on experimental pneumonia induced with penicillin-resistant pneumococci with various susceptibilities to fluoroquinolones. Author(s): Croisier D, Chavanet P, Lequeu C, Ahanou A, Nierlich A, Neuwirth C, Piroth L, Duong M, Buisson M, Portier H. Source: The Journal of Antimicrobial Chemotherapy. 2002 September; 50(3): 349-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12205059&dopt=Abstract

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Efficacy and safety of gatifloxacin in elderly outpatients with community-acquired pneumonia. Author(s): Nicholson SC, Wilson WR, Naughton BJ, Gothelf S, Webb CD. Source: Diagnostic Microbiology and Infectious Disease. 2002 September; 44(1): 117-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12376041&dopt=Abstract

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Efficacy and safety of gemifloxacin in the treatment of community-acquired pneumonia: a randomized, double-blind comparison with trovafloxacin. Author(s): File TM Jr, Schlemmer B, Garau J, Cupo M, Young C; 049 Clinical Study Group. Source: The Journal of Antimicrobial Chemotherapy. 2001 July; 48(1): 67-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11474633&dopt=Abstract

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Efficacy and safety of telithromycin in community-acquired pneumonia. Author(s): Van Rensburg DJ, Matthews PA, Leroy B. Source: Current Medical Research and Opinion. 2002; 18(7): 397-400. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12487505&dopt=Abstract

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Efficacy and tolerability of once-daily oral therapy with telithromycin compared with trovafloxacin for the treatment of community-acquired pneumonia in adults. Author(s): Pullman J, Champlin J, Vrooman PS Jr. Source: Int J Clin Pract. 2003 June; 57(5): 377-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12846341&dopt=Abstract

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Efficacy and tolerability of once-daily telithromycin compared with high-dose amoxicillin for treatment of community-acquired pneumonia. Author(s): Hagberg L, Torres A, van Rensburg D, Leroy B, Rangaraju M, Ruuth E. Source: Infection. 2002 December; 30(6): 378-86. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12478329&dopt=Abstract

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Efficacy of amoxicillin-sulbactam, given twice-a-day, for the treatment of communityacquired pneumonia: a clinical trial based on a pharmacodynamic model. Author(s): Jasovich A, Soutric J, Morera G, Mastruzzo M, Vesco E, Izaguirre M, Mobilia L, Prieto S, Franco D, Curcio D, Absi R, Larrateguy L, Bustos JL, Oliva ME, Arenoso H, Bantar C. Source: Journal of Chemotherapy (Florence, Italy). 2002 December; 14(6): 591-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12583551&dopt=Abstract

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Efficacy of cefepime versus ceftazidime in the treatment of adult pneumonia. Author(s): Lin JC, Yeh KM, Peng MY, Chang FY. Source: J Microbiol Immunol Infect. 2001 June; 34(2): 131-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11456359&dopt=Abstract

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Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency. Author(s): Busse PJ, Razvi S, Cunningham-Rundles C. Source: The Journal of Allergy and Clinical Immunology. 2002 June; 109(6): 1001-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12063531&dopt=Abstract

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Efficacy of recombinant human granulocyte colony-stimulating factor in a murine model of pneumococcal pneumonia: effects of lung inflammation and timing of treatment. Author(s): Dallaire F, Ouellet N, Simard M, Bergeron Y, Bergeron MG. Source: The Journal of Infectious Diseases. 2001 January 1; 183(1): 70-7. Epub 2000 November 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11087202&dopt=Abstract

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Elderly trauma patients with rib fractures are at greater risk of death and pneumonia. Author(s): Bergeron E, Lavoie A, Clas D, Moore L, Ratte S, Tetreault S, Lemaire J, Martin M. Source: The Journal of Trauma. 2003 March; 54(3): 478-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12634526&dopt=Abstract

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Electrocardiogram in Pneumocystis carinii pneumonia: can it be used as a prognostic variable? Author(s): Caldera AE, Crespo GJ, Maraj S, Kotler M, Braitman LE, Eiger G. Source: Critical Care Medicine. 2002 July; 30(7): 1425-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12130956&dopt=Abstract

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Elevated KL-6 levels in fatal measles pneumonia. Author(s): Narita M, Nakayama M, Yamada S, Togashi T. Source: European Journal of Pediatrics. 2001 July; 160(7): 454-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11475589&dopt=Abstract

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Elevated levels of thymus- and activation-regulated chemokine in bronchoalveolar lavage fluid from patients with eosinophilic pneumonia. Author(s): Miyazaki E, Nureki S, Fukami T, Shigenaga T, Ando M, Ito K, Ando H, Sugisaki K, Kumamoto T, Tsuda T. Source: American Journal of Respiratory and Critical Care Medicine. 2002 April 15; 165(8): 1125-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11956056&dopt=Abstract

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Elevation of serum KL-6 levels in patients with hematological malignancies associated with cytomegalovirus or Pneumocystis carinii pneumonia. Author(s): Tanaka M, Tanaka K, Fukahori S, Fujimatsu Y, Jojima H, Shiraishi K, Honda J, Oizumi K. Source: Hematology (Amsterdam, Netherlands). 2002 April; 7(2): 105-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12186700&dopt=Abstract

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Elevations in procalcitonin but not C-reactive protein are associated with pneumonia after cardiopulmonary resuscitation. Author(s): Oppert M, Reinicke A, Muller C, Barckow D, Frei U, Eckardt KU. Source: Resuscitation. 2002 May; 53(2): 167-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12009220&dopt=Abstract

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Email recruitment to use web decision support tools for pneumonia. Author(s): Flanagan JR, Peterson M, Dayton C, Strommer Pace L, Plank A, Walker K, Carlson WS. Source: Proceedings / Amia. Annual Symposium. Amia Symposium. 2002; : 255-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12463826&dopt=Abstract

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Emergence of levofloxacin-resistant pneumococci in immunocompromised adults after therapy for community-acquired pneumonia. Author(s): Anderson KB, Tan JS, File TM Jr, DiPersio JR, Willey BM, Low DE. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 August 1; 37(3): 376-81. Epub 2003 July 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12884162&dopt=Abstract

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Emergence of macrolide resistance during treatment of pneumococcal pneumonia. Author(s): Musher DM, Dowell ME, Shortridge VD, Flamm RK, Jorgensen JH, Le Magueres P, Krause KL. Source: The New England Journal of Medicine. 2002 February 21; 346(8): 630-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11856810&dopt=Abstract

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Emerging resistance to antibiotics against respiratory bacteria: impact on therapy of community-acquired pneumonia in children. Author(s): Esposito S, Principi N. Source: Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy. 2002 April; 5(2): 73-87. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12135583&dopt=Abstract

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Empiric treatment of community-acquired pneumonia with fluoroquinolones, and delays in the treatment of tuberculosis. Author(s): Dooley KE, Golub J, Goes FS, Merz WG, Sterling TR. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 June 15; 34(12): 1607-12. Epub 2002 May 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12032896&dopt=Abstract

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Endogenous endophthalmitis and necrotising pneumonia caused by Klebsiella pneumoniae in a child with beta-thalassaemia major. Author(s): Yao TC, Hung IJ, Su LH, Chiu CH. Source: European Journal of Pediatrics. 2001 July; 160(7): 449. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11475586&dopt=Abstract

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Enhanced expression of Duffy antigen in the lungs during suppurative pneumonia. Author(s): Lee JS, Frevert CW, Thorning DR, Segerer S, Alpers CE, Cartron JP, Colin Y, Wong VA, Martin TR, Goodman RB. Source: The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society. 2003 February; 51(2): 159-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12533524&dopt=Abstract

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Enhanced resistancy of thioredoxin-transgenic mice against influenza virus-induced pneumonia. Author(s): Nakamura H, Tamura S, Watanabe I, Iwasaki T, Yodoi J. Source: Immunology Letters. 2002 June 3; 82(1-2): 165-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12008049&dopt=Abstract

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Enteral naloxone reduces gastric tube reflux and frequency of pneumonia in critical care patients during opioid analgesia. Author(s): Meissner W, Dohrn B, Reinhart K. Source: Critical Care Medicine. 2003 March; 31(3): 776-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12626983&dopt=Abstract

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Eosinophilic pneumonia after administration of fludarabine for the treatment of nonHodgkin's lymphoma. Author(s): Trojan A, Meier R, Licht A, Taverna C. Source: Annals of Hematology. 2002 September; 81(9): 535-7. Epub 2002 August 01. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12373357&dopt=Abstract

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Eosinophilic pneumonia in an infant. Author(s): Makimoto A, Pearson MG, Jaffe N, Colasurdo GN. Source: Medical and Pediatric Oncology. 2002 January; 38(1): 75-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11835248&dopt=Abstract

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Eotaxin and monocyte chemoattractant protein-1 in chronic eosinophilic pneumonia. Author(s): Tateno H, Nakamura H, Minematsu N, Amakawa K, Terashima T, Fujishima S, Luster AD, Lilly CM, Yamaguchi K. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2001 May; 17(5): 962-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11488333&dopt=Abstract

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Epidemiologic trends in the hospitalization of elderly Medicare patients for pneumonia, 1991-1998. Author(s): Baine WB, Yu W, Summe JP. Source: American Journal of Public Health. 2001 July; 91(7): 1121-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11441742&dopt=Abstract

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Epidemiology and impact of aspiration pneumonia in patients undergoing surgery in Maryland, 1999-2000. Author(s): Kozlow JH, Berenholtz SM, Garrett E, Dorman T, Pronovost PJ. Source: Critical Care Medicine. 2003 July; 31(7): 1930-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12847385&dopt=Abstract

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Epidemiology and outcomes of ventilator-associated pneumonia in a large US database. Author(s): Rello J, Ollendorf DA, Oster G, Vera-Llonch M, Bellm L, Redman R, Kollef MH; VAP Outcomes Scientific Advisory Group. Source: Chest. 2002 December; 122(6): 2115-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12475855&dopt=Abstract

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Epidemiology of pneumonia hospitalizations in Spain, 1995-1998. Author(s): Gil A, San-Martin M, Carrasco P, Gonzalez A. Source: The Journal of Infection. 2002 February; 44(2): 84-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12076066&dopt=Abstract

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Estimated frequency of nursing facility-acquired pneumonia? Author(s): Metersky M, Angus DC, Linde-Zwirble WT. Source: American Journal of Respiratory and Critical Care Medicine. 2003 May 1; 167(9): 1287-8; Author Reply 1288. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12714345&dopt=Abstract

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Etanercept (Enbrel) administration for idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation. Author(s): Yanik G, Hellerstedt B, Custer J, Hutchinson R, Kwon D, Ferrara JL, Uberti J, Cooke KR. Source: Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. 2002; 8(7): 395-400. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12171486&dopt=Abstract

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Etiological diagnosis of childhood pneumonia by use of transthoracic needle aspiration and modern microbiological methods. Author(s): Vuori-Holopainen E, Salo E, Saxen H, Hedman K, Hyypia T, Lahdenpera R, Leinonen M, Tarkka E, Vaara M, Peltola H. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 March 1; 34(5): 583-90. Epub 2002 January 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11803504&dopt=Abstract

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Etiology and management of community-acquired pneumonia in Asia. Author(s): Matsushima T, Miyashita N, File TM Jr. Source: Current Opinion in Infectious Diseases. 2002 April; 15(2): 157-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11964917&dopt=Abstract

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Etiology of childhood community acquired pneumonia and its implications for vaccination. Author(s): Nascimento-Carvalho CM. Source: The Brazilian Journal of Infectious Diseases : an Official Publication of the Brazilian Society of Infectious Diseases. 2001 April; 5(2): 87-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11493414&dopt=Abstract

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Etiology of severe pneumonia in the very elderly. Author(s): El-Solh AA, Sikka P, Ramadan F, Davies J. Source: American Journal of Respiratory and Critical Care Medicine. 2001 March; 163(3 Pt 1): 645-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11254518&dopt=Abstract

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Etiology, reasons for hospitalization, risk classes, and outcomes of communityacquired pneumonia in patients hospitalized on the basis of conventional admission criteria. Author(s): Roson B, Carratala J, Dorca J, Casanova A, Manresa F, Gudiol F. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2001 July 15; 33(2): 158-65. Epub 2001 June 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11418874&dopt=Abstract

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European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.7.1 Late infections. Pneumocystis carinii pneumonia. Author(s): EBPG Expert Group on Renal Transplantation. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2002; 17 Suppl 4: 369. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12091642&dopt=Abstract

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Evaluation of a PCR assay for detection of Streptococcus pneumoniae in respiratory and nonrespiratory samples from adults with community-acquired pneumonia. Author(s): Murdoch DR, Anderson TP, Beynon KA, Chua A, Fleming AM, Laing RT, Town GI, Mills GD, Chambers ST, Jennings LC. Source: Journal of Clinical Microbiology. 2003 January; 41(1): 63-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12517826&dopt=Abstract

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Evaluation of children with recurrent pneumonia diagnosed by World Health Organization criteria. Author(s): Heffelfinger JD, Davis TE, Gebrian B, Bordeau R, Schwartz B, Dowell SF. Source: The Pediatric Infectious Disease Journal. 2002 February; 21(2): 108-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11840076&dopt=Abstract

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Evaluation of endotoxin release and cytokine production induced by antibiotics in patients with Gram-negative nosocomial pneumonia. Author(s): Maskin B, Fontan PA, Spinedi EG, Gammella D, Badolati A. Source: Critical Care Medicine. 2002 February; 30(2): 349-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11889308&dopt=Abstract

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Evaluation of nonresolving and progressive pneumonia. Author(s): Menendez R, Perpina M, Torres A. Source: Seminars in Respiratory Infections. 2003 June; 18(2): 103-11. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12840791&dopt=Abstract

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Evaluation of outcomes in community-acquired pneumonia: a guide for patients, physicians, and policy-makers. Author(s): Barlow GD, Lamping DL, Davey PG, Nathwani D. Source: The Lancet Infectious Diseases. 2003 August; 3(8): 476-88. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901890&dopt=Abstract

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Evaluation of panipenem/betamipron (PAPM/BP) in pneumonia in elderly patients. Author(s): Shibuya Y, Kitamura S, Tani G, Fukushima Y, Yatagai S, Nakamoto T, Motojima S. Source: Journal of Infection and Chemotherapy : Official Journal of the Japan Society of Chemotherapy. 2002 June; 8(2): 151-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12111568&dopt=Abstract

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Evaluation of the immunochromatographic Binax NOW assay for detection of Streptococcus pneumoniae urinary antigen in a prospective study of communityacquired pneumonia in Spain. Author(s): Gutierrez F, Masia M, Rodriguez JC, Ayelo A, Soldan B, Cebrian L, Mirete C, Royo G, Hidalgo AM. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 February 1; 36(3): 286-92. Epub 2003 January 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12539069&dopt=Abstract

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Evidence based medicine: review of BTS guidelines for the management of community acquired pneumonia in adults. Author(s): Mckean MC. Source: The Journal of Infection. 2002 November; 45(4): 213-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12423607&dopt=Abstract

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Evidence of type II pneumocyte apoptosis in the pathogenesis of idiopathic pulmonary fibrosis (IFP)/usual interstitial pneumonia (UIP). Author(s): Barbas-Filho JV, Ferreira MA, Sesso A, Kairalla RA, Carvalho CR, Capelozzi VL. Source: Journal of Clinical Pathology. 2001 February; 54(2): 132-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11215282&dopt=Abstract

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Evidence-based guidelines for management of nursing home-acquired pneumonia. Author(s): Hutt E, Kramer AM. Source: The Journal of Family Practice. 2002 August; 51(8): 709-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12184969&dopt=Abstract

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Exhaled breath condensate and serum levels of hepatocyte growth factor in pneumonia. Author(s): Nayeri F, Millinger E, Nilsson I, Zetterstrom, Brudin L, Forsberg P. Source: Respiratory Medicine. 2002 February; 96(2): 115-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11860168&dopt=Abstract

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Exogenous lipoid pneumonia following ingestion of liquid paraffin. Author(s): Ohwada A, Yoshioka Y, Shimanuki Y, Mitani K, Kumasaka T, Dambara T, Fukuchi Y. Source: Intern Med. 2002 June; 41(6): 483-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12135184&dopt=Abstract

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Exogenous lipoid pneumonia with unusual CT pattern and FDG positron emission tomography scan findings. Author(s): Tahon F, Berthezene Y, Hominal S, Blineau N, Guerin JC, Cinotti L, Marchand B. Source: European Radiology. 2002 December; 12 Suppl 3: S171-3. Epub 2002 October 01. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12522633&dopt=Abstract

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Experience with a clinical guideline for the treatment of ventilator-associated pneumonia. Author(s): Ibrahim EH, Ward S, Sherman G, Schaiff R, Fraser VJ, Kollef MH. Source: Critical Care Medicine. 2001 June; 29(6): 1109-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11395584&dopt=Abstract

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Exposure to allogeneic plasma and risk of postoperative pneumonia and/or wound infection in coronary artery bypass graft surgery. Author(s): Vamvakas EC, Carven JH. Source: Transfusion. 2002 January; 42(1): 107-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11896321&dopt=Abstract

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Exposure to metal fume and infectious pneumonia. Author(s): Palmer KT, Poole J, Ayres JG, Mann J, Burge PS, Coggon D. Source: American Journal of Epidemiology. 2003 February 1; 157(3): 227-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12543622&dopt=Abstract

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Factors associated with death among adults = 13 Years Old) With Pneumocystis carinii Pneumonia Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): U.S. Bioscience Purpose - Excerpt: To evaluate the safety and efficacy of trimetrexate glucuronate with leucovorin protection in European patients with Pneumocystis carinii pneumonia (PCP) who are refractory to or have demonstrated severe or life-threatening toxicities to standard therapies (e.g., TMP/SMX or parenteral pentamidine). Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002103

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A Compassionate Treatment Protocol for the Use of Trimetrexate Glucuronate With Leucovorin Protection for Patients With Pneumocystis carinii Pneumonia. Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): U.S. Bioscience Purpose - Excerpt: To provide trimetrexate glucuronate to immunosuppressed patients with Pneumocystis carinii pneumonia (PCP) for whom this investigational compound could provide significant medical benefit. Study Type: Interventional Contact(s): see Web site below

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Web Site: http://clinicaltrials.gov/ct/show/NCT00002102 •

A Controlled Comparative Trial of Trimethoprim - Sulfamethoxazole Versus Aerosolized Pentamidine for Secondary Prophylaxis of Pneumocystis carinii Pneumonia in AIDS Patients Receiving Azidothymidine (AZT) Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose Excerpt: To determine if the drug combination trimethoprim/sulfamethoxazole (TMP/SMX), given by mouth, and the drug pentamidine (PEN), given by inhaled aerosol, are effective in preventing a relapse of Pneumocystis carinii pneumonia (PCP) when they are given to patients who have recovered from a first episode of PCP and are being given zidovudine (AZT) to treat primary HIV infection. AZT prolongs survival in patients with AIDS and decreases the occurrence of opportunistic infections such as PCP. However, PCP recurs in about 43 percent of patients receiving AZT, indicating a need for other treatments to reduce the relapse rate. The two medications to be tested in this study, TMP / SMX, and aerosolized PEN, have also been partially effective in preventing recurrence of PCP. It is hoped that the combination of AZT with these medications will be more effective than AZT or one of the medications alone. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000727

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A Controlled Trial Comparing the Efficacy of Aerosolized Pentamidine and Parenteral / Oral Trimethoprim - Sulfamethoxazole in the Treatment of Pneumocystis carinii Pneumonia in AIDS Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): LyphoMed Purpose - Excerpt: This is a randomized double-blinded controlled study comparing aerosolized pentamidine with trimethoprim plus sulfamethoxazole (TMP / PurposeX). The latter drug will be administered intravenously for at least 5 days, then changed to oral administration if warranted by the patient's clinical condition. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002056

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A Controlled Trial Comparing the Efficacy of Aerosolized Pentamidine and Parenteral/Oral Trimethoprim-Sulfamethoxazole in the Treatment of Pneumocystis carinii Pneumonia in AIDS Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed.

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Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: To compare the safety and effectiveness of drug therapy with aerosolized pentamidine (PEN) with that of conventional therapy, trimethoprim plus sulfamethoxazole (TMP / SMX) in the treatment of Pneumocystis carinii pneumonia (PCP) in patients who have AIDS, are HIV positive, or are at high risk for HIV infection. New treatments are needed for PCP, a common lung infection in patients with AIDS, because many patients treated with the two standard treatments, PEN given by injections and TMP / SMX, have had adverse effects that required a change in treatment. There is also a high relapse rate after the standard treatments. Preliminary experiments in humans suggest that aerosolized PEN is as effective as the standard treatments for PCP, and causes few adverse effects. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000715 •

A Double-Blind Group Comparative Study To Evaluate the Long-Term Safety and Effectiveness of Two Different Doses of Aerosol Pentamidine in the Prophylaxis of Pneumocystis carinii Pneumonia in AIDS Patients With Multiple Episodes of PCP Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): Fisons Purpose - Excerpt: To evaluate and compare the safety, tolerability, and effectiveness of long-term biweekly administration of 1 of 2 doses of aerosol pentamidine when used as a prophylactic agent in patients who have had multiple episodes of AIDS associated Pneumocystis carinii pneumonia (PCP). Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002055

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A Double-Blind Placebo-Controlled Group Comparative Study To Evaluate the Safety and Effectiveness of Aerosol Pentamidine in the Prophylaxis of Pneumocystis carinii Pneumonia in Patients With AIDS Post First Episode PCP Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): Fisons Purpose - Excerpt: To evaluate and compare the safety, tolerability, and efficacy of biweekly administration of aerosol pentamidine versus placebo when used as a prophylactic agent in patients who have recovered from their first episode of AIDSassociated Pneumocystis carinii pneumonia (PCP). Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002053

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A Double-Blind Study To Evaluate the Long-Term Safety and Effectiveness of 60 mg Versus 120 mg of Aerosol Pentamidine in the Prophylaxis of Pneumocystis carinii Pneumonia in AIDS Patients Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): Fisons Purpose - Excerpt: To evaluate the safety, tolerability, and description of time to Pneumocystis carinii pneumonia (PCP) for long-term biweekly administration of 1 of 2 doses of aerosol pentamidine when used as a prophylactic agent in patients who have had one episode of AIDS-associated PCP. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002054

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A Phase II Open Randomized Comparison of 566C80 and Pentamidine Isethionate for the Treatment of Pneumocystis carinii Pneumonia in AIDS Patients Who are Intolerant of Trimethoprim / Sulfamethoxazole Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): Glaxo Wellcome Purpose - Excerpt: To compare the safety of atovaquone (566C80) with intravenous (IV) pentamidine for the treatment of mild to moderate Pneumocystis carinii pneumonia (PCP) in AIDS patients who are intolerant of therapy with trimethoprim / sulfamethoxazole (TMP / SMX) by comparing the incidence of premature discontinuation of therapy due to toxicity. To compare the efficacy of 566C80 with intravenous (IV) pentamidine for the treatment of mild to moderate PCP in the same population. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001996

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A Randomized, Double-Blind Study of 566C80 Versus Septra (Trimethoprim/Sulfamethoxazole) for the Treatment of Pneumocystis carinii Pneumonia in AIDS Patients Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID); Glaxo Wellcome Purpose - Excerpt: To evaluate the effectiveness of atovaquone (566C80) compared to a standard antipneumocystis agent, trimethoprim/sulfamethoxazole (TMP / SMX), for the treatment of mild to moderate Pneumocystis carinii pneumonia (PCP) in AIDS patients. To compare the safety of short-term (21 days) treatment with 566C80 and TMP / SMX in AIDS patients with an acute episode of PCP. Standard therapies for acute treatment of PCP involve either TMP/SMX or pentamidine isetionate. Although both

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treatments are equally effective, side effects prevent completion of therapy in 11-55 percent of patients. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000655 •

A Randomized, Double-Blind, Placebo Controlled Study of l-Leucovorin in Combination With Trimethoprim / Sulfamethoxazole in the Therapy of Pneumocystis carinii Pneumonia in Patients with the Acquired Immunodeficiency Syndrome Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): Lederle Laboratories Purpose - Excerpt: The primary objective of the study is to evaluate the effectiveness of l-leucovorin in preventing toxicity from high dose trimethoprim / sulfamethoxazole (TMP / SMX) used as a therapy for Pneumocystis carinii pneumonia (PCP) in patients with AIDS. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002002

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A Study of Neutrexin Plus Leucovorin in the Treatment of Pneumocystis Carinii Pneumonia (PCP) Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): U.S. Bioscience Purpose - Excerpt: To evaluate the safety and efficacy of trimetrexate glucuronate with leucovorin protection in patients with Pneumocystis carinii pneumonia (PCP) who are refractory to or have demonstrated severe or life-threatening toxicities to standard therapies (e.g., TMP/SMX or parenteral pentamidine). Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002434

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A Study of Pentamidine in the Prevention of Pneumocystis Carinii Pneumonia Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: To evaluate and compare 3 anti-pneumocystis regimens plus zidovudine (AZT) in persons with advanced HIV disease and T4 cell count < 200 cells/mm3. To establish the range of pentamidine (PEN) deposition in AIDS patients participating in ACTG 021 and ACTG 081. To identify factors (breathing pattern, pulmonary function) that may be important in affecting the actual dose delivered to a

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given patient. The specific system that is used to deliver PEN to the lungs may determine whether a therapeutically effective dose is attained in the lungs. Therefore, this study will establish the amount of PEN that is deposited in the lungs of patients enrolled in protocols ACTG 021 and ACTG 081, who are being treated with PEN administered from the Marquest Respirgard II nebulizer. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001003 •

A Study of Pentamidine in the Prevention of Pneumocystis Carinii Pneumonia (PCP) in HIV-Infected Children Who Cannot Take Trimethoprim-Sulfamethoxazole Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID); Fujisawa Pharmaceutical Purpose - Excerpt: Primary: To compare the pharmacokinetics of biweekly and monthly dose regimens of intravenous pentamidine in HIV-infected infants and children who require PCP prophylaxis and who are intolerant to oral trimethoprim sulfamethoxazole. To determine the safety and tolerance of these regimens in this patient population. Secondary: To obtain information on the rate of PCP breakthrough in infants and children receiving parenteral pentamidine prophylaxis. Prophylaxis against Pneumocystis carinii pneumonia is recommended for all HIV-infected children considered to be at high risk. In children younger than 5 years of age with intolerance to trimethoprim - sulfamethoxazole, parenteral pentamidine may be a successful alternative. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001027

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A Study of Pentamidine Plus Dapsone in the Prevention of Pneumocystis Carinii Pneumonia (PCP) in HIV-Infected Patients Who Cannot Take Trimethoprim or Sulfonamides Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is terminated. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID); Jacobus Pharmaceutical; Fujisawa Pharmaceutical Purpose - Excerpt: To compare the safety and efficacy of aerosolized pentamidine and dapsone in the prevention of Pneumocystis carinii pneumonia (PCP) in high-risk HIVinfected patients who are intolerant to trimethoprim and/or sulfonamides. Both aerosolized pentamidine and dapsone have been shown to prevent PCP, but both drugs cause side effects. This study attempts to determine which drug is more efficacious as prophylaxis against PCP in patients who cannot tolerate trimethoprim/sulfamethoxazole. Phase(s): Phase III

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Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001028 •

A Study of Trimetrexate in the Treatment of Pneumocystis carinii Pneumonia (PCP) in Patients with AIDS Not Previously Treated for PCP Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: To evaluate the safety and effectiveness of trimetrexate (TMTX) given at increasing doses along with the leucovorin calcium (LCV) for treating Pneumocystis carinii pneumonia (PCP) in AIDS patients TMTX is an experimental new drug which is effective for treatment of PCP, but has been given to only a few patients. Therefore it is not certain if TMTX is better, the same as, or not as effective as conventional drugs against PCP. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000998

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A Study of Trimetrexate Plus Leucovorin in Children with Pneumocystis Carinii Pneumonia Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): U.S. Bioscience Purpose - Excerpt: To evaluate the safety and efficacy of trimetrexate glucuronate with leucovorin protection in pediatric patients with Pneumocystis carinii pneumonia (PCP) who are refractory to or have demonstrated severe or life-threatening toxicities to standard therapies (e.g., TMP/SMX or parenteral pentamidine). Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002317

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A Study of Trimetrexate With Leucovorin Rescue for AIDS Patients Who Are Refractory to Standard Therapies for Pneumocystis carinii Pneumonia Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: To study the safety and effectiveness of trimetrexate (TMTX) plus leucovorin calcium rescue (LCV) in the treatment of Pneumocystis carinii pneumonia (PCP) in patients who have AIDS, patients who are HIV positive, or those for whom laboratory confirmation of HIV infection has not yet been established if they are at high risk for HIV infection, and who have not responded to standard treatments or who have

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demonstrated severe or life-threatening intolerance to both conventional therapies for PCP. The drugs trimethoprim / sulfamethoxazole (TMP / SMX) and pentamidine, usually used to treat PCP in AIDS patients, have proven ineffective in many patients and have had to be discontinued in many other patients because of severe side effects. TMTX was chosen for this trial because it was found to be very active against the PCP organism in laboratory tests and, in a preliminary trial in combination with LCV, there was a high response rate without severe toxicity. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000724 •

A Study of Two Forms of Pentamidine in HIV-Infected Children Who May Have Pneumocystis carinii Pneumonia Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: To evaluate the delivery of a single dose of aerosolized pentamidine to children; to evaluate the tolerance of pentamidine administration by mask; to compare intravenous pentamidine first dose pharmacokinetics (blood levels) in children with information previously collected on adults; and to compare plasma pentamidine levels in children after an aerosolized treatment with levels previously collected on adults. Pneumocystis carinii pneumonia (PCP) is the most common serious infection in children with AIDS and is associated with a high death rate. Current approved treatment includes intravenous trimethoprim - sulfamethoxazole (TMP / SMX) and intravenous pentamidine, which are both effective in treatment of the first episode of PCP pneumonia. However, both therapies have a 50 percent or greater incidence of adverse reactions. Because of serious toxicities, drug treatment has had to be discontinued. Animal studies show that aerosolized pentamidine (pentamidine given through inhalation) is as effective as intravenous pentamidine. It is hoped that the aerosolized route will be less toxic than intravenous pentamidine. The study is the first step in evaluating the delivery of aerosolized pentamidine to children. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000974

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A Study of Two Forms of Pentamidine in the Treatment of Pneumocystis carinii Pneumonia (PCP) in Patients with AIDS Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): LyphoMed Purpose - Excerpt: To compare parenteral versus inhaled pentamidine in patients with documented Pneumocystis carinii pneumonia (PCP) with AIDS. Study Type: Interventional

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Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002292 •

A Study of WR 6026 in the Treatment of Pneumocystis carinii Pneumonia (PCP) in HIV-Infected Patients Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: To evaluate the efficacy of WR 6026 once daily in the treatment of mild PCP. To evaluate the safety and tolerance of WR 6026. To assess the correlation between plasma WR 6026 concentrations and outcome/toxicity. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000863

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A Study to Evaluate the Impact of Stopping Treatment for the Prevention of Pneumonia in HIV-Positive Patients Receiving Anti-HIV Drugs Who Have Increased CD4 Cell Counts Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: The purpose of this study is to see how often Pneumocystis carinii pneumonia (PCP) occurs in HIV-positive patients who have stopped taking medications that help prevent PCP. The risk of developing PCP may be decreased when an HIVpositive patient's CD4 cell counts (cells of the immune system which fight infection) are more than 200 cells/mm3. This study looks at whether it is acceptable to stop PCP prevention treatment in these patients. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000908

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A Treatment IND for 566C80 Therapy of Pneumocystis carinii Pneumonia Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): Glaxo Wellcome Purpose - Excerpt: To facilitate provision of atovaquone (566C80) to patients who have mild to moderate Pneumocystis carinii pneumonia (PCP) and are intolerant and/or unresponsive to trimethoprim / sulfamethoxazole (TMP / SMX ); to monitor serious adverse events attributable to 566C80. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001991

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Aerosols in the Treatment of Asymptomatic Pneumocystis Pneumonia: A Pilot Study Assessing the Effectiveness of Aerosolized Pentamidine as Treatment of Subclinical Pneumocystis Infection in Patients With No Clinical Symptoms Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: To confirm the ability of pulmonary (lung) function testing (PFT) to detect Pneumocystis carinii pneumonia (PCP) before the development of clinical symptoms and to determine if pentamidine (PEN), a drug used in treating PCP, can be given effectively as an aerosol (inhaled mist). Other goals include the measurement of the actual amount of PEN that reaches the lung, and to determine if close clinical observation is safer and as effective as drug therapy for the prevention of subsequent episodes of PCP. Many AIDS patients develop PCP, but the effectiveness of early diagnosis and treatment of PCP is not known. The effectiveness of PEN may be improved if treatment is begun when the parasite burden (the number of organisms in the lung) is still small, and before respiratory symptoms appear. If PFT of HIV-infected patients is able to identify patients in the early stages of infection, outpatient treatment of these patients offers a possible alternative to the expense and toxicity of continuous preventive therapy of all high-risk patients. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000707

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Aerosols in the Treatment of Pneumocystis Pneumonia: A Pilot Study Quantitating the Deposition of Aerosolized Pentamidine as Delivered in ACTG 040 and Comparing Its Toxicity With Parenteral Pentamidine Therapy Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: To compare the use of pentamidine aerosol (inhaled mist) with the standard intravenous method of administration in patients with AIDS related Pneumocystis carinii pneumonia (PCP), to measure the amount of pentamidine aerosol that actually reaches the lung, and to see if close clinical observation is safer and as effective as drug therapy in the prevention of PCP recurrences. To compare the efficiency of 2 nebulizers - the Respirgard II nebulizer and the Cadema Aerotech II nebulizer. Aerosolized pentamidine was as effective as intravenous pentamidine in treating PCP in animals. More of the pentamidine reached the lungs and less was found in the liver and kidney after pentamidine was given by aerosol than after an intravenous injection. This suggests that the toxicity of pentamidine may be less if given by aerosol than if given by the intravenous route. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000722

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An Open Label Study to Evaluate the Long-Term Safety and Effectiveness of Aerosol Pentamidine in the Prophylaxis of Pneumocystis carinii Pneumonia in AIDS Patients Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): Fisons Purpose - Excerpt: To evaluate the safety, tolerability, and efficacy of long term, biweekly administration of aerosol pentamidine when used as a prophylactic agent in patients who have had at least two or more episodes of AIDS-associated Pneumocystis carinii pneumonia (PCP). Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002030

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An Open, Prospective, Multicenter Study of Trimetrexate With Leucovorin Rescue for AIDS Patients With Pneumocystis carinii Pneumonia (PCP) and Serious Intolerance to Approved Therapies Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: To determine the safety and effectiveness of an investigational drug therapy (trimetrexate plus leucovorin calcium (TMTX / LCV)) in the treatment of Pneumocystis carinii pneumonia (PCP) in patients who have AIDS, are HIV positive, or are at high risk for HIV infection, and who have suffered severe or life-threatening ill effects from both conventional therapies for PCP. AMENDED: 08/01/90 As of August 31, 1989, 437 patients were enrolled into uncontrolled studies of trimetrexate for PCP:214 in TX 301/ACTG 0=039 (trimetrexate for patients intolerant of approved therapies) and 223 in NS 401 (trimetrexate for patients refractory to approved therapies). The analysis of overall response rate, stringently defined as having received at least 14 days of trimetrexate and being alive at follow-up 1 month after the completion of therapy, reveals 84/159 intolerant patients and 48/160 refractory patients had responded, for rates of 53 percent and 30 percent, respectively. These response rates include all individuals who received at least one dose of trimetrexate. Of the 111 patients who were ventilator-dependent at study entry, 18 completed a course of therapy and were alive a month later, for a response rate of 16 percent. All other ventilated patients died. The most common severe (grades 3 and 4) toxicities were: transaminase elevation (> 5 x normal) in 94 patients, anemia (< 7.9 g/dl) in 109, neutropenia (< 750 cells/mm3) in 58, fever (> 40 C) in 37, and thrombocytopenia (< 50000 platelets/mm3) in 27. Toxicity required discontinuation of therapy in approximately 5 percent of all patients. Original design: The drugs usually used to treat PCP in AIDS patients, trimethoprim / sulfamethoxazole and pentamidine, have had to be discontinued in many patients because of severe side effects. Currently there are no proven alternatives to these drugs. TMTX was chosen for this trial because it was found to be very active against the PCP organism in laboratory tests. Also TMTX, in combination with LCV, had a high response rate and did not cause severe toxicity in a preliminary trial. Phase(s): Phase III Study Type: Interventional

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Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000714 •

An Open-Label, Uncontrolled Clinical Trial of Oral 566C80 for the Treatment of Patients with Severe PCP Who Are Intolerant and/or Unresponsive to Therapy with Trimethoprim/Sulfamethoxazole and Parenteral Pentamidine Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): Glaxo Wellcome Purpose - Excerpt: To facilitate provision of atovaquone (566C80) to patients who have severe Pneumocystis carinii pneumonia (PCP) and are intolerant and/or unresponsive to trimethoprim / sulfamethoxazole ( TMX / SMX ); to monitor serious adverse events attributable to 566C80. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001990

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Comparison of Three Treatments for Pneumocystis Pneumonia in AIDS Patients Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is terminated. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: This study compares three different therapies for treatment of refractory Pneumocystis carinii pneumonia (PCP) in patients with AIDS. "Refractory" means that the patient has failed to respond to at least 4 days of treatment with either of two standard therapies: (1) trimethoprim / sulfamethoxazole (TMP / SMX) or (2) pentamidine (PEN). This study compares therapy with trimetrexate (TMTX) and leucovorin (LCV) to standard therapy and standard therapy plus high-dose steroids (methylprednisolone). The purpose is to find better and safer forms of treatment for PCP in AIDS patients. There is at present no scientific information about the best treatment for an AIDS patient with PCP who is not improving while receiving the standard therapies (TMP / SMX or PEN). New drug treatments are available, including steroid therapy and TMTX, but there is no information proving that these new treatments work better than the standard therapies. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000730

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Comparison of Trimetrexate Plus Leucovorin Calcium Rescue Versus TrimethoprimSulfamethoxazole in the Treatment of Pneumocystis carinii Pneumonia (PCP) in Patients with AIDS Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID)

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Purpose - Excerpt: To compare the safety and effectiveness of an investigational drug therapy (trimetrexate plus leucovorin calcium) with that of conventional therapy (trimethoprim plus sulfamethoxazole) in the treatment of moderately severe Pneumocystis carinii pneumonia (PCP) in patients who have AIDS, are HIV positive, or are at high risk for HIV infection. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001013 •

Comparison of Two Dosage Regimens of Oral Dapsone for Prophylaxis of Pneumocystis carinii Pneumonia in Pediatric HIV Infection Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): Jacobus Pharmaceutical; National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: Primary: To compare the toxicity of daily versus weekly dapsone in HIV-infected infants and children; to study the pharmacokinetics of orally administered dapsone in HIV-infected infants and children. Secondary: To obtain information on the rate of Pneumocystis carinii pneumonia ( PCP ) breakthrough in children receiving two different dose regimens of dapsone. Prophylaxis for Pneumocystis carinii pneumonia ( PCP ) is recommended for all HIV-infected children considered to be at high risk. Approximately 15 percent of children are intolerant to trimethoprim / sulfamethoxazole, the first choice drug for PCP prophylaxis. Since many children are also unable to take or tolerate aerosolized pentamidine, dapsone is a second choice for PCP prophylaxis. The most favorable dose regimen for dapsone has not been established. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000739

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Dapsone 100 mg Versus 50 as Primary Prophylaxis for Pneumocystis carinii Pneumonia (PCP) in Patients With AIDS-Related Complex (ARC) Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): Jacobus Pharmaceutical Purpose - Excerpt: To determine which of 2 doses of dapsone is effective prophylaxis for Pneumocystis carinii pneumonia (PCP) in patients with oral thrush or hairy leukoplakia and less than 400 CD4 lymphocytes per mm3. To determine whether the long-term toxicities associated with daily dapsone in this population are tolerable. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002043

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Effects of Hormone Therapy on the Immune Systems of Postmenopausal Women with Chronic Infections Condition(s): Atherosclerosis; Chlamydia Infections; Cytomegalovirus Infections; Pneumonia, Bacterial; Postmenopause Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Hardening of the arteries (atherosclerosis) and heart disease are much more common in men than in women. However, as women grow older, especially after menopause the incidence of atherosclerosis and heart disease increases. These findings suggest that estrogen may be protective and help in preventing heart disease. Studies of large groups of post-menopausal women suggest that hormone replacement therapy (therapy that includes estrogen) reduces the risk of heart disease. Estrogen causes favorable changes in particles that carry cholesterol in the blood stream and improves function of blood vessels. Estrogen may also stimulate the immune system's ability to fight off infections that may lead to or contribute to atherosclerosis. Researchers believe two specific infectious agents (Chlamydia pneumoniae and human cytomegalovirus) may cause damage to the lining of blood vessels resulting in inflammation and the development of atherosclerosis. The purpose of this study is to determine if estrogen treatment can change how the immune system responds to chronic infections, by Chlamydia pneumoniae and human cytomegalovirus, in postmenopausal women. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001890

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Gradual Initiation of Trimethoprim/Sulfamethoxazole as Primary Pneumocystis carinii Pneumonia Prophylaxis Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID); Glaxo Wellcome Purpose Excerpt: To determine whether gradual initiation of trimethoprim/sulfamethoxazole (TMP/SMX) reduces the incidence of treatmentlimiting adverse reactions compared to the routine initiation of the drugs for Pneumocystis carinii pneumonia (PCP) prophylaxis in HIV-infected patients. Although a number of clinical trials have demonstrated the superiority of TMP/SMX for PCP prophylaxis, the incidence of adverse reactions to this medication is high. In a pilot study in which patients were initiated with TMP/SMX prophylaxis by gradually increasing the dose over 2 weeks, no significant adverse reactions have occurred. Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000816

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Intravenous azithromycin plus intravenous ceftriaxone followed by oral azithromycin with intravenous levofloxacin followed by oral levofloxacin for the treatment of moderate to severely ill hospitalized patients with community acquired pneumonia. Condition(s): Pneumonia Study Status: This study is completed. Sponsor(s): Pfizer Purpose - Excerpt: A trial in which patients over 18 years of age who are hospitalized with community acquired pneumonia and are otherwise eligible for entry into the study are randomly selected to receive one of two treatment regimens. After written informed consent is obtained, patients will receive one of the following two treatment regimens: 1) intravenous administration of azithromycin and ceftriaxone followed by azithromycin tablets, or 2) intravenous administration of levofloxacin followed by levofloxacin tablets. At least four study visits are normally conducted up to approximately one month after starting therapy. The objective of this study is to compare the safety and efficacy of the two treatment regimens. Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00035347

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New Antibiotic to treat patients with community-acquired pneumonia due to a specific bacteria (S. pneumoniae pneumonia) Condition(s): Pneumonia, Pneumococcal; Community Acquired Infections; GramPositive Bacterial Infections Study Status: This study is completed. Sponsor(s): (Sponsor Name Pending) Purpose - Excerpt: This study will treat patients who have a community-acquired pneumonia that is due to a specific bacteria (S. pneumoniae) Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00035269

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Randomized Phase I Study of Trimetrexate Glucuronate (TMTX) With Leucovorin (LCV) Protection Plus Dapsone Versus Trimethoprim / Sulfamethoxazole (TMP/SMX) for Treatment of Moderately Severe Episodes of Pneumocystis carinii Pneumonia Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): U.S. Bioscience; Jacobus Pharmaceutical Purpose - Excerpt: To evaluate the safety of the combination of trimetrexate glucuronate (TMTX) and dapsone with leucovorin protection versus trimethoprim/sulfamethoxazole (TMP/SMX) in patients with AIDS and moderately severe Pneumocystis carinii pneumonia (PCP). To determine the pharmacokinetic

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parameters of TMTX, leucovorin, and dapsone and of TMP/SMX when given to patients with AIDS and moderately severe PCP. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002120 •

The Safety and Effectiveness of Methylprednisolone in the Treatment of Pneumocystis carinii Pneumonia (PCP) in Children with AIDS Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is terminated. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID); Upjohn Purpose - Excerpt: To determine the effect of methylprednisolone on respiratory failure in HIV-infected patients with presumed or confirmed pneumocystis carinii pneumonia who are stratified for presence or absence of respiratory failure at the time of randomization to the study. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000741

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The Safety and Effectiveness of Pentamidine in the Prevention of Pneumocystis carinii Pneumonia (PCP) in Patients with AIDS Who Have Had PCP Before Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): Fisons Purpose - Excerpt: To evaluate and compare the safety, tolerability, and efficacy of biweekly administration of 1 of 3 doses of aerosol pentamidine when used as a prophylactic agent in patients who have recovered from their first episode of AIDSassociated Pneumocystis carinii pneumonia (PCP). Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002291

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The Safety and Efficacy of Clindamycin and Primaquine in the Treatment of Mild Moderate Pneumocystis carinii Pneumonia in Patients With AIDS Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: To determine the safety and effectiveness of clindamycin and primaquine in the treatment of mild Pneumocystis carinii pneumonia (PCP) in AIDS patients. As many as 80 percent of AIDS patients experience at least one episode of PCP and about one-third of these patients have a recurrence of the disease. Drugs currently

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used for treatment of acute PCP are toxic to the majority of AIDS patients. The combination of clindamycin and primaquine reduces the numbers of PCP organisms in laboratory tests and in animal studies. Both drugs can be given orally, concentrate in lung tissue, and have been used safely in humans for treatment of other diseases. It is possible that the combination may prove to be as good or better than standard therapy for PCP and side effects may be less. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000717 •

Trimetrexate Plus Leucovorin Calcium Rescue Versus TrimethoprimSulfamethoxazole in the Treatment of Pneumocystis carinii Pneumonia (PCP) in Patients with AIDS Condition(s): Pneumonia, Pneumocystis carinii; HIV Infections Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: To compare the safety and effectiveness of an investigational drug therapy (trimetrexate plus leucovorin calcium) with that of conventional therapy (trimethoprim plus sulfamethoxazole) in the treatment of moderately severe Pneumocystis carinii pneumonia (PCP) in patients who have AIDS, are HIV positive, or are at high risk for HIV infection. New treatments are needed to reduce the mortality rate from PCP in AIDS patients and to reduce the high relapse rate found after conventional therapy. Trimetrexate (TMTX) was chosen for this trial because it was found to be much more potent than trimethoprim / sulfamethoxazole (TMP / SMX) against the PCP organism in laboratory tests. Also TMTX, in combination with leucovorin (LCV), did not cause severe toxicity in a preliminary trial. It is believed that TMTX will be more effective in treating PCP and in preventing a recurrence of PCP. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001014

Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “pneumonia” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical

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trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/

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For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html

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For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/

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For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm

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For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm

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For trials on aging, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm

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For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp

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For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm

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For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/

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For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm

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For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm

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For trials on diseases of the digestive system and kidneys, and diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases: http://www.niddk.nih.gov/patient/patient.htm

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For drug abuse trials, visit and search the Web site sponsored by the National Institute on Drug Abuse: http://www.nida.nih.gov/CTN/Index.htm

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For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm

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For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials

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CHAPTER 6. PATENTS ON PNEUMONIA Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.9 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “pneumonia” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on pneumonia, we have not necessarily excluded nonmedical patents in this bibliography.

Patents on Pneumonia By performing a patent search focusing on pneumonia, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an 9Adapted

from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

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example of the type of information that you can expect to obtain from a patent search on pneumonia: •

Aspiration screening process for assessing post surgery patient's risk for pneumonia Inventor(s): Addington; W. Robert (118 Tradewinds Terrace, Indialantic, FL 32903), Stephens; Robert E. (5224 N.W. Bluff Dr., Parkville, MO 64152) Assignee(s): none reported Patent Number: 6,004,268 Date filed: April 21, 1998 Abstract: Whether a post surgery intubated patient is at risk for aspiration-based pneumonia is determined by requiring the patient to inhale an aerosol of tartaric acid that will stimulate a sensory innervation of the patient's larynx, if functionally recovered, thereby causing the patient to cough. The resulting cough or lack of cough is graded to determine whether the patient is at risk for pneumonia caused by the aspiration of matter present in the patient's mouth. In a further embodiment, the inability or difficulty of a patient to voluntarily expel potentially threatening fluid and matter from the patient's airway can be remedied by repeated applications of the aerosol chemostimulant spray. Excerpt(s): The present invention relates in general to the field of post surgery patient recovery, and is particularly directed to an involuntary cough-based process for determining whether a patient, who has undergone general anesthesia, is at risk for developing aspiration-based pneumonia. This is accomplished by causing the patient to inhale an aerosol chemostimulant that will stimulate a fully functional (recovered) sensory innervation of the patient's larynx, causing the patient to involuntarily cough. If the patient fails to cough, however, it is inferred that the patient's involuntary cough reflex is not yet fully functional, and that the patient is at risk of developing aspirationbased pneumonia. Any patient who is to be given a general anesthetic for a surgical procedure is intubated prior to surgery. The anesthetic effectively pharmacologically suppresses brainstem function, inluding a variety of involuntary physiological responses, not the least of which is the ability to cough and clear the upper airway. These brainstem reflexes are suppressed until the anesthetic wears off. Because the tubing that has been inserted into the patient's airway tends to act like a wick--drawing fluid (e.g., secreted saliva) that may be present in the patient's mouth into the patient's airway and lungs--it is critical that the patient's involuntary cough reflex be fully functional at the time the patient is extubated. Unfortunately, there is currently no mechanism for accurately determining whether or not the patient's ability to involuntarily clear the airway has been fully restored. Instead, because each patient's anesthesia recovery time is different, the standard medical practice is to have a skilled medical practitioner (e.g., anesthesiologist) observe the patient, and then make an `educated guess` that the patient's anesthetic state has completely subsided, and that it is `reasonably safe` to extubate the patient, and allow the patient to receive fluids and/or nutrients by mouth. If the patient's involuntary cough reflex is not yet fully restored, however, the patient is at considerable risk of developing pneumonia, as a result of entry into the airway from the patient's mouth of what would otherwise be expelled secretion and/or foreign matter that could be a substrate for breeding bacteria. Web site: http://www.delphion.com/details?pn=US06004268__

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Compositions and treatments for pneumonia in animals Inventor(s): Potter; Andrew A. (Saskatoon, CA) Assignee(s): University of Saskatchewan (Saskatoon, CA) Patent Number: 5,849,531 Date filed: May 31, 1995 Abstract: New proteins and subunit antigens from P. haemolytica for use in stimulating immunity against respiratory diseases such as pneumonia, including shipping fever pneumonia, are disclosed. The subunit antigens include immunogenic amino acid sequences of P. haemolytica fimbrial protein, P. haemolytica plasmin receptor protein, and P. haemolytica 50K outer membrane protein and P. haemolytica leukotoxin. The antigens can be used in a vaccine composition, either alone or in combination. Also disclosed are methods of vaccination as well as methods of making the subunit antigens employed in the vaccines. Excerpt(s): The present invention relates generally to subunit antigens, vaccine compositions, and methods of administering the same. More particularly, the present invention relates to Pasteurella haemolytica proteins for use in stimulating immunity against pneumonia. Respiratory disease affecting feedlot cattle causes tremendous losses yearly to the cattle industry. Calves are the most severely affected, and a large number of these calves die. This disease is associated with pathogenic microorganisms, particularly Pasteurellae species, and various stresses, such as transportation and overcrowding. Shipping fever is the most economically important respiratory disease associated with Pasteurella species. The disease is characterized by sudden onset, usually within two weeks of stress. The symptoms include dyspnea, cough, ocular and nasal discharge, inappetance and rapid weight loss, fever, increased lung sounds, immunosuppression, general depression, viral and/or bacterial infection of the lungs. Various bacteria and viruses have been isolated from affected animals including Pasteurella spp., bovine herpes virus 1, parainfluenza-3 virus, bovine respiratory syncytial virus and Mycoplasma species. The disease typically affects 15-30% of exposed animals and the resulting deaths are typically 2-5% of the exposed population. Web site: http://www.delphion.com/details?pn=US05849531__

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Diamidines and bis(imidazolines) for the treatment of and prophylaxis against pneumocystis carinii pneumonia Inventor(s): Hall; James E. (Chapel Hill, NC), Geratz; Dieter J. (Chapel Hill, NC), Tidwell; Richard R. (Chapel Hill, NC), Ohemeng; Kwasi A. (Clinton, NJ) Assignee(s): University of North Carolina at Chapel Hill (Chapel Hill, NC) Patent Number: 4,933,347 Date filed: October 25, 1988 Abstract: Certain new diamidine and bis(imidazoline) compounds having activity against Pneumocystis carinii pneumonia are disclosed along with formulations and methods for treating Pneumocystis carinii pneumonia employing said compounds. Excerpt(s): This application relates, in general, to methods for treating Pneumocystis carinii pneumonia and in particular to new compounds which are pharmaceutically active against Pneumocystis carinii, to pharmaceutical formulations containing such compounds, and to methods for the treatment of, and prophylaxis against,

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Pneumocystis carinii pneumonia. Pentamidine, in the form of its hydrochloride salt, was first discovered by Ewins et al., as shown in U.S. Pat. No. 2,277,861, and water-soluble salts were subsequently developed as shown by U.S. Pat. No. 2,410,796 to Newberry et al, which is directed to such water soluble salts, particularly the hydroxy-ethane sulfonic acid and the hydroxy-propane sulfonic acid salts of pentamidine. The former compound is generally referred to as pentamidine isethionate. Pentamidine isethionate is presently marketed by LyphoMed, Inc. under the trademark Pentam, for intravenous and intramuscular injection, and is indicated for the treatment of pneumonia due to Pneumocystis carinii, the latter ailment typically being referred as "PCP". The importance of pentamidine isethionate has dramatically escalated recently due to the marked increase of patients suffering from PCP. The increase in the afflicted patient population is an unfortunate consequence of the increasing presence of the Acquired Immunodeficiency Syndrome ("AIDS"). It is now estimated that approximately 70 percent of AIDS patients contract PCP. Because of the high incidence of PCP in AIDS patients, pentamidine isethionate has found utility not only in the treatment of PCP, but also for prophylaxis, in preventing or delaying the initial onset or recurrence of PCP, especially in AIDS patients. Web site: http://www.delphion.com/details?pn=US04933347__ •

Method for the control of shipping fever pneumonia in cattle Inventor(s): Irwin; Michael R. (New City, NY) Assignee(s): American Cyanamid Co. (Stamford, CT) Patent Number: 4,282,210 Date filed: December 20, 1979 Abstract: There is provided a method for the control of shipping fever pneumonia in cattle, comprising administering to said cattle an immunizing amount of an infectious bovine rhinotracheitis virus vaccine and a potentiating amount of a potentiator therefor, selected from the group consisting of pharmaceutically acceptable salts of dl 6-phenyl2,3,5,6-tetrahydroimidazo[2,1-b]thiazole and pharmaceutically acceptable salts of 1(-)6phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole. This invention also relates to a method for reducing morbidity associated with shipping fever pneumonia in cattle by the parenteral treatment of said cattle with from 2 mg/kg to 8 mg/kg of animal body weight of a pharmaceutically acceptable salt of dl 6-phenyl-2,3,5,6tetrahydroimidazo[2,1-b]thiazole or 1(-)6-phenyl-2,3,5,6-tetrahydroimidazo[2,1b]thiazole and a prophylactically effective amount of infectious bovine rhinotracheitis virus vaccine. Excerpt(s): Shipping fever is generally recognized, by those involved in the beef cattle industry, as the disease responsible for a major portion of the economic losses encountered in the production and handling of cattle. The syndrome is characterized clinically by fever, acute inflammation of the airways, nasal discharge, anorexia, depression, fibrimous pneumonia, necrosis of the tissues involved, and is a major cause of death among young cattle. The disease is most frequently encountered in feedlots following shipping and is responsible for an estimated annual loss to the industry of one hundred million dollars. This loss is directly attributable to mortality associated with the disease, the high costs of prophylaxis and treatment, the loss of weight and condition, and incomplete recovery from the disease which results in poorer weight gains. The pathogenesis of shipping fever is generally considered to involve adverse external influences predisposing to the initiation of a viral respiratory infection which, in turn,

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produces a pabulum favorable for the proliferation of bacteria. Previous research has concentrated on the prevention of the disease by vaccine development, changes in management procedures, and antibiotic therapy. Some improvements in these areas have been made as a result of this research, however, no entirely satisfactory method for inhibiting and/or treating shipping in cattle has, heretofore, been disclosed. It is therefore an object of this invention to provide a method for the prophylactic treatment of cattle subject to stress, viral infection and/or bacterial infection, to inhibit and/or prevent the development of shipping fever in said cattle. Web site: http://www.delphion.com/details?pn=US04282210__ •

Method for treating pneumocystis carinii pneumonia patients with clindamycin and primaquine Inventor(s): Smith; James W. (Indianapolis, IN), Queener; Sherry F. (Indianapolis, IN), Bartlett; Marilyn S. (Indianapolis, IN) Assignee(s): Indiana University Foundation (Bloomington, IN) Patent Number: 4,835,140 Date filed: August 20, 1987 Abstract: The combination of clindamycin and primaquine or pharmaceutical salts thereof is effective in treating patients with Pneumocystis carinii pneumonia. Excerpt(s): This invention is a novel treatment of patients having Pneumocystis carinii pneumonia. Clindamycin and primaquine are drugs that have been used extensively in humans. Clindamycin is an lincosamide antibiotic active against a variety of bacteria including aerobic gram positive cocci, anaerobic gram negative bacilli, anaerobic gram positive nonspore-forming bacilli, and anaerobic and microaerophilic cocci. The preparation of clindamycin is given by Magerlein, et al., in Anti-microbial Agents and Chemotherapy, 727 (1966). Clindamycin also has activity against malarial parasites although the exact effect on plasmodia is not known. The drug is rapidly and virtually completely absorbed after oral dosage and distributes well into body fluids and tissues. Primaquine is a potent anti-malarial agent now used mainly for radical cure of vivax malaria. The preparation of primaquine is given by Elderfield, et al., in Journal of the American Chemical Society, 4816 (1955). The drug is rapidly absorbed after oral dosage and has extensive tissue distribution. An estimated one to one and one-half million people in the United States are infected with a human retrovirus, the human immunodeficiency virus type I, HIV-1, which is the etiological agent of acquired immunodeficiency syndrome, AIDS, Norman, C., Science, 661-662 (1986). Of those infected, an estimated two hundred and fifty thousands people will develop AIDS in the next five years, Curran, J.W., et al., Science, 1352-1357 (1985). Pneumocystis carinii pneumonia is the most common life threatening infection in patients with aids. The infection occurs at least once in as many as eighty percent of AIDS patients and about one third of the total number of episodes of pneumocystis carinii pneumonia are fatal. Fewer than one half of the AIDS patients treated with conventional drugs, either trimethoprim/sulfamethoxazole or pentamidine, are able to complete a full course of therapy because a majority of these patients develop one or more serious adverse reactions such as severe rash, neutropenia, thrombocytopenia, anemia, liver disfunction, renal failure or disturbances in serum glucose, calcium or sodium levels. Web site: http://www.delphion.com/details?pn=US04835140__

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Method of diagnosing and treating increased risk of death from community-acquired pneumonia associated with the a allele of the TNF.alpha.-238 polymorphism Inventor(s): Wunderink; Richard Glenn (8363 Barncliff Cove, Germantown, TN 38139), Waterer; Grant William (3/13 Hayes Ave., Yokine 6060, AU) Assignee(s): none reported Patent Number: 6,294,339 Date filed: December 21, 2000 Abstract: This invention relates to diagnostic methods based upon a particular genotype in the Tumor Necrosis Factor (TNF.alpha.) gene, more specifically, GA or AA at the -238 site rather than the GG at this locus. More specifically, this invention relates to a method for diagnosis of increased risk of death in patients with community-acquired pneumonia (CAP) and diagnosing pre-disposition or susceptibility to increased risk of death in patients who develop CAP, by screening for the presence of this polymorphism. The invention also relates to compositions for screening for the polymorphism and improved treatment choices for patients having the polymorphism of the present invention. The invention also relates to screening assays and therapeutic and prophylactic methods. Excerpt(s): This invention relates to diagnostic methods based upon a particular genotype in the Tumor Necrosis Factor (TNF.alpha.) gene, more specifically, a guanine (G) to adenine (A) transition at the -238 site in one of the TNF.alpha. genes giving a GA (or adenine adenine genotype, AA) genotype rather than the GG genotype at this locus. More specifically, this invention relates to a method for diagnosis of increased risk of death in patients with community-acquired pneumonia (CAP) and diagnosing predisposition or susceptibility to increased risk of death in patients who develop CAP, by screening for the presence of this A allele risk polymorphism. The invention also relates to compositions for screening for the polymorphism and improved treatment choices for patients having the polymorphism of the present invention. The invention also relates to screening assays and therapeutic and prophylactic methods. Pneumonia is a common clinical entity, particularly among the elderly. A thorough understanding of the epidemiology and microbiology of community-acquired pneumonia (CAP) is essential for appropriate diagnosis and management. Although the microbiology of CAP has remained relatively stable over the last decade, there is new information on the incidence of atypical pathogens, particularly in patients not admitted to hospital, and new information on the incidence of pathogens in cases of severe CAP and in CAP in the elderly. Recent studies have provided new data on risk factors for mortality in CAP, which can assist the clinician in decisions about the need for hospital admission. The emergence of antimicrobial resistance in Streptococcus pneumonia, the organism responsible for most cases of CAP, has greatly affected the approach to therapy, especially in those patients who are treated empirically. Guidelines for the therapy of CAP have been published by the American Thoracic Society, the British Thoracic Society, and, most recently, the Infectious Diseases Society of America and others. These guidelines differ in their emphasis on empirical versus pathogenic-specific management. The past 20 years has seen an explosion in our knowledge of human immunology and we are only now beginning to explore the therapeutic possibilities this has made available. The next 10 years promises to finally provide a significant advance in the therapy of pneumonia, the first substantial gain since penicillin. Web site: http://www.delphion.com/details?pn=US06294339__

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Method of preventing Pneumocystis carinii pneumonia using pentamidine in an aerosol form Inventor(s): Armstrong; Donald (New York, NY), Bernard; Edward M. (New York, NY) Assignee(s): Sloan-Kettering Institute for Cancer Research (New York, NY) Patent Number: 5,262,157 Date filed: December 20, 1988 Abstract: Pneumocystis carinii pneumonia may be prevented in a subject susceptible to infection by Pneumocystis carinii by administering to the subject an amount of a pentamidine in aerosol form effective to prevent infection by Pneumocystis carinii and thus prevent Pneumocystis carinii pneumonia. Also, this invention provides a composition for the prevention of Pneumocystis carinii pneumonia which comprises an amount of a pentamidine effective to prevent infection by Pneumocystis carinii and thus prevent Pneumocystis carinii pneumonia in aerosol form and a pharmaceutically acceptable carrier. Excerpt(s): Throughout this application various publications are referenced by numbers within parentheses. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. Pneumocystis carinii pneumonia (PCP) is the most common life-threatening opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS). There is no safe and effective prophylaxis for this infection in patients with AIDS. Prevention of PCP would mean a reduction in mortality, morbidity, and medical costs. Treatment of the infection is costly, facilities for its diagnosis and treatment are scarce, and the number of people at risk is increasing. Pneumonia due to Pneumocystis carinii occurs in patients with AIDS and in cancer and organ transplant patients. The infection has also been seen in epidemics among premature and malnourished infants. The report in 1981 of PCP in otherwise healthy male homosexuals signaled the emergence of the AIDS epidemic (1). More than 65% of AIDS patients develop PCP (2). In many cases the development of PCP is the first sign of immune dysfunction and thus provides the basis for the diagnosis of AIDS. Web site: http://www.delphion.com/details?pn=US05262157__

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Methods of combating Pneumocystis carinii pneumonia and compounds useful therefor Inventor(s): Tidwell; Richard R. (Chapel Hill, NC), Dykstra; Christine C. (Chapel Hill, NC), Tidwell; Richard R. (Chapel Hill, NC), Hall; James E. (Chapel Hill, NC), Hall; James E. (Chapel Hill, NC), Dykstra; Christine C. (Chapel Hill, NC), Tidwell; Richard R. (Chapel Hill, NC), Dykstra; Christine C. (Chapel Hill, NC), Tidwell; Richard R. (Chapel Hill, NC), Hall; James E. (Chapel Hill, NC), Hall; James E. (Chapel Hill, NC), Dykstra; Christine C. (Chapel Hill, NC) Assignee(s): The University of North Carolina at Chapel Hill (Chapel Hill, NC), The University of North Carolina at Chapel Hill (Chapel Hill, NC), The University of North Carolina at Chapel Hill (Chapel Hill, NC), The University of North Carolina at Chapel Hill (Chapel Hill, NC) Patent Number: 5,578,631 Date filed: April 24, 1995 Abstract: Disclosed is a method of combating Pneumocystis carinii Pneumonia in a subject in need of such treatment. The method comprises administering to to the subject an effective Pneumocystis carinii-combating amount of a bis-benzimidazole compound such as bis[5-(2-imidazolyl)-2-benzimidazolyl]methane, 1,4-bis[5-2-imidazolyl)-2benzimidazolyl]butane, or a pharmaceutically acceptable salt thereof. Pharmaceutical formulations for carrying out the method and novel compounds are also disclosed, along with methods of combating Giardia lamblia. Excerpt(s): The present invention relates to methods of combatting Pneumocystis carinii Pneumonia with bis-benzimidazoles, and novel bis-benzimidazoles useful therefore. The present invention relates to methods of combatting Pneumocystis carinii Pneumonia with bis-benzimidazoles, and novel bis-benzimidazoles useful therefore. The present invention relates to methods of combatting Pneumocystis carinii Pneumonia with bis-benzimidazoles, and novel bis-benzimidazoles useful therefore. The present invention relates to methods of combatting Pneumocystis carinii Pneumonia with bis-benzimidazoles, and novel bis-benzimidazoles useful therefore. Pentamidine, in the form of its hydrochloride salt, was first discovered by Ewins et al., as shown in U.S. Pat. No. 2,277,861, and water-soluble salts were subsequently developed as shown by U.S. Pat. No. 2,410,796 to Newberry et al, which is directed to such water soluble salts, particularly the hydroxy-ethane sulfonic acid and the hydroxypropane sulfonic acid salts of pentamidine. the former compound is generally referred to as pentamidine isethionate. Pentamidine, in the form of its hydrochloride salt, was first discovered by Ewins et al., as shown in U.S. Pat. No. 2,277,861, and water-soluble salts were subsequently developed as shown by U.S. Pat. No. 2,410,796 to Newberry et al, which is directed to such water soluble salts, particularly the hydroxy-ethane sulfonic acid and the hydroxy-propane sulfonic acid salts of pentamidine. the former compound is generally referred to as pentamidine isethionate. Pentamidine, in the form of its hydrochloride salt, was first discovered by Ewins et al., as shown in U.S. Pat. No. 2,277,861, and water-soluble salts were subsequently developed as shown by U.S. Pat. No. 2,410,796 to Newberry et al, which is directed to such water soluble salts, particularly the hydroxy-ethane sulfonic acid and the hydroxy-propane sulfonic acid salts of pentamidine. the former compound is generally referred to as pentamidine isethionate. Pentamidine, in the form of its hydrochloride salt, was first discovered by Ewins et al., as shown in U.S. Pat. No. 2,277,861, and water-soluble salts were subsequently developed as shown by U.S. Pat. No. 2,410,796 to Newberry et al, which is directed to such water soluble salts, particularly the hydroxy-ethane sulfonic acid and

Patents 367

the hydroxy-propane sulfonic acid salts of pentamidine. the former compound is generally referred to as pentamidine isethionate. Pentamidine isethionate is presently marketed by LyphoMed, Inc. under the trademark Pentam, for intravenous and intramuscular injection, and is indicated for the treatment of pneumonia due to Pneumocystis carinii, the latter ailment typically being referred as "PCP". The importance of pentamidine isethionate has dramatically escalated recently due to the marked increase of patients suffering from PCP. The increase in the afflicted patient population is an unfortunate consequence of the increasing presence of the Acquired Immunodeficiency Syndrome ("AIDS"). It is now estimated that approximately 70 percent of AIDS patients contract PCP. Because of the high incidence of PCP in AIDS patients, pentamidine isethionate has found utility not only in the treatment of PCP, but also of prophylaxis, in preventing or delaying the initial onset or recurrence of PCP, especially in AIDS patients. Pentamidine isethionate is presently marketed by LyphoMed, Inc. under the trademark Pentam, for intravenous and intramuscular injection, and is indicated for the treatment of pneumonia due to Pneumocystis carinii, the latter ailment typically being referred as "PCP". The importance of pentamidine isethionate has dramatically escalated recently due to the marked increase of patients suffering from PCP. The increase in the afflicted patient population is an unfortunate consequence of the increasing presence of the Acquired Immunodeficiency Syndrome ("AIDS"). It is now estimated that approximately 70 percent of AIDS patients contract PCP. Because of the high incidence of PCP in AIDS patients, pentamidine isethionate has found utility not only in the treatment of PCP, but also of prophylaxis, in preventing or delaying the initial onset or recurrence of PCP, especially in AIDS patients. Pentamidine isethionate is presently marketed by LyphoMed, Inc. under the trademark Pentam, for intravenous and intramuscular injection, and is indicated for the treatment of pneumonia due to Pneumocystis carinii, the latter ailment typically being referred as "PCP". The importance of pentamidine isethionate has dramatically escalated recently due to the marked increase of patients suffering from PCP. The increase in the afflicted patient population is an unfortunate consequence of the increasing presence of the Acquired Immunodeficiency Syndrome ("AIDS"). It is now estimated that approximately 70 percent of AIDS patients contract PCP. Because of the high incidence of PCP in AIDS patients, pentamidine isethionate has found utility not only in the treatment of PCP, but also of prophylaxis, in preventing or delaying the initial onset or recurrence of PCP, especially in AIDS patients. Pentamidine isethionate is presently marketed by LyphoMed, Inc. under the trademark Pentam, for intravenous and intramuscular injection, and is indicated for the treatment of pneumonia due to Pneumocystis carinii, the latter ailment typically being referred as "PCP". The importance of pentamidine isethionate has dramatically escalated recently due to the marked increase of patients suffering from PCP. The increase in the afflicted patient population is an unfortunate consequence of the increasing presence of the Acquired Immunodeficiency Syndrome ("AIDS"). It is now estimated that approximately 70 percent of AIDS patients contract PCP. Because of the high incidence of PCP in AIDS patients, pentamidine isethionate has found utility not only in the treatment of PCP, but also of prophylaxis, in preventing or delaying the initial onset or recurrence of PCP, especially in AIDS patients. Web site: http://www.delphion.com/details?pn=US05578631__

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Patent Applications on Pneumonia As of December 2000, U.S. patent applications are open to public viewing.10 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to pneumonia: •

Aspiration Screening Process For Assessing Post Surgery Patient's Risk For Pneumonia Inventor(s): Stephens, Robert E. (Parkville, MO), Addington, W. Robert; (Indialantic, FL) Correspondence: Law Offices of Charles E Wands; 5240 Babcock Street NE; Suite 211; Palm Bay; FL; 32905 Patent Application Number: 20020104529 Date filed: November 18, 1999 Abstract: Whether a post surgery intubated patient is at risk for aspiration-based pneumonia is determined by requiring the patient to inhale an aerosol of tartaric acid that will stimulate a sensory innervation of the patient's larynx, if functionally recovered, thereby causing the patient to cough. The resulting cough or lack of cough is graded to determine whether the patient is at risk for pneumonia caused by the aspiration of matter present in the patient's mouth. In a further embodiment, the inability or difficulty of a patient to voluntarily expel potentially threatening fluid and matter from the patient's airway can be remedied by repeated applications of the aerosol chemostimulant spray. Excerpt(s): The present invention relates in general to the field of post surgery patient recovery, and is particularly directed to an involuntary cough-based process for determining whether a patient, who has undergone general anesthesia, is at risk for developing aspiration-based pneumonia. This is accomplished by causing the patient to inhale an aerosol chemostimulant that will stimulate a fully functional (recovered) sensory innervation of the patient's larynx, causing the patient to involuntarily cough. If the patient fails to cough, however, it is inferred that the patient's involuntary cough reflex is not yet fully functional, and that the patient is at risk of developing aspirationbased pneumonia. Any patient who is to be given a general anesthetic for a surgical procedure is intubated prior to surgery. Because the anesthetic effectively pharmacologically suppresses brainstem function, inluding a variety of involuntary physiological responses, not the least of which is the ability to cough and clear the upper airway. These brainstem reflexes are suppressed until the anesthetic wears off. Because the tubing that has been inserted into the patient's airway tends to act like a wick-drawing fluid (e.g., secreted saliva) that may be present in the patient's mouth into the patient's airway and lungs--it is critical that the patient's involuntary cough reflex be fully functional at the time the patient is extubated. Unfortunately, there is currently no mechanism for accurately determining whether or not the patient's ability to involuntarily clear the airway has been fully restored. Instead, because each patient's anesthesia recovery time is different, the standard medical practice is to have a skilled medical practitioner (e.g., anesthesiologist) observe the patient, and then make an `educated guess` that the patient's anesthetic state has completely subsided, and that it is `reasonably safe` to extubate the patient, and allow the patient to receive fluids and/or nutrients by mouth. If the patient's involuntary cough reflex is not yet fully

10

This has been a common practice outside the United States prior to December 2000.

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restored, however, the patient is at considerable risk of developing pneumonia, as a result of entry into the airway from the patient's mouth of what would otherwise be expelled secretion and/or foreign matter that could be a substrate for breeding bacteria. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for identifying type 2 hypercarbic respiratory failure associated with community acquired pneumonia Inventor(s): Waterer, Grant William; (Yokine, AU), Wunderink, Richard Glenn; (Germantown, TN) Correspondence: Licata & Tyrrell P.C. 66 E. Main Street; Marlton; NJ; 08053; US Patent Application Number: 20020115087 Date filed: October 10, 2001 Abstract: A method of identifying patients having a predisposition to Type 2 Hypercarbic Respiratory Failure and/or an increased requirement for mechanical ventilation when they have community-acquired pneumonia (CAP) through detection of IL 10 gene polymorphisms at the -1082 site. The method can be used to diagnose predisposition or susceptibility to Type 2 Hypercarbic Respiratory Failure and/or an increased requirement for mechanical ventilation in patients with CAP. Compositions for said diagnosis are provided. Methods of treatment of CAP in such patient are provided, comprising identifying an individual having a predisposition or susceptibility to Type 2 Hypercarbic Respiratory Failure and/or an increased requirement for mechanical ventilation and subsequently treating that individual for such condition. Excerpt(s): This application claims the benefit of priority from U.S. provisional application Ser. No. 60/238,977 filed Oct. 10, 2001. This invention relates methods based upon a polymorphism in the Interleukin 10 (IL-10) gene, more specifically, guanine (G) at the -1082 site rather than the usual adenine (A). More specifically, this invention relates to a method for identification of patients having a predisposition to Type 2 Hypercarbic Respiratory Failure and/or an increased requirement for mechanical ventilation with Community-Acquired Pneumonia (CAP), by screening for the presence of this polymorphism at the -1082 site. The invention also relates to compositions for screening for the polymorphism and improved treatment choices for patients identified with such susceptibility by the method of the present invention. This invention also relates to novel compound screening and treatments. Pneumonia is a common clinical entity, particularly among the elderly. A thorough understanding of the epidemiology and microbiology of Community-Acquired Pneumonia (CAP) is essential for appropriate diagnosis and management. Although the microbiology of CAP has remained relatively stable over the last decade, there is new information on the incidence of atypical pathogens, particularly in patients not admitted to hospital, and new information on the incidence of pathogens in cases of CAP and in CAP in the elderly. Recent studies have provided new data on risk factors for mortality in CAP, which can assist the clinician in decisions about the need for hospital admission. The emergence of antimicrobial resistance in Streptococcus pneumonia, the organism responsible for most cases of CAP, has greatly affected the approach to therapy, especially in those patients who are treated empirically. Guidelines for the therapy of CAP have been published by the American Thoracic Society, the British Thoracic Society, and, most recently, the Infectious Diseases Society of America and others. These guidelines differ in their emphasis on empirical versus pathogenic-specific management.

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Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for indentifying increased risk of death from community acquired pneumonia Inventor(s): Waterer, Grant William; (Yokine, AU), Wunderink, Richard Glenn; (Germantown, TN) Correspondence: Licata & Tyrrell P.C. 66 E. Main Street; Marlton; NJ; 08053; US Patent Application Number: 20020086016 Date filed: October 10, 2001 Abstract: This invention relates to diagnostic methods based upon a particular genotype in the Tumor Necrosis Factor (TNF.alpha.) gene, more specifically, an adenine and guanine ("GA") at the -308 site (or AA) rather than the GG at this locus. More specifically, this invention relates to a method for diagnosis of increased risk of death in patients with community-acquired pneumonia (CAP) and diagnosing pre-disposition or susceptibility to increased risk of death in patients who develop CAP, by screening for the presence of this polymorphism. The invention also relates to compositions for screening for the polymorphism and improved treatment choices for patients having the polymorphism of the present invention.The invention also relates to screening assays and therapeutic and prophylactic methods. Excerpt(s): This application claims the benefit of priority from U.S. provisional application Serial No. 60/239,133 filed Oct. 10, 2001. This invention relates to diagnostic methods based upon a particular genotype in the Tumor Necrosis Factor (TNF.alpha.) gene, more specifically, a guanine (G) to adenine (A) transition at the -308 site in one of the TNF.alpha.genes giving a GA (or adenine adenine genotype, AA) genotype rather than the GG genotype at this locus. More specifically, this invention relates to a method for diagnosis of increased risk of death in patients with community-acquired pneumonia (CAP) and diagnosing pre-disposition or susceptibility to increased risk of death in patients who develop CAP, by screening for the presence of this A allele risk polymorphism. The invention also relates to compositions for screening for the polymorphism and improved treatment choices for patients having the polymorphism of the present invention. The invention also relates to screening assays and therapeutic and prophylactic methods. Pneumonia is a common clinical entity, particularly among the elderly. A thorough understanding of the epidemiology and microbiology of community-acquired pneumonia (CAP) is essential for appropriate diagnosis and management. Although the microbiology of CAP has remained relatively stable over the last decade, there is new information on the incidence of atypical pathogens, particularly in patients not admitted to hospital, and new information on the incidence of pathogens in cases of severe CAP and in CAP in the elderly. Recent studies have provided new data on risk factors for mortality in CAP, which can assist the clinician in decisions about the need for hospital admission. The emergence of antimicrobial resistance in Streptococcus pneumonia, the organism responsible for most cases of CAP, has greatly affected the approach to therapy, especially in those patients who are treated empirically. Guidelines for the therapy of CAP have been published by the American Thoracic Society, the British Thoracic Society, and, most recently, the Infectious Diseases Society of America and others. These guidelines differ in their emphasis on empirical versus pathogenic-specific management. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Patents 371

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Method of diagnosing and treating pneumonia and pneumonia-related sepsis associated with the IL6-174 gene polymorphism Inventor(s): Wunderink, Richard Glenn; (Germantown, TN), Waterer, Grant William; (Yokine, AU) Correspondence: Licata & Tyrrell P.C. 66 E. Main Street; Marlton; NJ; 08053; US Patent Application Number: 20020160407 Date filed: April 1, 2002 Abstract: Methods and compositions for diagnosing diseases associated with a genetic polymorphism in an IL6 gene via determination of the genotype of an IL6 gene at the 174 site are provided. The methods of this invention can be used to diagnose diseases such as pneumonia and septic shock or to diagnosis a predisposition or susceptibility to pneumonia and pneumonia-related sepsis. Also related are methods for the treatment of pneumonia or predisposition or susceptibility to pneumonia or pneumonia-related sepsis. Compositions are also provided for identifying the genetic polymorphism. Excerpt(s): This application claims the benefit of priority from U.S. provisional application Serial No. 60/281,227, filed Apr. 3, 2001. This invention relates to diagnostic methods based upon the identification of a polymorphism in the Interleukin 6 ("IL6") gene, more specifically, a Guanine ("G") to Cytosine ("C") transition at position -174 within the promoter region of the IL6 gene wherein the G allele is associated with greater IL6 gene transcription and IL6 production. This invention also relates to a method for diagnosis of pneumonia, and a method of identifying and diagnosing predisposition for septic shock in patients with pneumonia. The invention further relates to compositions for screening for the polymorphism and improved treatment choices for patients diagnosed with pneumonia or diagnosed as being susceptible to pneumonia or pneumonia-related sepsis by the methods of the present invention. Pneumonia is a common clinical entity, particularly among the elderly. Pneumonia is a major health problem worldwide. Pneumonias are classified as being either community-acquired or hospital-acquired (nosocomial). In the United States, Community Acquired Pneumonia (CAP) is the leading cause of death due to infection and the sixth most common cause of death overall. Further, nosocomial pneumonia or hospital-acquired pneumonia, defined as pneumonia occurring more than 48 hours after admission to the hospital is a major cause of morbidity and mortality in hospitalized patients. Nosocomial pneumonia is the second most common cause of hospital acquired infection and has a mortality rate of about thirty percent. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Methods of preventing ventilator associated pneumonia by oral administration of antimicrobial IB-367 peptides Inventor(s): Fuchs, Henry; (San Francisco, CA), Redman, Rebecca; (San Jose, CA) Correspondence: COOLEY GODWARD, LLP; 3000 EL CAMINO REAL; 5 PALO ALTO SQUARE; PALO ALTO; CA; 94306; US Patent Application Number: 20030073625 Date filed: February 12, 2002

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Abstract: The present invention provides methods of preventing respiratory infections associated with intubation and/or mechanical ventilation, such as ventilator-associated pneumonia, in intubated patients. The method generally involves topical administration of a composition comprising an IB-367 peptide to the oral cavity of an intubated patient. As IB-367 peptides engender very little resistance, a significant advantage of the invention is that the prophylactic therapy may be applied without having to worry about creating resistant strains of pathogens. Excerpt(s): This application claims benefit under 35 U.S.C.sctn.119(e) to provisional application No. 60/268,585, filed Feb. 13, 2001. The contents of this provisional application are incorporated herein by reference. The present invention relates to the prevention of respiratory infections commonly associated with intubation in patients requiring mechanical ventilation. Ventilator-associated pneumonia ("VAP") is a common disorder among patients in intensive care units and long-term care facilities. It is associated with complications of intubation (insertion of an endotracheal tube) and mechanical ventilator support. Placement of an endotracheal tube allows bacteria to enter the lower respiratory tract directly and promotes microbial colonization by interference with the cough reflex, inhibition of mucociliary clearance and/or stimulation of excessive mucus secretion. The incidence of nosocomial, or hospitalacquired, pneumonia increases by as much as 6 to 20 times in patients receiving mechanical ventilatory support. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Remedies for interstitial pneumonia , method of constructing animal model of this disease, and screening method with the use of the same Inventor(s): Hoshino, Tomoaki; (Fukuoka, JP) Correspondence: ARMSTRONG,WESTERMAN & HATTORI, LLP; 1725 K STREET, NW; SUITE 1000; WASHINGTON; DC; 20006; US Patent Application Number: 20030099637 Date filed: October 25, 2002 Abstract: A remedy for interstitial pneumonia, comprising at least one, or two or more kinds of an interleukin 18 inhibitor and/or an interleukin 2 inhibitor as an active ingredient.A method of preparing an animal model of said disease, and a method of screening the remedy for interstitial pneumonia using the same.The remedy exerts a therapeutic effect by suppressing over-expression of an action of IL-18/IL-2 relating to the onset of interstitial pneumonia. The animal model is precisely capable of screening a drug, which can be expected to be clinically useful, because it resembles closely to the human clinical finding. Excerpt(s): The present invention relates to a remedy for interstitial pneumonia, comprising at least one, or two or more kinds of an interleukin 18 inhibitor and/or an interleukin 2 inhibitor as an active ingredient. Also the present invention relates to a method of preparing an animal model of a remedy for interstitial pneumonia, and a method of screening a remedy for interstitial pneumonia using said animal model. Interstitial pneumonia is a disease that is characterized by cardinal symptoms such as dry cough and shortness of breath and is sometimes accompanied by fever and arthralgia, while other systemic symptoms develop in case interstitial pneumonia is complicated with the systemic disease. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Treatment of severe pneumonia by administration of tissue factor pathway inhibitor ( TFPI) Inventor(s): Creasey, Abla; (Piedmont, CA) Correspondence: Chiron Corporation; Intellectual Property - R440; P.O. Box 8097; Emeryville; CA; 94662-8097; US Patent Application Number: 20030139339 Date filed: October 15, 2002 Abstract: Methods for prophylactically or therapeutically treating severe pneumonia involve administration of tissue factor pathway inhibitor (TFPI) or a TFPI analog to patients suffering from or at risk of developing this condition. The methods involve the use of continuous intravenous infusion of TFPI or a TFPI analog, preferably at low doses to avoid adverse side effects. Excerpt(s): This application claims priority to Provisional Application Serial No. 60/328,806 filed Oct. 15, 2001, hereby incorporated by reference in its entirety. The present invention relates to a method for therapeutically treating severe pneumonia. More specifically, it relates to administering a tissue factor pathway inhibitor protein to attenuate exuberant or amplified physiological pathways associated with severe pneumonia. Pneumonia results from an acute infection of one or more functional elements of the lung, including alveolar spaces and interstitial tissue. In the USA, about 2 million people develop pneumonia each year, and 40,000 to 70,000 of these people die. Pneumonia ranks sixth among all disease categories as a cause of death and is the most common lethal nosocomial (hospital-acquired) infection. Community-acquired pneumonia (CAP) has a significant impact on health care costs in the United States, accounting for an estimated $14 billion per year in direct costs and $9 billion in lost wages. (Lynch J P, Martinez F J. Community-acquired pneumonia. Curr Opin Pulm Med. 1998; 4:162-172). In developing countries, lower respiratory tract infections typically are either the major cause of death or rank second only to infectious diarrhea. (The Merck Manual, Sec. 6, Ch. 73, Pneumonia, 2000). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Keeping Current In order to stay informed about patents and patent applications dealing with pneumonia, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “pneumonia” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on pneumonia. You can also use this procedure to view pending patent applications concerning pneumonia. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

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CHAPTER 7. BOOKS ON PNEUMONIA Overview This chapter provides bibliographic book references relating to pneumonia. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on pneumonia include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.

Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “pneumonia” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on pneumonia: •

Pneumocystis Carinii Pneumonia Contact: Marcel Dekker, Incorporated, 270 Madison Ave, New York, NY, 10016, (800) 228-1160. Summary: This book presents a comprehensive examination of all aspects of Pneumocystis carinii pneumonia (PCP). This form of pneumonia is prevalent among people with AIDS and other immunosuppressed patients. The author has included a review of recent advances in basic biology, epidemiology, pathophysiology, clinical features, diagnosis, treatment, and prevention of this opportunistic infection. The book contains a treatment section detailing important topics in drug development and includes discussions of pentamidine; folate antagonists; primaquine, other 8aminoquinolines, and clindamycin; hydroxynapthoquinones, glucan synthetase inhibitors, and corticosteroids.

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Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “pneumonia” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “pneumonia” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “pneumonia” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

2003 Essential Medical Guide to SARS (Severe Acute Respiratory Syndrome) and Atypical Pneumonia, Influenza (Flu), Antiviral Drugs, Respiratory and Lung Diseases, Infection Control, Coronavirus - Authoritative Federal Information from the CDC, FDA, and NIH for Health Care Providers, Physicians, and Patients (Two CDROM Set) by PM Medical Health News (2003); ISBN: 1592482163; http://www.amazon.com/exec/obidos/ASIN/1592482163/icongroupinterna

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21st Century Collection Centers for Disease Control (CDC) Emerging Infectious Diseases (EID) ¿ Guide to SARS (Severe Acute Respiratory Syndrome) and Atypical Pneumonia, Influenza (Flu), Antiviral Drugs, Respiratory and Lung Diseases, Infection Control, Coronavirus ¿ Authoritative Information from the CDC, FDA, WHO, and NIH for Health Care Providers, Physicians, and Patients (Two CD-ROM Set) by PM Medical Health News; ISBN: 1592482317; http://www.amazon.com/exec/obidos/ASIN/1592482317/icongroupinterna

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Community Acquired Pneumonia by Thomas J. Marrie (Editor); ISBN: 0306468344; http://www.amazon.com/exec/obidos/ASIN/0306468344/icongroupinterna

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Community-Acquired Pneumonia: A Plan for Implementing National Guidelines at the Local Hospital Level by Julio A., Md. Ramirez (2003); ISBN: 0781744830; http://www.amazon.com/exec/obidos/ASIN/0781744830/icongroupinterna

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Contemporary Diagnosis and Management of Community-Acquired Pneumonia by G. Douglas Campbell Jr. ISBN: 1884065600; http://www.amazon.com/exec/obidos/ASIN/1884065600/icongroupinterna

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Diagnosis and Management of Pneumonia and Other Respiratory Infections by Alan Fein, et al (1999); ISBN: 1884735428; http://www.amazon.com/exec/obidos/ASIN/1884735428/icongroupinterna

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Interstitial Pneumonia of Unknown Etiology by Michiyoshi Harasawa (Editor), et al (1989); ISBN: 0608012041; http://www.amazon.com/exec/obidos/ASIN/0608012041/icongroupinterna

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Mechanism - Treatment - Prevention of Aspiration Pneumonia (Theodor Billroth) by Karel B. Absolon, J. Lee Sedwitz (1999); ISBN: 0930329708; http://www.amazon.com/exec/obidos/ASIN/0930329708/icongroupinterna

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Mycoplasma pneumoniae infection Serological, aetiological and epidemiological studies by Klaus Lind; ISBN: 8774373064; http://www.amazon.com/exec/obidos/ASIN/8774373064/icongroupinterna

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Nosocomial Pneumonia by William R. Jarvis (Editor); ISBN: 0824703847; http://www.amazon.com/exec/obidos/ASIN/0824703847/icongroupinterna

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Pneumocystis Carinii Pneumonia by Peter D. Walzer (Editor); ISBN: 0824788540; http://www.amazon.com/exec/obidos/ASIN/0824788540/icongroupinterna

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Pneumocystis Carinii Pneumonia: Pathogenesis, Diagnosis, Treatment (Lung Biology in Health and Disease, Vol 22) by Lowell S. Young (Editor) (1984); ISBN: 0824770773; http://www.amazon.com/exec/obidos/ASIN/0824770773/icongroupinterna

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Pneumonia by Bartlett; ISBN: 0444008438; http://www.amazon.com/exec/obidos/ASIN/0444008438/icongroupinterna

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Pneumonia - pocketbook by Simon Godfrey, Robert Wilson (1996); ISBN: 1853172413; http://www.amazon.com/exec/obidos/ASIN/1853172413/icongroupinterna

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Pneumonia and Pneumococcal Infections by Lambert; ISBN: 0808912879; http://www.amazon.com/exec/obidos/ASIN/0808912879/icongroupinterna

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Pneumonia, with Special Reference to Pneumococcus Lobar Pneumonia by Benjamin White, Roderick Heffron (1979); ISBN: 0674674448; http://www.amazon.com/exec/obidos/ASIN/0674674448/icongroupinterna

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Pneumonia: Medical Subject Analysis Reference and Research Guidebook by Dominic L. Stannic (1987); ISBN: 0881645931; http://www.amazon.com/exec/obidos/ASIN/0881645931/icongroupinterna

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Pneumonias by Hobart A. Reimann (1971); ISBN: 0875271197; http://www.amazon.com/exec/obidos/ASIN/0875271197/icongroupinterna

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Pneumonias by Douglas Borland; ISBN: 0946717354; http://www.amazon.com/exec/obidos/ASIN/0946717354/icongroupinterna

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Pneumonias: A Clinical Approach to Infectious Diseases of the Lower Respiratory Tract by Matthew E. Levison; ISBN: 072367020X; http://www.amazon.com/exec/obidos/ASIN/072367020X/icongroupinterna

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Seminars in Infectious Disease Pneumonias by Louis Weinstein; ISBN: 0865770913; http://www.amazon.com/exec/obidos/ASIN/0865770913/icongroupinterna

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Serodiagnosis of the Infectious Diseases: Mycoplasma Pneumoniae by Nevio Cimolai (1999); ISBN: 0792385683; http://www.amazon.com/exec/obidos/ASIN/0792385683/icongroupinterna

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Severe Community Acquired Pneumonia (Perspectives on Critical Care Infectious Diseases, Volume 3) by Jordi Rello (Editor), Kenneth Leeper (Editor); ISBN: 0792373383; http://www.amazon.com/exec/obidos/ASIN/0792373383/icongroupinterna

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Streptococcus Pneumoniae: Molecular Biology & Mechanisms of Disease by Alexander Tomasz (Editor); ISBN: 0913113859; http://www.amazon.com/exec/obidos/ASIN/0913113859/icongroupinterna

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The Official Patient's Sourcebook on Chlamydia Pneumonia: A Revised and Updated Directory for the Internet Age by Icon Health Publications (2002); ISBN: 0597832900; http://www.amazon.com/exec/obidos/ASIN/0597832900/icongroupinterna

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The Official Patient's Sourcebook on Mycoplasma Pneumonia: A Revised and Updated Directory for the Internet Age by Icon Health Publications (2003); ISBN: 0597835411; http://www.amazon.com/exec/obidos/ASIN/0597835411/icongroupinterna

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The Official Patient's Sourcebook on Pneumonia by Icon Health Publications; ISBN: 0597829934; http://www.amazon.com/exec/obidos/ASIN/0597829934/icongroupinterna

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The Pneumonias by Monroe Karetzky, et al (1993); ISBN: 038797945X; http://www.amazon.com/exec/obidos/ASIN/038797945X/icongroupinterna

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Ventilator-Associated Pneumonia by Richard D. Wunderink (Editor), Jordi Rello (Editor); ISBN: 0792374444; http://www.amazon.com/exec/obidos/ASIN/0792374444/icongroupinterna

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Ventilator-Associated Pneumonia in Surgical Patients: Focus on Pathogenesis, Diagnosis & Prevention (Acta Biomedica Lovaniensia, 263) by Charles Verwaest (2002); ISBN: 9058672344; http://www.amazon.com/exec/obidos/ASIN/9058672344/icongroupinterna

The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select “Search LOCATORplus.” Once you are in the search area, simply type “pneumonia” (or synonyms) into the search box, and select “books only.” From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine:11 •

[Report of lobar pneumonia in Pittsburgh. Author: Pittsburgh. Bureau of Infectious Diseases.; Year: 1964; Pittsburgh, 1940?]

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Bacteriological and clinical observations on pneumonia and empyemata, with special reference to the pneumococcus and to serum treatment, by Ernest E. Glynn, F. R. C. P., and Lettice Digby. Author: Glynn, Ernest Edward.; Year: 1950; London, H. M. Stationery off. [printed by F. Hall, at the University press, Oxford] 1923

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Contagious caprine pleuro-pneumonia, a study of the disease in Nigeria. Author: Longley, E. O.; Year: 1963; London, H. M. Stationery Off., 1951

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Diagnosis and treatment of pneumococcus pneumonia. Author: Iowa. State Dept. of Health. Advisory Committee on Pneumonia Control.; Year: 1964; [Des Moines? 1939?]

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Diathermy with special reference to pneumonia, by Harry Eaton Stewart. with fortyfive illustrations and fifteen charts. Author: Stewart, Harry Eaton,; Year: 1965; New York, P. B. Hoeber, inc., 1926

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Excess deaths from influenza and pneumonia and from important chronic diseases during epidemic periods, 1918-51 [by] Selwyn D. Collins [and] Josephine Lehmann. Author: Collins, Selwyn De Witt,; Year: 1967; [Washington, 1953]

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Factors associated with mortality in adults less than fifty-five years old hospitalized for community-acquired pneumonia Author: Marrie, Thomas J.; Year: 1926; [Edmonton]: Alberta Centre for Health Services Utilization Research, [2003]

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In addition to LOCATORPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a "Books" button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.

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Home care predicts an increase in admission rate and adverse outcomes from community-acquired pneumonia Author: Johnson, David,; Year: 2003; [Edmonton]: Alberta Centre for Health Services Utilization Research, [2002]

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Hospital costs and long term mortality outcomes in seniors requiring hospitalization for community-acquired pneumonia in Alberta Author: Jin, Yan,; Year: 1962; [Edmonton]: Alberta Centre for Health Services Utilization Research, [2002]

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Hospitalization for community-acquired pneumonia in Alberta patients with human immunodeficiency virus infection: a case control study Author: Johnson, David,; Year: 1965; [Edmonton]: Alberta Centre for Health Services Utilization Research, [2003]

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Investigation and control of pneumonia, influenza, and the common cold. Hearings before a subcommittee of the Committee on Education and Labor, United States Senate, Seventy-sixth congress, third session, on S. 3914. A bill to impose additional duties upon the United States Public Health Service in connection with investigation and control of pneumonia, influenza, and the common cold. May 6 and 10, 1940. Author: United States. Congress. Senate. Committee on Education and Labor.; Year: 2003; Washington, U. S. Govt. Print. Off., 1940

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Is mortality associated with physician volume, specialist certification, or health care organization after hospitalization for community-acquired pneumonia? Author: Marrie, Thomas J.; Year: 1965; [Edmonton]: Alberta Centre for Health Services Utilization Research, [2003]

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Lobar pneumonia, a Roentgenological study. (A correlation of Roentgen-ray findings with clinical and pathological manifestations) By L. R. Sante. with a foreword by James T. Case. Author: Sante, Le Roy,; Year: 1964; New York, P. B. Hoeber, inc., 1928

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Mycoplasma pneumoniae infection; serological, aetiological and epidemiological studies. Author: Lind, Klaus.; Year: 1966; København, F. A. D. L. s forlag [c1973]; ISBN: 0877437306

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Pneumococcus pneumonia; diagnosis and treatment. Author: Iowa. State Dept. of Health. Advisory Committee on Pneumonia Control.; Year: 1964; [Des Moines? 1940?]

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Pneumonia in decline. Author: Office of Health Economics (London, England); Year: 2001; London [1963]

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Pneumonia mortality and measures for prevention. Report of Advisory committee on prevention of pneumonia mortality. Author: United States. Public health service. Advisory committee on prevention of pneumonia mortality.; Year: 1966; Washington, U. S. Govt. print. off., 1938

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Pneumonia. Author: Reimann, Hobart A. (Hobart Ansteth),; Year: 1970; Springfield, Thomas [c1954]

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Pneumonia; its etiology, diagnosis and treatment. Prepared by the Committee on Pneumonia Control representing the Tennessee Dept. of Health and Tennessee State Medical Assn. Author: Tennessee. Dept. of Public Health.; Year: 1971; [Nashville?] 1940

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Pneumonia; with special reference to pneumococcus lobar pneumonia [by] Roderick Heffron. Author: Heffron, Roderick,; Year: 1964; New York, The Commonwealth fund; London, H. Milford, Oxford university press, 1939

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Pulmonary function in pneumonia related to radiological and microbiological observations. Author: Ruosteenoja, Reino.; Year: 2002; Helsinki, 1966

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Researches regarding the haemodynamics in rabbits in normal condition and during experimental pneumonia, by Fredrik Leegaard. Author: Leegaard, Fredrik Christian,; Year: 1964; Oslo, Kirstes boktrykkeri, 1926

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The identification and mode of action of Miyagawanella as related to trachoma, atypical pneumonia and other clinical disorders including the therapeutic implications there of [by] Toshio Goto. Author: Sagamihara. Kokuritsu Sagamihara By¯oin.; Year: 1940; [Tokyo, 1960]

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The pneumonias, by Hobart A. Reimann. with a foreword by Rufus Cole. Author: Reimann, Hobart A. (Hobart Ansteth),; Year: 1959; Philadelphia and London, W. B. Saunders company, 1938

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The pneumonias. Author: Reimann, Hobart A. (Hobart Ansteth),; Year: 1965; St. Louis, Green [c1971]

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The pneumonias; management with antibiotic therapy. Author: Chas. Pfizer; Co.; Year: 1964; [Brooklyn, N. Y., c1953]

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Variation in management of community-acquired pneumonia requiring admission to Alberta hospitals Author: Jin, Yan,; Year: 1886; [Edmonton]: Alberta Centre for Health Services Utilization Research, [2002]

Chapters on Pneumonia In order to find chapters that specifically relate to pneumonia, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and pneumonia using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “pneumonia” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on pneumonia: •

Role of Antibiotics in Comfort Care Source: in Olson, E. Chichin, E.R. Libow, L.S., eds. Controversies in Ethics in Long-Term Care. New York, NY: Springer Publishing Company. 1996. p. 91-107. Contact: Springer Publishing Company. 536 Broadway, New York, NY 10012-9904. (212) 431-4370; FAX (212) 941-7842. PRICE: $34.95 (for the book). ISBN: 0826186009. Summary: This book chapter examines the role of antibiotics in comfort care for endstage dementia patients, and suggests a flexible approach to deciding when to provide or forgo antibiotic therapy. The authors discuss what is meant by comfort care, whether the usual outcomes of antibiotic treatment are consistent with the goals of comfort care, when the use of antibiotics may be considered comfort care, and when the use of antibiotics is more likely to be burdensome. They suggest that the characterization of any treatment option is based on its ability to influence both symptom relief (quality of life) and survival (quantity of life), and propose that antibiotic therapy may be considered comfort care when it is uniquely effective at relieving symptoms. They also present the examples of pneumonia, urinary tract infection, and infected pressure sores to show how the proposed approach to decision making applies to the problem of infection in end-stage dementia patients residing in long-term care facilities. These examples also illustrate how optimal comfort care is achieved when an antibiotic's unique effectiveness is weighed against its potential to prolong life, in comparison with alternative palliative measures. The authors conclude with a proposal for a flexible approach to comfort care that takes into account the patient's premorbid quality of life,

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the type of infection, and the likely response in terms of both quality and quantity of life. 22 references. •

Rheumatic Fever Source: in Maddison, P.J. et al., Eds. Oxford Textbook of Rheumatology. Volume 2. New York, NY: Oxford University Press, Inc. 1993. p. 613-620. Contact: Available from Oxford University Press, Inc., New York, NY. Summary: This chapter for health professionals presents an overview of rheumatic fever. The classical ways in which rheumatic fever may manifest itself are outlined. The epidemiology and pathogenesis are discussed. The role of group A streptococcus and genetics in the disease process of rheumatic fever is examined. Theories on the pathological mechanisms of group A streptococcus in rheumatic fever are presented. The clinical features of acute rheumatic fever are described, including arthritis, carditis, rheumatic heart disease, chorea, subcutaneous nodules, and erythema marginatum. The minor manifestations of rheumatic fever are identified, including fever, abdominal pain, epistaxis, and rheumatic pneumonia. The use of laboratory tests in the diagnosis of rheumatic fever is discussed. The clinical course and treatment of rheumatic fever is explained, and the use of antibiotic prophylaxis following resolution of the acute episode is considered. 56 references, 1 figure, and 3 tables.

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Contributions of Speech-Language Pathology in Critical Care Source: in Mackay, L.E. Chapman, P.E. Morgan, A.S. Maximizing Brain Injury Recovery: Integrating Critical Care and Early Rehabilitation. Gaithersburg, MD: Aspen Publishers, Inc. 1997. p. 444-482. Contact: Available from Aspen Publishers, Inc. 200 Orchard Ridge Drive, Suite 200, Gaithersburg, MD 20878. (800) 638-8437. Website: www.aspenpub.com. PRICE: $79.00. ISBN: 0834206552. Summary: This chapter on speech language pathology is from a text on integrating critical care and early rehabilitation in order to maximize recovery from brain injury. The authors stress that the speech language pathologist plays an integral role in the critical care rehabilitative needs of patients with severe brain injury. Interventions from this discipline should be initiated within 24 hours of admission. The speech language pathologist establishes a functional communication system for the patient and assesses and treats cognitive and linguistic impairments. These impairments can be a major deficit for these patients, manifesting as reduced responsiveness and level of alertness, decreased attention, and difficulties with auditory comprehension, orientation, and memory. Speech language pathology intervention in the intensive care unit (ICU) also includes assessment and treatment of vocal cord function and dysphagia, because patients with severe brain injury are at increased risk for aspiration and pneumonia. The chapter discusses patient equipment and monitoring devices, patient observation, assessment, formal assessment tools, treatment, vocal cord integrity, swallowing, and family involvement. The authors also emphasize the importance of educating staff and family regarding effective ways to interact with the patient and environmental modifications that can be made to optimize communication and safety. 16 figures. 127 references.

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Otolaryngologic Manifestations of AIDS Source: in Jafek, B.W. Stark, A.K., eds. ENT Secrets: Questions You Will Be Asked On Rounds, In the Clinic, In the OR, On Exams. Philadelphia, PA: Hanley and Belfus. 1996. p. 153-158. Contact: Available from Hanley and Belfus. Medical Publishers, 210 South 13th Street, Philadelphia, PA 19107. (800) 962-1892 or (215) 546-7293; Fax (215) 790-9330; http://www.hanleyandbelfus.com. PRICE: $35.95 plus shipping and handling. ISBN: 1560531592. Summary: This chapter on the otolaryngologic manifestations of AIDS is from a book that utilizes a question and answer format to review details of the specialty of otorhinolaryngology (ear, nose and throat, or ENT). Topics discussed include the transmission of HIV, risk factors of acquiring HIV infection from blood transfusion or from mother to child, the percentage of HIV positive patients who develop AIDS, AIDS indicator diseases (including pneumocystis carinii pneumonia, most common index disease for the diagnosis of AIDS), CD4 counts and how they classify HIV infection, toxoplasmosis, problems with cytomegalovirus (CMV), common dermatologic manifestations of HIV infection, Kaposi's sarcoma, chronic otitis externa, serous and acute otitis media (the most common otologic condition seen in HIV infected patients), problems with pneumococcus as a middle ear pathogen, Ramsay Hunt syndrome (herpes zoster oticus), sinusitis and its treatment, oral candidiasis, hairy leukoplakia, salivary gland disease, risks of seroconversion after needlestick exposure from an HIV positive patient, non-Hodgkin's lymphoma, indications for lymph node biopsy, infection control measures for nasopharyngoscopy, and management of benign lymphoepithelial cysts. The chapter focuses on helping readers acquire the vocabulary required to discuss the otolaryngologic care of patients with AIDS. 1 figure. 1 table. 13 references.

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Abdominal Pain Source: in Carlson, K.J. Eisenstat, S.A. Ziporyn, T. Harvard Guide to Women's Health. Cambridge, MA: Harvard University Press. 1996. p. 1-6. Contact: Available from Harvard University Press. Customer Service Department, 79 Garden Street, Cambridge, MA 02138. (800) 448-2242. Fax (800) 962-4983. PRICE: $24.95 (paperback). ISBN: 0674367693 (paperback). Summary: This chapter on abdominal pain is from a consumer handbook on women's health. The authors discuss the classification and evaluation of abdominal pain and describe causes of pain in different areas. Pain in the lower abdomen may stem from appendicitis, aortic aneurysm, ectopic pregnancy, kidney disorders, bowel disorders, or lactose intolerance. Right upper quadrant pain can be caused by irritable bowel syndrome, liver disease, gallstones and other gallbladder disorders, pancreatic disorders, pneumonia and pleurisy, rib cage pain, or shingles. Pain in the left upper quadrant and midline may be from gastritis, peptic ulcer disease, stomach cancer, or enlarged or ruptured spleen. The chapter concludes with a reference to related chapters in the book. 3 figures.

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Enteral Nutrition Source: in Whitney, E.N., Cataldo, C.B., and Rolfes, S.R. Understanding Normal and Clinical Nutrition. 4th ed. St. Paul, MN: West Publishing Company. 1994. p. 723-751.

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Contact: Available from West Publishing. 620 Opperman Drive, St. Paul, MN 55164. (800) 340-9378 or (612) 687-7000. PRICE: $67.00. ISBN: 0314041788. Summary: This chapter on enteral nutrition is from an introductory medical textbook on nutrition. Topics include feeding strategies such as supplemental nutrition, tube feedings, feeding-tube placement, and feeding tubes; formula characteristics, including the types of formulas, nutrient composition, and formula selection; tube-feeding techniques including formula preparation, formula administration, and methods of delivery; tube feedings for infants, young children, and teenagers; prevention of tubefeeding complications, including inappropriate formula delivery, diarrhea, dehydration and electrolyte imbalance, aspiration pneumonia, and other gastrointestinal problems; record-keeping and charting considerations; drug administration through feeding tubes; and the transition from tube feedings to table foods. The chapter concludes with study questions, clinical application questions, and a 'highlight' section addressing the medical marketplace of enteral formulas. 3 figures. 5 tables. 35 references. (AA-M). •

Infection Source: Cambridge, MA: Harvard University Press. 1991. 13 p. Contact: Available from Harvard University Press. 79 Garden Street, Cambridge, MA 02138-9983. (617) 495-2577 or (617) 495-2480. PRICE: $24.95 plus shipping and handling. ISBN: 067464235X. Summary: This chapter, from a patient education book about organ transplantation, discusses the task of preventing infection in patients who have received donor organs. Topics include the role of good tissue typing and matching in prevention of infection; reducing the risks of infection; preoperative, perioperative and postoperative measures taken to reduce the risk of infection; a timetable used to divide the times when the recipient is susceptible; urinary tract infection; pneumonia; special viral infections including general infections like influenza and those infections for which the transplant recipient faces a higher-than-average risk; the herpes group of viruses, including cytomegalovirus, Epstein-Barr virus, herpes simplex virus, and varicella-zoster virus; hepatitis; and suggestions for reducing the risks of acquiring a contagious disease. The chapter presents detailed medical information about these topics in clear, easy-tounderstand language designed for the layperson.

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Complications Source: in Du Bois, D. Enteral Feedings in the Nursing Home. La Grange, TX: M and H Publishing Company, Inc. 1990. p. 53-58. Contact: Available from M and H Publishing Company, Inc. P.O. Box 268, La Grange, TX 78945-0268. (409) 968-9508. PRICE: $10.95 plus $2.50 shipping and handling. ISBN: 1877735205. Summary: This chapter, from a nursing guidebook about enteral feedings in the nursing home population, discusses potential complications arising from tube feedings. Topics include complications of insertion; mechanical complications; complications of administration, including aspiration, diarrhea, nausea, vomiting, constipation, and dehydration; metabolic complications, including dehydration, fluid overload, hyperglycemic hyperosmolar nonketosis, simple hyperglycemia, electrolyte abnormalities, and hyponatremia; and infectious complications, including aspiration This chap. 15 references.

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Infection and Diabetes Source: in Harris, M.I., et al., eds., for the National Diabetes Data Group (NDDG). Diabetes in America. 2nd ed. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. 1995. p. 485-499. Contact: Available from National Diabetes Information Clearinghouse (NDIC). 1 Information Way, Bethesda, MD 20892-3560. (800) 860-8747 or (301) 654-3327. Fax (301) 634-0716. E-mail: [email protected]. Also available at http://www.niddk.nih.gov/. PRICE: Full-text book and chapter available online at no charge; book may be purchased for $20.00. Order number: DM-96 (book). Summary: This chapter on infection and diabetes is from a compilation and assessment of data on diabetes and its complications in the United States. The authors characterize infections related to diabetes as 'probable' (the data support the presence of the association), 'possible' (presence or absence of an association cannot be established from current data) and 'doubtful' (data argue for no association). People with diabetes probably have a higher risk of the following infections: asymptomatic bacteriuria, lower extremity infections, reactivation tuberculosis in American Indians, infections in surgical wounds after sternotomy and total hip replacement, and group B streptococcal. Support for these associations comes from controlled observational studies in all cases, except for lower extremity infections, where the magnitude of the association between foot and ankle infection and diabetes from hospital-based data appears too great to be explained by detection, selection, or other potential biases. Local and systemic immunologic defects probably account for higher infection rates in patients with diabetes. Autonomic and sensory neuropathy probably account for higher bacteriuria and lower extremity infection rates, while systemic immunologic effects of diabetes may be responsible for the increased risk of surgical wound infection and tuberculosis reinfection. Populationbased data also support a probable higher influenza and pneumonia mortality rate in patients with diabetes. There is a possible association between diabetes and prevalence of the following infections: cystitis, pyelonephritis, candida vulvovaginitis and cystitis, pneumonia, influenza, chronic bronchitis, bacteremia, primary tuberculosis, reactivation tuberculosis in non-American Indians, mucormycosis, malignant otitis externa, and Fournier's gangrene. Doubtful associations exist between diabetes and prevalence of chronic sinusitis or S. aureus colonization (staph infection). 6 tables. 103 references. (AAM).

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Nephroureterectomy Source: in Graham, S.D., Jr., et al., eds. Glenn's Urologic Surgery. 5th ed. Philadelphia, PA: Lippincott Williams and Wilkins. 1998. p. 147-153. Contact: Available from Lippincott Williams and Wilkins. P.O. Box 1600, Hagerstown, MD 21741. (800) 638-3030 or (301) 714-2300. Fax (301) 824-7390. Website: lww.com. PRICE: $199.00 plus shipping and handling. ISBN: 0397587376. Summary: Nephroureterectomy with excision of a cuff of bladder is the classic surgical procedure for carcinoma of the renal pelvis or ureter. This chapter on nephroureterectomy is from an exhaustive textbook on urologic surgery. The author notes that malignant tumors of the upper urinary tract are uncommon; most of these upper tract tumors are transitional cell carcinoma (TCC). Approximately 80 percent of patients with TCC present with hematuria (blood in the urine). Intravenous pyelography (IVP) is the initial study of choice in the evaluation of a patient suspected of having a renal pelvic or ureteral tumor. The author reviews indications for surgery, alternative therapy, and the surgical techniques used, focusing on the two incision

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approach. Early complications include hemorrhage, wound infection, pneumothorax, atelectasis, and pneumonia. Meticulous dissection around the renal vessels, aorta, and vena cava will aid in decreasing intraoperative blood loss. The author cautions that patients treated with a conservative approach (distal ureterectomy and ureteroneocystostomy) are at increased risk of local recurrence and require frequent and careful followup including IVPs, retrograde pyelograms, and endoscopies. The survival rate after nephroureterectomy is dependent on the stage and grade of the tumor. Superficial low grade tumors rarely metastasize and, when adequately treated, rarely decrease life expectancy. Invasive lesions have a higher metastatic rate and are associated with a poorer prognosis. Patients with low grade and high grade tumors have approximately 80 percent and 20 percent survival at 5 years, respectively. 8 figures. 6 references. •

Infections Source: in Daugirdas, J.T. and Ing, T.S., eds. Handbook of Dialysis. 2nd ed. Boston, MA: Little, Brown and Company. 1994. p. 469-490. Contact: Available from Lippincott-Raven Publishers. 12107 Insurance Way, Hagerstown, MD 21740. (800) 777-2295. Fax (301) 824-7390. E-mail: [email protected]. Website: http://www.lrpub.com. PRICE: $37.95. ISBN: 0316173835. Summary: This chapter on infections is from a handbook that outlines all aspects of dialysis therapy, emphasizing the management of dialysis patients. Topics include the derangement of immune function in uremia, including etiology and the increased susceptibility to infection; the derangement of temperature control in uremia; the incidence and management of bacterial infections in hemodialysis and peritoneal dialysis patients; infections unrelated to the access site, including urinary tract infection, pneumonia, intraabdominal infections, tuberculosis, listeriosis, Salmonella septicemia, Yersinia septicemia, and mucormycosis; viral infections, including hepatitis A, hepatitis B, hepatitis C, cytomegalovirus and mononucleosis, influenza, AIDS, routine screening, and dialysis in patients who are HIV positive; vaccination in dialysis patients; and antimicrobial usage in dialysis patients. The authors present information in outline form, for easy reference. The chapter features a lengthy chart outlining the usual nonuremic dosage, dialysis patient dosage, post-hemodialysis supplements, and dosage for CAPD for each antimicrobial agent in common use. 3 tables. 21 references.

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Systemic Effects of Periodontal Diseases Source: in Wilson, T.G., Jr. Kornman, K.S. Fundamentals of Periodontics. 2nd ed. Chicago, IL: Quintessence Publishing Co., Inc. 2003. p. 228-237. Contact: Available from Quintessence Publishing Co, Inc. 551 Kimberly Drive, Carol Stream, IL 60188-9981. (800) 621-0387 or (630) 682-3223. Fax (630) 682-3288. E-mail: [email protected]. Website: www.quintpub.com. PRICE: $82.00 plus shipping and handling. ISBN: 0867154055. Summary: A healthy mouth is part of a healthy lifestyle and recent evidence suggests that poor oral health may be as detrimental to general health as other risk factors, such as smoking or high cholesterol levels. Although the beneficial systemic effects of oral therapy have not been demonstrated, the oral benefits clearly have a positive impact on the quality of life. This chapter on the systemic effects of periodontal diseases is from a periodontics textbook that focuses on diagnosis and clinical management. The authors discuss which systemic diseases are linked with periodontal disease, who is most at risk,

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how oral infection can affect overall health, the entry of periodontal pathogens into the bloodstream, systemic inflammation caused by periodontal pathogens, the evidence linking periodontal disease to heart disease, periodontal infection during pregnancy, the relationship among periodontitis, pneumonia and osteoporosis, the risks associated with periodontal disease in people with diabetes, animal models, and the potential impact on dentistry. The authors note that the recognition of the medical necessity for periodontal care will increase the perceived importance of dental services, and the demand for dental services will increase. 88 references. •

Pediatric HIV Infection Source: in Greenspan, J.S. Greenspan, D., eds. Oral Manifestations of HIV Infection: Proceedings of the Second International Workshop on the Oral Manifestations of HIV Infection. Carol Stream, IL: Quintessence Publishing Company, Inc. 1995. p. 229-233. Contact: Available from Quintessence Publishing Company, Inc. 551 North Kimberly Drive, Carol Stream, IL 60188-1881. (800) 621-0387 or (630) 682-3223; Fax (630) 682-3288; E-mail: [email protected]; http://www.quintpub.com. PRICE: $64.00 plus shipping and handling. ISBN: 0867152869. Summary: This chapter on pediatric HIV infection is from the proceedings of the Second International Workshop on the Oral Manifestations of HIV Infection, held in February 1993 in San Francisco, California. The author hypothesizes that those infants with earlyonset disease were infected in utero, whereas those with a longer incubation period were infected during the peripartum period. The chapter's topics include the clinical presentation of pediatric AIDS; classification; and approaches to therapy, including antiretroviral therapy, and prophylaxis for Pneumocystis carinii pneumonia. 1 table. 11 references.

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Dental Disease and Systemic Infections Source: in Montgomery, M.T. Redding, S.W., eds. Oral-Facial Emergencies: Diagnosis and Management. Portland, OR: JBK Publishing, Inc. 1994. p. 89-102. Contact: Available from Special Care Dentistry. 211 East Chicago Avenue, Chicago, IL 60611. (312) 440-2660. Fax (312) 440-2824. PRICE: $27.00 (member) or $30.00 (nonmember), plus shipping and handling; institutional prices and bulk orders available. ISBN: 0945892055. Summary: This chapter on dental disease and systemic infections is from an emergency room handbook that addresses a variety of orofacial injuries that are likely to be encountered in an acute care setting. The author notes that diseases of the orofacial complex are not always localized and can play a role in causing or exacerbating certain systemic disorders. Conversely, systemic disease is frequently manifested in the oral cavity. The purpose of this chapter is to examine the relationship of orofacial disease to certain systemic illnesses. Topics include fevers of unknown origin, aspiration pneumonia, immunosuppression, and diabetic ketoacidosis. For each, the author presents detailed information on diagnosis and clinical presentation and treatment recommendations. The author does not provide a comprehensive discussion of oral manifestations of systemic disease. 1 figure. 7 tables. 27 references. (AA-M).

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CHAPTER 8. MULTIMEDIA ON PNEUMONIA Overview In this chapter, we show you how to keep current on multimedia sources of information on pneumonia. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine.

Video Recordings An excellent source of multimedia information on pneumonia is the Combined Health Information Database. You will need to limit your search to “Videorecording” and “pneumonia” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find video productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Videorecording (videotape, videocassette, etc.).” Type “pneumonia” (or synonyms) into the “For these words:” box. The following is a typical result when searching for video recordings on pneumonia: •

Understanding PCP: AIDS Pneumonia; A Patient Education Video Program Contact: Burroughs Wellcome Company, 11502 Brighton Ln, Meadows, TX, 77477, (713) 933-1539. Summary: Part one of a two-part series, this video recording educates the viewer about the symptoms and diagnosis of Pneumocystis carinii pneumonia (PCP), in people with AIDS. Physicians and counselors describe PCP and stress the fact that PCP is preventable and treatable. People with AIDS discuss their fears of being diagnosed with PCP and how prophylactic therapy can prevent PCP. The Leader's Guide includes a transcript of the video and lists discussion topics.

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Audio Recordings The Combined Health Information Database contains abstracts on audio productions. To search CHID, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find audio productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Sound Recordings.” Type “pneumonia” (or synonyms) into the “For these words:” box. The following is a typical result when searching for sound recordings on pneumonia: •

What's New With AIDS? Contact: California Medical Association, Audio Digest Foundation, 1577 E Chevy Chase Dr, Glendale, CA, 91206, (213) 245-8505. Summary: This sound recording contains the transcripts of speeches given by three physicians that discuss HIV infection. The first speaker, Dr. Mitchell Katz, traces the scope of HIV infection in the United States and examines the consequences or the new definition of AIDS. He then poses epidemiologic considerations, factors affecting CD4 staging, and the drugs approved for treating HIV infection, AZT and ddI. Other drugs that inhibit reverse transcriptase are also included, as well as the efficacy of antiviral combination therapy. The second speaker, Dr. Neil Flynn, expands on the management of HIV and opportunistic infections. He discusses herpes, bacterial pneumonia, mycobacterium infection, cryptococcal meningitis, PCP, toxoplasmosis, and Kaposi's sarcoma. The concluding speaker, Dr. Faith Fitzgerald, shares some thoughts on the epidemic, including the public perceptions of AIDS and the differing response to this epidemic as opposed to previous ones.

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Lucha Contra el HIV: Un Curso de Supervivencia Contra el SIDA. [Fight Back Against HIV: An AIDS Survival Course.] Contact: Image Enhancement, Incorporated, Glendale, CA, 92109. Summary: This sound recording is hosted by Bill Roberts, who was diagnosed with AIDS-related complex (ARC) in 1987, but says he is now symptom-free. He says that a diagnosis of Human immunodeficiency virus (HIV) infection is no longer a death sentence, because of early intervention and the effective treatments that are now in place. He discusses diagnostic tests and preventive treatment for Pneumocystis carinii pneumonia (PCP). The sound recording discusses the spectrum of HIV disease and the symptoms that accompany each stage. Roberts points out that many people are infected with the virus, but do not realize it because of the slow progression of the disease. Without treatment, 87 percent of those infected will progress to ARC or Acquired immunodeficiency syndrome (AIDS) within 7 to 10 years of infection. But, the sound recording says, with treatment this statistic can be lowered drastically. It urges people to take the HIV-antibody test and then to have their immune systems monitored regularly. The sound recording explains how HIV affects the immune system, and the effect that stress can have on the brain and on the immune system. The importance of thinking positively is emphasized, and the role of visualization in fighting disease is explained. Side two demonstrates a visualization session, emphasizing the importance of sleep, exercise, nutrition, and effective treatment.

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Infectious Diseases and HIV Drug Abusers Contact: Audio Visual, Incorporated, 5542 Tuxedo Rd, Cheverly, MD, 20781, (301) 3225600.

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Summary: This sound recording of a National Institute on Drug Abuse Conference presents a panel discussion held January 15, 1991 of a variety of infectious diseases which affect people with Human immunodeficiency virus (HIV) infection or Acquired immunodeficiency syndrome (AIDS). The first speaker describes the diseases, besides HIV, which he found in a cohort of 800 Intravenous drug users (IVDU's) in the Bronx. Tuberculosis (TB), bacterial pneumonia, and pneumocystis carinii pneumonia (PCP) were among the most common ones found. The second speaker examines vaccines which HIV-positive people may take without ill effects. These include hepatitis, pneumococcal, and various influenza vaccines. Oral polio vaccine should never be given. The third speaker discusses results of examining the death certificates of drug addicts. •

Patient Management and Treatment Contact: Health Impact, PO Box 9443, Seattle, WA, 98109-9443, (206) 284-3865, http://www.healthimpact.org/. Summary: This sound recording deals with the management and treatment of persons with Human immunodeficiency virus (HIV) infection or Acquired immunodeficiency virus (AIDS). Various opportunistic infections, including pneumocystis carinii pneumonia, cytomegalovirus, and certain neurological disorders are described, along with the treatment programs recommended for each at the time the recording was made. Since diagnosis of some opportunistic infections is difficult, various options for laboratory tests are also listed. Review questions and visuals are included in the booklet that accompanies this recording.

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AIDS Update: ED Management, Part II Contact: California Medical Association, Audio Digest Foundation, 1577 E Chevy Chase Dr, Glendale, CA, 91206, (213) 245-8505. Summary: This sound recording, along with accompanying pre-test and post-test questions, comprises part of an ongoing series of educational activities. The first speaker, George F. Risi Jr., Assistant Professor of Medicine at Louisiana State University School of Medicine in New Orleans, looks at the evolution of the Acquired immunodeficiency syndrome (AIDS) epidemic between 1981 and 1986. He discusses the test for Human immunodeficiency virus (HIV) antibodies, HIV transmission, early theories about the origin of the illness, and the Centers for Disease Control and Prevention (CDC) classification system for AIDS patients. David F. Dreis, of the Section of Chest and Infectious Diseases at Virginia Mason Medical Center in Seattle, looks at symptoms and opportunistic infections associated with AIDS in the second presentation. He examines Pneumocystis carinii pneumonia (PCP), Candida Albicans, Kaposi's sarcoma, decreased vision, headache, unexplained fever, leukoplakia, pulmonary diseases, cryptosporidium, toxoplasmosis, and tuberculosis (TB). Asymptomatic carriers are discussed.

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AIDS in ENT Contact: California Medical Association, Audio Digest Foundation, 1577 E Chevy Chase Dr, Glendale, CA, 91206, (213) 245-8505. Summary: This sound recording, along with accompanying pre-test and post-test questions, is part of an ongoing series of educational activities. The first speaker, James S. Atkins Jr. of Wilford Hall United States Air Force Medical Center in San Antonio, TX, discusses Human immunodeficiency virus (HIV) infection and sensorineural hearing

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loss. His presentation deals with subclinical signs of infection and the etiology of the loss. Darius Kohan, Senior Resident in the Deparment of Otolaryngology at New York University Medical Center in New York City, looks at otologic manifestations of Acquired immunodeficiency syndrome (AIDS). Next, Marshall E. Smith, of the Division of Head and Neck Surgery at the University of California Los Angeles Medical Center, examines the neurosyphilis connection. The possibility of HIV transmission through otologic homografts is explored by Glenn W. Knox of the Department of Otolaryngology at Vanderbilt University Medical Center in Nasvhille, TN. Pneumocystis carinii pneumonia (PCP) plays a role in the next presentation, on AIDS and the Bronchoesophagologist. This presentation also looks at oral cavity lesions and cutaneous Kaposi's sarcoma. Michael J. Lanser, Chief Resident of the Department of Otolaryngology/Head and Neck Surgery at the University of California San Francisco Medical Center gives a presention on rhinosporidiosis and other rhinologic manifestations. The final segment, given by Jan Wersall, professor of otolaryngology at Karolinski Institute in Stockholm, deals with personal integrity and protection of patients, health care personnel, and the population in Sweden. •

AIDS: Counseling Patient and Family Contact: California Medical Association, Audio Digest Foundation, 1577 E Chevy Chase Dr, Glendale, CA, 91206, (213) 245-8505. Summary: This sound recording, along with an accompanying pre-test and post-test, is part of an ongoing series of educational activities. It opens with a presentation on Acquired immunodeficiency syndrome (AIDS) and the primary-care physician given by Thomas C. Cesario, professor of medicine at the University of California, Irvine, College of Medicine. He describes the Human immunodeficiency virus (HIV) and its effects on the immune system, then discusses routes of HIV transmission. The HIV-antibody test and its reliability is explained, and criteria for clinical AIDS and for AIDS-related complex (ARC) are given. He goes on to discuss various opportunistic infections, such as Pneumocystis carinii pneumonia (PCP), cryptosporidium, toxoplasmosis, cytomegalovirus, atypical tuberculosis, candidal infections, Kaposi's sarcoma, and hairy leukoplakia. Treatment with azidothymidine (AZT) is explained. The second presentation comes from Sherman N. Williamson, Department of Family Medicine at the University of California, Irvine, College of Medicine. He discusses managing the families of AIDS patients. He looks at specific risk groups and which members needed to be tested, then goes on to list specific goals in family management, other precautionary measures to take, and other considerations.

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AIDS Update: ED Management, Part 1 Contact: California Medical Association, Audio Digest Foundation, 1577 E Chevy Chase Dr, Glendale, CA, 91206, (213) 245-8505. Summary: This sound recording, along with accompanying pre-test and post-test questions, is part on an ongoing series of educational activities. The first speaker, David F. Dreis, from the Section of Chest and Infectious Diseases at the Virginia Mason Medical Center in Seattle, discusses prevalence and detection of Acquired immunodeficiency syndrome (AIDS). He explains the risks involved in blood transfusions, routes of Human immunodeficiency virus (HIV) transmission, the HIVantibody test, and the potential for development of AIDS. David A. Talan, assistant professor of medicine at the University of California Los Angeles School of Medicine, looks at physicians' fear of infection. His presentation deals with the risks of infection for emergency personenel, the possibility of transmission through casual contact, and

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the risks of transmission in the emergency room. He then presents Centers for Disease Control and Prevention (CDC) recommendations for infection control and occupational safety, and procedures for handling a needlestick. The final speaker, George F. Risi Jr., assistant professor of Medicine at Lousiana State University School of Medicine in New Orleans, looks at opportunistic infections in the lung, gut, and brain. His presentation deals with pneumocystis carinii pneumonia (PCP), common respiratory pathogens, gastrointestinal mainfestations, and neurologic manifestations. •

AIDS: Disease, Patient, Internist Contact: California Medical Association, Audio Digest Foundation, 1577 E Chevy Chase Dr, Glendale, CA, 91206, (213) 245-8505. Summary: This sound recording, along with accompanying pre-test and post-test questions, comprises part of an ongoing series of educational activities. The first speaker, Michael S. Gottlieb, of Allergy and Immunology Associates in Santa Monica, CA, discusses real and perceived risks of Human immunodeficiency virus (HIV) transmission. He points out that there are three important routes of transmission: Sexual, parenteral, and perinatal. The likelihood of transmission through insect bites or casual contact is dismissed; the risks in the health-care setting are assessed. Following his speech is a dramatization of a doctor-patient interchange presented by the Los Angeles County Medical Association. The dramatization covers awareness of the patient's sexual behavior; symptoms; asymptomatic carriers; high-risk sexual behavior, possibly risky behavior, and low-risk behavior; and other considerations. Early diagnosis and treatment is the subject of a presentation by Lowell S. Young, clinical professor of medicine at the University of California, San Francisco, School of Medicine; Chief, Division of Infectious Diseases, Pacific Presbyterian Medical Center; and Director, Kuzell Institute for Arthritis and Infectious Diseases, San Francisco. He outlines the various opportunistic infections that may afflict Persons with AIDS (PWA's), including Pneumocystis carinii pneumonia (PCP), leukopenia, cryptosporidiosis, toxoplasmosis, thrush, CMV infection, mycobacterium avium infection, and Kaposi's sarcoma. He also looks at antiviral therapy and bolstering immunity as methods of treatment.

Bibliography: Multimedia on Pneumonia The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the multimedia database, go to the following Web site: http://locatorplus.gov/. Select “Search LOCATORplus.” Once in the search area, simply type in pneumonia (or synonyms). Then, in the option box provided below the search box, select “Audiovisuals and Computer Files.” From there, you can choose to sort results by publication date, author, or relevance. The following multimedia has been indexed on pneumonia: •

Antibiotic therapy for pneumonia, three case presentations [videorecording] Source: produced by Virginia Hospital Television Network, Office of Continuing Education in Medicine and Allied Health Professions, Medical College of Virginia/VirginiaCommonwealth Univ; Year: 1990; Format: Videorecording; [Richmond, Va.]: The College, c1990

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Approach to pneumonias in children [slide] Source: the Radiological Society of North America; Year: 1990; Format: Slide; Oak Brook, Ill.: RSNA, c1990

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Atypical pneumonias [videorecording] Source: presented by Department of Medicine, Emory University, School of Medicine; Year: 1983; Format: Videorecording; Atlanta, Ga.: Emory Medical Television Network, 1983

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Breaking the chain of nosocomial pneumonia [videorecording] Source: produced by Southern Illinois University School of Medicine, Office of Continuing Education, Division of Biomedical Communications and Division of Infectious Diseases of the Department of Medic; Year: 1992; Format: Videorecording; Chapel Hill, NC: Health Sciences Consortium, c1992

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Care of the patient with pneumonia [filmstrip] Source: Trainex Corporation; Year: 1974; Format: Filmstrip; Garden Grove, Calif.: Trainex, c1974

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Community acquired pneumonias [videorecording]: current clinical approaches Source: with George A. Sarosi; Year: 1988; Format: Videorecording; Secaucus, N.J.: Network for Continuing Medical Education, 1988

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Community-acquired pneumonia [videorecording] Source: presented by Department of Medicine, Emory University, School of Medicine; Year: 1982; Format: Videorecording; Atlanta, Ga.: Emory Medical Television Network, 1982

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Eaton agent pneumonia [motion picture] Source: produced by the Communicable Disease Center for the National Institute of Allergy and Infectious Diseases, National Institutes of Health; [presented by] the U.S. Department of Health, Education, and Welfare, Publi; Year: 1962; Format: Motion picture; United States: Dept. of Health, Education, and Welfare, [1962]

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GI grand rounds [videorecording]: the 70-year-old with COPD, pneumonia, and diarrhea Source: with Eugene M. Bozymski; Year: 1987; Format: Videorecording; Secaucus, N.J.: Network for Continuing Medical Education, 1987

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Gram-negative bacillary pneumonia [motion picture] Source: Schering Corporation, in cooperation with American Thoracic Society and American Urologic Association; Year: 1973; Format: Motion picture; Kenilworth, N. J.: Schering: [for loan by Schering Professional Film Library], c1973

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Home nursing in pneumonia [motion picture] Source: [presented by] the State of New York; produced by N.Y. State Dept. of Health; Year: 1940; Format: Motion picture; United States: The Department, 1940

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Hospital-a[c]quired pneumonias [videorecording] Source: CME Productions, Inc., in cooperation with the Infectious Disease Section, Yale University, School of Medicine; Year: 1981; Format: videorecording; [S.l.]: CME Productions, c1981

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Mrs. Trooper, a lady with pneumonia [electronic resource] Source: by Sharon Peirce Corbin; Year: 1992; Format: Electronic resource; Philadelphia, PA: J.B. Lippincott, c1992

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Nosocomial pneumonia [videorecording] Source: the University of Texas Medical School at Houston; produced by UT-TV; Year: 1992; Format: Videorecording; [Houston, Tex.]: UT-TV Houston, c1992

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Pathophysiology of pneumonia [filmstrip] Source: Trainex Corporation; Year: 1974; Format: Filmstrip; Garden Grove, Calif.: Trainex, c1974

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Pneumonia [videorecording] Source: [produced by] Hahnemann Medical College & Hospital and World Video Corp; Year: 1981; Format: Videorecording; Philadelphia, Pa.: Medcare Associates, c1981

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Pneumonias [videorecording]: mycoplasma Source: [presented by] CME Productions, Inc., in cooperation with the Infectious Disease Section, Yale University, School of Medicine; Year: 1981; Format: Videorecording; [S.l.]: CME Productions, c1981

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The Pneumonias [slide] Source: Felix A. Sarubbi, Joseph S. Pagano, Neil Chafetz; Year: 1976; Format: Slide; New York: Medcom, c1976

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The Pneumonias and their complications [slide] Source: Averill A. Liebow; Year: 1974; Format: Slide; [Poway, Calif.: Cal-Med Photo, 1974?]

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The Treatment of pneumonia [videorecording] Source: [presented by] Marshfield Clinic, Saint Joseph's Hospital [and] Marshfield Medical Research Foundation; Year: 1990; Format: Videorecording; Marshfield, WI: Marshfield Video Network, [1990]

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The Viral pneumonias [videorecording] Source: WRAMC-TV, Walter Reed Army Medical Center; Year: 1976; Format: Videorecording; Washington: WRAMC-TV, [1976]

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Ward care of pneumonia patients [motion picture] Source: [presented by] the United States Army; Year: 1950; Format: Motion picture; United States: War Office, 1950

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CHAPTER 9. PERIODICALS AND NEWS ON PNEUMONIA Overview In this chapter, we suggest a number of news sources and present various periodicals that cover pneumonia.

News Services and Press Releases One of the simplest ways of tracking press releases on pneumonia is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “pneumonia” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to pneumonia. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “pneumonia” (or synonyms). The following was recently listed in this archive for pneumonia: •

Vaccine works against more strains of pneumonia bug Source: Reuters Health eLine Date: October 01, 2003 http://www.reutershealth.com/archive/2003/10/01/eline/links/20031001elin008.htm l

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US army stumped by pneumonia among Mideast troops Source: Reuters Health eLine Date: September 12, 2003

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IntraBiotics pneumonia drug gets FDA fast track Source: Reuters Industry Breifing Date: September 05, 2003

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CDC helps U.S. military probe pneumonia cases Source: Reuters Health eLine Date: August 25, 2003

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U.S. says pneumonia cases in Iraq seem 'sporadic' Source: Reuters Health eLine Date: August 05, 2003

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Vaccine for elderly won't prevent pneumonia Source: Reuters Health eLine Date: April 30, 2003

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Pneumococcal vaccine does not prevent pneumonia in elderly Source: Reuters Industry Breifing Date: April 30, 2003

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Pneumonia not a disease of Asians, expert stresses Source: Reuters Health eLine Date: April 08, 2003

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Asia pneumonia outbreak seen disrupting tech links Source: Reuters Health eLine Date: April 03, 2003

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Multi-drug resistant Streptococcus pneumoniae a growing concern Source: Reuters Industry Breifing Date: April 02, 2003

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Asia on edge as killer pneumonia spreads Source: Reuters Health eLine Date: March 28, 2003

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Taiwan reports 4 more deadly pneumonia cases Source: Reuters Health eLine Date: March 27, 2003

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Ontario declares pneumonia emergency Source: Reuters Health eLine Date: March 27, 2003

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China pneumonia toll jumps; Singapore shuts schools Source: Reuters Health eLine Date: March 26, 2003

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Two viruses scrutinized in mystery pneumonia cases Source: Reuters Health eLine Date: March 25, 2003

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Hong Kong Hospital chief ill with pneumonia Source: Reuters Health eLine Date: March 24, 2003

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Four more die from mysterious pneumonia in Asia Source: Reuters Health eLine Date: March 24, 2003

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Diagnostic test for killer pneumonia developed Source: Reuters Health eLine Date: March 24, 2003

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Argentina checks woman for deadly pneumonia Source: Reuters Health eLine Date: March 21, 2003

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Guests flee HK hotel linked to deadly pneumonia Source: Reuters Health eLine Date: March 20, 2003

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German officials accused of stirring pneumonia panic Source: Reuters Health eLine Date: March 20, 2003

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WHO: Killer pneumonia being contained outside Asia Source: Reuters Health eLine Date: March 19, 2003

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UK officials spot 2nd suspected pneumonia case Source: Reuters Health eLine Date: March 19, 2003

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Scientists track source of mystery pneumonia Source: Reuters Health eLine Date: March 19, 2003

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Pneumonia virus may be from species-jumping family Source: Reuters Health eLine Date: March 19, 2003

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Doctors in Hong Kong identify deadly pneumonia virus Source: Reuters Health eLine Date: March 19, 2003

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WHO to visit China over deadly pneumonia Source: Reuters Health eLine Date: March 18, 2003 The NIH

Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “pneumonia” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or


you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “pneumonia” (or synonyms). If you know the name of a company that is relevant to pneumonia, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/. BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “pneumonia” (or synonyms).

Newsletter Articles Use the Combined Health Information Database, and limit your search criteria to “newsletter articles.” Again, you will need to use the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter Article.” Type “pneumonia” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months. The following is a typical result when searching for newsletter articles on pneumonia: •

Delirium in the Medically Ill Elderly Source: Center for the Study of Aging Newsletter. 12(3): 3, 13.Fall 1990. Contact: Available from University of Pennsylvania, Center for the Study of Aging. 3615 Chestnut Street, Philadelphia, PA 19104-6006. (215) 898-3163 or FAX (215) 898-0580. PRICE: Call for price information. Summary: This newsletter articles examines the etiology and treatment of delirium, which affects approximately twenty percent of older adults hospitalized for medical illness. Delirium is an acute phenomenon that has no confirmed etiology or risk factors. Because it is acute, it should not be confused with chronic diseases like Alzheimer's disease or dementia. Recognition of delirium is essential in order to treat underlying medical illnesses. A rapid change in mental function or sudden confusion indicates the need for an evaluation. Medical disorders associated with delirium include acute infections such as urinary tract infections, pneumonia, or meningitis. Medications that affect the central nervous system such as those for Parkinson's disease and drugs to treat peptic ulcers, hypertension, and cardiovascular disease have also been implicated. People who have Alzheimer's disease appear to be at a greater risk for delirium, although older people without cognitive impairment may develop delirium when in a hospital. A prospective study of medically hospitalized elderly persons found that 16 percent of the patients admitted for acute medical care developed delirium while in the hospital. Researchers hope to use information about the development of delirium to more effectively determine its cause and develop new treatments.

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Smoking and Lupus: A Double Whammy! Source: Lupus News. 20(3): 3,9. Summer 2000.

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Contact: Available from Lupus Foundation of America. 1300 Piccard Drive, Suite 200, Rockville, MD 20850-4303. (800) 558-0121 or (301) 670-9292. Fax (301) 670-9486. Website: www.lupus.org/lupus. Summary: This newsletter article provides people who have lupus with information on the impact of smoking on lupus. The article presents evidence demonstrating that smoking complicates and accelerates the adverse effects of lupus. For example, smoking cigarettes increases the risk of pneumonococcal pneumonia and chronic bronchitis, and people who have lupus are more susceptible to infections, particularly respiratory infections. People who have lupus and who smoke have a greater risk of coronary artery disease. Both lupus and smoking can affect blood vessels and circulation, kidney and liver function, wound healing, the digestive system, hair, and bone density. In addition, lupus can cause skin disease, which may be effectively treated with antimalarial medications, but smoking interferes with the benefits of these medications. The article also offers tips for smoking cessation. •

Pulmonary Manifestations of SLE Source: Lupus News. 20(2): 18-19. Spring 2000. Contact: Available from Lupus Foundation of America. 1300 Piccard Drive, Suite 200, Rockville, MD 20850-4303. (800) 558-0121 or (301) 670-9292. Fax (301) 670-9486. Website: www.lupus.org/lupus. Summary: This newsletter article provides people who have lupus with information on its pulmonary manifestations. The prevalence of lung involvement in people with lupus is very high. Lupus manifestations within the lung parenchyma include infections, pneumonitis, interstitial lung disease (ILD), diffuse alveolar hemorrhage, and acute reversible hypoxia syndrome. Infection is the most common cause of an abnormal chest x ray involving the lung parenchyma. People who have lupus are susceptible to infections because their immune system functions abnormally and because the medications they use decrease the ability to resist infection. Infections are caused by bacteria, viruses, fungi, and parasites. Pneumonitis, noninfectious pneumonia, is a form of inflammation within the alveoli that is not associated with infection. ILD is inflammation within the interstitium, which leads to fibrosis in the area if the inflammation persists. Diffuse alveolar hemorrhage is a severe and life threatening complication of lupus and probably reflects vasculitis of the pulmonary blood vessels. Acute reversible hypoxia causes shortness of breath from low oxygen within the blood. Fifty to eighty percent of people who have lupus develop inflammation of the lining around the lungs and the heart, causing fluid to accumulate around these organs. Blood clot formation or elevation of the blood pressure within the pulmonary arteries may also occur in people who have lupus. In rare cases, pulmonary neuromuscular system involvement in lupus can cause shrinking lung syndrome. Drugs used to treat lupus may also have pulmonary side effects. 1 figure.

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Update on the Treatment of Wegener's Granulomatosis Source: Bulletin on the Rheumatic Diseases. 48(11): 1-4. 1999. Contact: Available from Arthritis Foundation. 1330 West Peachtree Street, Atlanta, GA 30309. (404) 872-7100. Fax (404) 872-9559. Summary: This newsletter article provides health professionals with information on the diagnosis and treatment of Wegener's granulomatosis (WG). The etiology of this granulomatous vasculitis involving the upper respiratory tract, lungs, and kidneys is


unknown. WG is diagnosed on the basis of clinical features and laboratory data. Although treatment was once regarded as futile, the disease is currently treated with daily oral cyclophosphamide and glucocorticoids. Cyclophosphamide has been the most effective drug for the induction of WG remission, but its long term use is limited by serious cumulative toxic effects. Opportunistic infections such as Herpes zoster and Pneumocystis carinii pneumonia also complicate cyclophosphamide therapy. As a result of cyclophosphamide toxicity, other drug treatments for WG have been investigated, including intravenous pulse cyclophosphamide; methotrexate; trimethoprim and sulfamethoxazole; azathioprine; and experimental treatments such as intravenous immunoglobulin, cyclosporine, etoposide, anti T cell antibodies, and tumor necrosis factor inhibitors. Maintaining remission is difficult because relapse is common. Predictors of relapse include chronic nasal presence of Staphylococcus aureus and rising c-ANCA titers. Treatment for relapses is determined by the severity of the manifestations. Options for maintenance therapy include methotrexate and azathioprine. The efficacy of using TMSx for maintaining remission is still unknown. 2 tables and 18 references. •

What Else Can We Attribute to GERD? Source: Digestive Health Matters. 3(4): 1-2. Fall 2001. Contact: Available from International Foundation for Functional Gastrointestinal Disorders (IFFGD). P.O. Box 170864, Milwaukee, WI 53217. (888) 964-2001 or (414) 9641799. Fax (414) 964-7176. Website: www.iffgd.org. Summary: This health newsletter article reviews some seldom discussed complications of gastroesophageal reflux disease (GERD). GERD is characterized by the return (reflux) of gastric (stomach) acid backwards into the esophagus. The common symptoms of GERD include heartburn, unexplained chest pain, and inflammation and scarring of the lower esophagus (esophageal stricture) leading to swallowing difficulty. In this article, the author discusses other symptoms associated with GERD which may be common and can cause great distress. These symptoms are sore throat and cough, nocturnal choking, aspiration pneumonia, asthma, acid laryngitis, dental erosions, and reflux dyspareunia (heartburn during sexual intercourse). The author also considers problems with misdiagnosis and treatment options for these lesser-known complications of GERD. Treatment is focused on the rigorous prevention of reflux (drug therapy, lifestyle and dietary changes). 3 references.

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Pediatric Functional Bowel Disorders Source: Gut Waves. 2(1): 1-2. Spring 1997. Contact: Available from APHS, Inc. 158 Pleasant Street, North Andover, MA 01845. (508) 685-4477. Fax (508) 685-4488. E-mail: [email protected]. Summary: This newsletter article, the first in a two-part series on pediatric functional bowel disorders, reviews infant regurgitation and toddler's diarrhea. The author notes that these disorders are not dangerous when the indications and parent concerns are treated and addressed; however, the failure of a caregiver to respond to a functional issue may cause unnecessary physical and or emotional discomfort and, in the most severe cases, prolonged disability. Half of all healthy infants between two and eight months of age vomit two or more times a day; this is perceived as a problem by nearly half of their mothers. Normally, infant regurgitation resolves itself spontaneously after a few months. For the spitting infant with no symptoms such as anemia, pneumonia, refusal to eat, or bloody emesis, tests are not needed, and doctors should concentrate on

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effective reassurance, which has three parts: educating the infant's caregivers about what they can expect, informing the parents of what can be done to help the baby, and promising continuing availability. Toddler's diarrhea is characterized by loose stools, described as running over the diaper and down the leg four to eight times daily, in an otherwise asymptomatic toddler. If the parent is not given effective reassurance that there is not a problem, there will be a series of elimination diets and medical tests, all of which will be unrevealing at best and result in malnutrition at worst. The author recommends that, in an otherwise healthy child, physicians should perform a scrupulously careful examination under the watchful eyes of the parents, and should test stool for occult blood, ova, and parasites. (AA-M). •

Under-the-weather Workouts Source: Consumer Reports on Health. 15(3):7. March 2003. Contact: 101 Truman Avenue, Yonkers, New York. 10703-1057. Summary: This article addresses whether one should exercise when ill. Most health experts feel that this depends on one's condition. With a cold, moderate exercise does not appear to have any affect. It is best to stay below one's usual intensity, however. For more serious infections, like pneumonia or the flu, exercise can overtax the immune system and worsen the illness. In these cases, one is recommended to place workouts on hold until symptoms are gone, and to avoid intense activity for 1 to 2 weeks. At least three clinical trials have shown that regular exercise may help one avoid getting sick in the first place.

•

Growing Older: Health Issues for Minorities Source: Closing the Gap. p.1-2. May 2000. Contact: Department of Health and Human Services. Office of Public Health and Science. Office of Minority Health Resource Center, P.O. Box 37337, Washington, DC 20013-7337. Summary: This article reviews the health issues facing minorities who are age 65 and older. Cardiovascular disease, diabetes, and immunizations are of special concern to this population. Cardiovascular disease is the leading killer among men and women, across all racial and ethnic groups. Diabetes affects 6.3 million people age 65 and over, and occurs most often among older African Americans, Hispanic Americans, and American Indians. Influenza and pneumonia were the fifth leading cause of death for African Americans and Hispanics age 65 and older. The article discusses the health issues for older Asian Americans and Pacific Islanders, Native Americans and Alaska Natives, African Americans, and Hispanics and Latinos.

Academic Periodicals covering Pneumonia Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to pneumonia. In addition to these sources, you can search for articles covering pneumonia that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.”


If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”

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CHAPTER 10. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.

U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for pneumonia. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a nonprofit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI Advice for the Patient can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with pneumonia. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The

406 Pneumonia

following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to pneumonia: Antifungals, Azole •

Systemic - U.S. Brands: Diflucan; Nizoral; Sporanox http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202697.html

Atovaquone •

Systemic - U.S. Brands: Mepron http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202648.html

Azithromycin •

Systemic - U.S. Brands: Zithromax http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202642.html

Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed •

Systemic - U.S. Brands: Acel-Imune; Certiva; Infanrix; Tripedia http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202201.html

http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202911.html •

Systemic - U.S. Brands: Tetramune http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202911.html

Loracarbef •

Systemic - U.S. Brands: Lorabid http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202680.html

Measles Virus Vaccine Live •

Systemic - U.S. Brands: Attenuvax http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202338.html

Palivizumab •

Systemic - U.S. Brands: Synagis http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203646.html

Pentamidine •

Inhalation - U.S. Brands: NebuPent http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202448.html

Pneumococcal Conjugate Vaccine •

Systemic - U.S. Brands: Prevnar http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500121.html

Pyrimethamine •

Systemic - U.S. Brands: Daraprim http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202494.html

Researching Medications 407

Respiratory Syncytial Virus Immune Globulin Intravenous •

Systemic - U.S. Brands: RespiGam http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203069.html

Ribavirin •

Systemic - U.S. Brands: Virazole http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202509.html

Sparfloxacin •

Systemic - U.S. Brands: Zagam http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203530.html

Sulfonamides and Trimethoprim •

Systemic - U.S. Brands: Bactrim; Bactrim DS; Bactrim I.V. Bactrim Pediatric; Cofatrim Forte; Cotrim; Cotrim DS; Cotrim Pediatric; Septra; Septra DS; Septra Grape Suspension; Septra I.V. Septra Suspension; Sulfatrim; Sulfatrim Pediatric; Sulfatrim S/S; Sulfatrim Suspension; S http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202781.html

Trimethoprim •

Systemic - U.S. Brands: Proloprim; Trimpex http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202579.html

Varicella Virus Vaccine Live •

Systemic - U.S. Brands: Varivax http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202998.html

Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.

Mosby’s Drug Consult Mosby’s Drug Consult database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/.

PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html.

408 Pneumonia

Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee.

Researching Orphan Drugs Although the list of orphan drugs is revised on a daily basis, you can quickly research orphan drugs that might be applicable to pneumonia by using the database managed by the National Organization for Rare Disorders, Inc. (NORD), at http://www.rarediseases.org/. Scroll down the page, and on the left toolbar, click on “Orphan Drug Designation Database.” On this page (http://www.rarediseases.org/search/noddsearch.html), type “pneumonia” (or synonyms) into the search box, and click “Submit Query.” When you receive your results, note that not all of the drugs may be relevant, as some may have been withdrawn from orphan status. Write down or print out the name of each drug and the relevant contact information. From there, visit the Pharmacopeia Web site and type the name of each orphan drug into the search box at http://www.nlm.nih.gov/medlineplus/druginformation.html. You may need to contact the sponsor or NORD for further information. NORD conducts “early access programs for investigational new drugs (IND) under the Food and Drug Administration’s (FDA’s) approval ‘Treatment INDs’ programs which allow for a limited number of individuals to receive investigational drugs before FDA marketing approval.” If the orphan product about which you are seeking information is approved for marketing, information on side effects can be found on the product’s label. If the product is not approved, you may need to contact the sponsor. The following is a list of orphan drugs currently listed in the NORD Orphan Drug Designation Database for pneumonia: •

Pentamidine isethionate (trade name: Pentam 300) http://www.rarediseases.org/nord/search/nodd_full?code=343

•

Pentamidine isethionate (trade name: Nebupent) http://www.rarediseases.org/nord/search/nodd_full?code=348

•

Trimetrexate glucuronate (trade name: Neutrexin) http://www.rarediseases.org/nord/search/nodd_full?code=172

•

Pentamidine isethionate (inhalation) (trade name: Pneumopent) http://www.rarediseases.org/nord/search/nodd_full?code=350

•

Primaquine phosphate http://www.rarediseases.org/nord/search/nodd_full?code=425

•

Cytomegalovirus immune globulin intravenous (human http://www.rarediseases.org/nord/search/nodd_full?code=434

•

Dapsone USP (trade name: Dapsone) http://www.rarediseases.org/nord/search/nodd_full?code=440

Researching Medications 409

•

Dapsone USP (trade name: Dapsone) http://www.rarediseases.org/nord/search/nodd_full?code=442

•

Beractant (trade name: Survanta Intratracheal Suspension) http://www.rarediseases.org/nord/search/nodd_full?code=591

•

Clindamycin (trade name: Cleocin) http://www.rarediseases.org/nord/search/nodd_full?code=649

•

Clindamycin (trade name: Cleocin) http://www.rarediseases.org/nord/search/nodd_full?code=650

•

Atovaquone (trade name: Mepron) http://www.rarediseases.org/nord/search/nodd_full?code=675

•

Atovaquone (trade name: Mepron) http://www.rarediseases.org/nord/search/nodd_full?code=676

•

Pentamidine Isethionate http://www.rarediseases.org/nord/search/nodd_full?code=892

If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.

411

APPENDICES

413

APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute12: •

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

•

National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/

•

National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html

•

National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25

•

National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm

•

National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm

•

National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375

•

National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/

12

These publications are typically written by one or more of the various NIH Institutes.

414 Pneumonia

•

National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm

•

National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/

•

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm

•

National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm

•

National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/

•

National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/

•

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm

•

National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html

•

National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm

•

National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm

•

National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm

•

National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html

•

National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm

•

Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp

•

National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/

•

National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp

•

Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html

•

Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm

Physician Resources 415

NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.13 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:14 •

Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html

•

HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

•

NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html

•

Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/

•

Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html

•

Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html

•

Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/

•

Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html

•

Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html

•

Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html

•

MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html

13

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 14 See http://www.nlm.nih.gov/databases/databases.html.

416 Pneumonia

•

Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html

•

Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html The Combined Health Information Database

A comprehensive source of information on clinical guidelines written for professionals is the Combined Health Information Database. You will need to limit your search to one of the following: Brochure/Pamphlet, Fact Sheet, or Information Package, and “pneumonia” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For the publication date, select “All Years.” Select your preferred language and the format option “Fact Sheet.” Type “pneumonia” (or synonyms) into the “For these words:” box. The following is a sample result: •

Pneumocystis Pneumonia - Los Angeles Source: Morbidity and Mortality Weekly Report; Vol. 45, No. 34, Aug. 30, 1996. Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. Summary: This article is one of a series of reprints of articles of historical interest to public health. This article was the first published report about AIDS. It considered the incidence of Pneumocystis carinii pneumonia in five homosexual men in Los Angeles between October 1980 and May 1981. A case report for each of the five patients is presented. All five patients also have laboratory-confirmed cytomegalovirus. This report alerted the medical and public health communities 4 months prior to the first peerreviewed article on AIDS was published.

•

Recommendations for Prophylaxis Against Pneumocystis Carinii Pneumonia for Adults and Adolescents Infected with Human Immunodeficiency Virus Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. Massachusetts Medical Society, Medical Publishing Group, CSPO Box 9121, Waltham, MA, 02254, (800) 843-6356. Summary: This report contains revised recommendations issued by the U.S. Public Health Service Task Force on Antipneumocystis Prophylaxis for Patients with Human Immunodeficiency Virus (HIV) Infection. The Task Force initially met in 1989, and concluded that morbidity, mortality, and cost due to Pneumocystis carinii pneumonia (PCP) could be reduced through prophylactic treatment. From then through August 1991, additional information became available about the efficacy and safety of aerosol pentamidine and oral TMP-SMX, two drugs used extensively in PCP prophylaxis. A clinical trial conducted by the National Institue of Allergy and Infectious Disease (NIAID) AIDS Clinical Trials Group showed that oral TMP-SMX seemed more effective. Based on that information, the Task Force issued new recommendations, covering primary and secondary prophylaxis, evaluation before beginning treatment, and prophylactic regimens. Adverse reactions and monitoring of patients are covered. Separate recommendations for children are issued.


•

Guidelines for Prophylaxis Against Pneumocystis Carinii Pneumonia for Children Infected With Human Immunodeficiency Virus Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. Summary: This report recommends various types of chemotherapeutic regimens that can be used to prevent Pneumocystis carinii pneumonia (PCP) or its symptoms for Human immunodeficiency virus (HIV)-infected or -exposed children. It details the risk for an initial episode or recurrent PCP. It examines the prophylactic regimens of trimethoprim sulfamethoxazole and aerosol pentamidine. The report concludes with recommendations for initiation of PCP prophylaxis for HIV-infected children, patient evaluation, chemoprophylaxis regimen, and alternative regimens.

•

A Treatment IND for the Use of Aerosolized Pentamidine in HIV-Infected Individuals at High Risk for Pneumocystis Carinii Pneumonia Contact: Fujisawa Healthcare Incorporated, Parkway N Center 3 Pky N, Deerfield, IL, 60015-2548, (847) 317-8800, http://www.fujisawa.com. Summary: This report discusses the treatment Investigational new drug (IND) for aerosolized pentamidine as a prophylactic therapy in persons infected with Human immunodeficiency virus (HIV), the etiologic agent of Acquired immunodeficiency syndrome (AIDS), who are at particular risk of developing pneumocystis carinii pneumonia (PCP). The results of a clinical trial of the drug treatment are described; a dose response in favor of a 300 mg dose of aerosolized pentamidine administered every four weeks via the Respirgard II Nebulizer System was found. Various factors related to the trial are described, including study intent and objectives, type of study, patient selection, dose and administration, and patient enrollment and management. The treatment IND also covers adverse experiences, withdrawal from aerosolized pentamidine therapy, evaluation of outcome, and biohazards. The appendix includes informed consent materials.

•

Guidelines for Prophylaxis Against Pneumocystis Carinii Pneumonia for Persons Infected With Human Immunodeficiency Virus Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. Massachusetts Medical Society, Medical Publishing Group, CSPO Box 9121, Waltham, MA, 02254, (800) 843-6356. Summary: This report recommends various types of chemotherapeutic regimens that can be used to prevent Pneumocystis carinii pneumonia (PCP) or its symptoms in Acquired immunodeficiency syndrome (AIDS). It details the risk for an initial episode or recurrent PCP. It examines the prophylactic regimens of trimethoprim sulfamethoxazole and aerosol pentamidine. The report concludes with recommendations for patient evaluation, the choice of a prophylactic agent, patient follow-up, and prophylaxis for infants and children.

•

Increase in Pneumonia Mortality Among Young Adults and the HIV Epidemic - New York City, United States Source: Morbidity and Mortality Weekly Report; Vol. 37, no. 38. Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. Massachusetts Medical Society, Medical Publishing Group, CSPO Box 9121, Waltham, MA, 02254, (800) 843-6356.

418 Pneumonia

Summary: This report looks at the rising rate of death among younger persons in New York City as the rate of Human immunodeficiency virus (HIV) infection also rises. It says that most pneumonia-attributable deaths occur among the elderly, but in New York City, pneumonia death rates among those under 44 have taken a sharp jump, especially in those groups perceived to be at increased risk for Acquired immunodeficiency syndrome (AIDS). Similar trends appear to be taking place in 121 other major cities. The report suggests that further investigations of pneumonia deaths should take into consideration the role of underlying HIV infection.

The NLM Gateway15 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.16 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “pneumonia” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total

Items Found 67189 860 397 2378 34 70858

HSTAT17 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.18 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.19 Simply search by “pneumonia” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

15

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.

16

The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 17 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 18 19

The HSTAT URL is http://hstat.nlm.nih.gov/.

Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community


Coffee Break: Tutorials for Biologists20 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.21 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.22 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •

CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.

•

Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

The Genome Project and Pneumonia In the following section, we will discuss databases and references which relate to the Genome Project and pneumonia. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).23 The database contains textual

Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations. 20 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html. 21

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 22 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process. 23 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.

420 Pneumonia

information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “pneumonia” (or synonyms) into the search box, and click “Submit Search.” If too many results appear, you can narrow the search by adding the word “clinical.” Each report will have additional links to related research and databases. In particular, the option “Database Links” will search across technical databases that offer an abundance of information. The following is an example of the results you can obtain from the OMIM for pneumonia: •

Cholesterol Pneumonia Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?215030

•

Lymphoid Interstitial Pneumonia Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?247610 Genes and Disease (NCBI - Map)

The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. This Web site categorizes each disorder by system of the body. Go to http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to revisit it from time to time. The following systems and associated disorders are addressed: •

Cancer: Uncontrolled cell division. Examples: Breast and ovarian cancer, Burkitt lymphoma, chronic myeloid leukemia, colon cancer, lung cancer, malignant melanoma, multiple endocrine neoplasia, neurofibromatosis, p53 tumor suppressor, pancreatic cancer, prostate cancer, Ras oncogene, RB: retinoblastoma, von Hippel-Lindau syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Cancer.html

•

Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn’s disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html

•

Metabolism: Food and energy. Examples: Adreno-leukodystrophy, atherosclerosis, Best disease, Gaucher disease, glucose galactose malabsorption, gyrate atrophy, juvenile-onset diabetes, obesity, paroxysmal nocturnal hemoglobinuria, phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html

•

Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan syndrome, myotonic dystrophy, spinal muscular atrophy. Web site: http://www.ncbi.nlm.nih.gov/disease/Muscle.html

•

Nervous System: Mind and body. Examples: Alzheimer disease, amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, fragile X syndrome,


Friedreich’s ataxia, Huntington disease, Niemann-Pick disease, Parkinson disease, Prader-Willi syndrome, Rett syndrome, spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html •

Signals: Cellular messages. Examples: Ataxia telangiectasia, Cockayne syndrome, glaucoma, male-patterned baldness, SRY: sex determination, tuberous sclerosis, Waardenburg syndrome, Werner syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Signals.html

•

Transporters: Pumps and channels. Examples: Cystic fibrosis, deafness, diastrophic dysplasia, Hemophilia A, long-QT syndrome, Menkes syndrome, Pendred syndrome, polycystic kidney disease, sickle cell anemia, Wilson’s disease, Zellweger syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Transporters.html Entrez

Entrez is a search and retrieval system that integrates several linked databases at the National Center for Biotechnology Information (NCBI). These databases include nucleotide sequences, protein sequences, macromolecular structures, whole genomes, and MEDLINE through PubMed. Entrez provides access to the following databases: •

3D Domains: Domains from Entrez Structure, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

•

Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books

•

Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome

•

NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/

•

Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide

•

OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

•

PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset

•

ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

•

Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein

•

PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed

•

Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure

422 Pneumonia

•

Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy

To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=genome, and then select the database that you would like to search. The databases available are listed in the drop box next to “Search.” Enter “pneumonia” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database24 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html. The Genome Database25 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “pneumonia” (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms).

24

Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 25 Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.

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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on pneumonia can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.

Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to pneumonia. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages” which list links to available materials relevant to pneumonia. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for “pneumonia”:

424 Pneumonia

•

Guides on pneumonia Pneumonia http://www.nlm.nih.gov/medlineplus/pneumonia.html

•

Other guides Heart Failure http://www.nlm.nih.gov/medlineplus/heartfailure.html Influenza http://www.nlm.nih.gov/medlineplus/influenza.html Meningitis http://www.nlm.nih.gov/medlineplus/meningitis.html Pneumocystis Carinii Infections http://www.nlm.nih.gov/medlineplus/pneumocystiscariniiinfections.html Respiratory Diseases http://www.nlm.nih.gov/medlineplus/respiratorydiseases.html

Within the health topic page dedicated to pneumonia, the following was listed: •

General/Overviews Pneumonia Source: American Lung Association http://www.lungusa.org/diseases/lungpneumoni.html

•

Diagnosis/Symptoms Radiography -- Chest (Chest X-ray) Source: American College of Radiology, Radiological Society of North America http://www.radiologyinfo.org/content/chest_radiography.htm

•

Specific Conditions/Aspects HIV/AIDS and Lung Disease Source: American Lung Association http://www.lungusa.org/diseases/lungaids2.html Walking Pneumonia Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=AN00137

•

Children Pneumococcal Vaccine: When Is It Appropriate for Older Children Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=AN00170 Pneumonia Source: Nemours Foundation http://kidshealth.org/parent/infections/bacterial_viral/pneumonia.html

Patient Resources 425

Pneumonia (For Kids) Source: Nemours Foundation http://kidshealth.org/kid/ill_injure/sick/pneumonia.html •

From the National Institutes of Health Pneumococcal Pneumonia Source: National Institute of Allergy and Infectious Diseases http://www.niaid.nih.gov/factsheets/pneumonia.htm

•

Latest News Vaccine Works Against More Strains of Pneumonia Bug Source: 10/01/2003, Reuters Health http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_14159 .html

•

Organizations American Lung Association http://www.lungusa.org/ National Center for Infectious Diseases http://www.cdc.gov/ncidod/index.htm National Institute of Allergy and Infectious Diseases http://www.niaid.nih.gov/ National Institute on Aging http://www.nia.nih.gov/

•

Prevention/Screening Pneumococcal Conjugate Vaccine: What You Need to Know http://www.cdc.gov/nip/publications/VIS/vis-PneumoConjugate.pdf Pneumonia Prevention: It's Worth a Shot Source: National Institute on Aging http://www.nia.nih.gov/health/agepages/pneum.htm

•

Research Cost-Effectiveness of Pneumococcal Vaccine for People 50 through 64 Years of Age Source: American College of Physicians http://www.annals.org/cgi/content/full/138/12/I-42 Drug Resistant Pneumococcal Bacteria Increasing as Antibiotic Use Grows Source: American Medical Association http://www.medem.com/medlb/article_detaillb.cfm?article_ID=ZZZV34JJXSC&s ub_cat=620 New Measure May Help Prevent Patients with Pneumonia from Being Sent Home Too Soon Source: Agency for Healthcare Research and Quality http://www.ahrq.gov/news/press/pr2002/pneumpr.htm

426 Pneumonia

Ventilator-Associated Pneumonia Source: American College of Physicians http://www.annals.org/cgi/content/full/138/6/I-67 •

Statistics FASTATS: Pneumonia Source: National Center for Health Statistics http://www.cdc.gov/nchs/fastats/pneumonia.htm Percent of Adults Aged 65 Years and Over Who Had Ever Received Pneumococcal Vaccine, by Race/Ethnicity: United States, Quarter One 2002 Source: National Center for Health Statistics http://www.cdc.gov/nchs/about/major/nhis/released200209/figures05_15_3.htm

You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on pneumonia. CHID offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: •

AIDS Pneumonia (PCP): How to Prevent It Contact: Gay Mens Health Crisis, 119 W 24th St Tisch Bldg, New York, NY, 10011-1995, (212) 367-1205, http://www.gmhc.org. Summary: This brochure uses a question-and-answer format to discuss how to prevent pneumocystis carinii pneumonia (PCP). It explains how to find out if you are HIVpositive, what a T-cell test is, and how to obtain one. It describes what medications are used to prevent PCP and lists phone numbers for more information.

•

AgePage: Pneumonia Prevention: It's Worth a Shot Source: Gaithersburg, MD: National Institute on Aging. 1994. 1 p. folded. Contact: National Institute on Aging. P.O. Box 8057, Gaithersburg, MD 20898-8057. (800) 222-2225; TTY (800) 222-4225. PRICE: Free. Summary: This pamphlet provides key facts about pneumonia. It explains the need for older people and those with special risk factors to get vaccinated, and describes the side effects of the vaccination. Medicare covers the cost of the vaccination. Everyone over age


65 should be vaccinated, whether the person has ever had pneumonia or not The side effects are usually mild and last a short time. The pamphlet lists several resource centers for information about adult immunizations. •

PCP (Pneumocystis Carinii Pneumonia) Contact: University of New Mexico School of Medicine, New Mexico AIDS Education and Training Center, New Mexico AIDS InfoNet, PO Box 810, Arroyo Seco, NM, 87514, (505) 776-8032, http://www.aidsinfonet.org. Summary: This information sheet discusses pneumocystis carinii pneumonia (PCP), an opportunistic infection in people with the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). The disease is caused by a fungus that is in almost everyone's body. PCP attacks the lungs of individuals with weakened immune systems and causes a form of pneumonia. The information sheet describes the symptoms of PCP, prevention and treatment, and discusses which antibiotic is most effective against PCP.

•

Pneumocystis Carinii Pneumonia (PCP) Prophylaxis Contact: National AIDS Treatment Information Project, Beth Israel Deaconess Medical Center, Beth Israel Hospital, 330 Brookline Ave Libby Bldg 317, Boston, MA, 02215, (617) 667-5520, http://www.natip.org. Summary: This fact sheet, written for persons with the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), discusses prophylactic treatments available for pneumocystis carinii pneumonia (PCP). Pneumocystic carinnii is a microorganism that causes disease in person whose immune system is damaged by HIV. PCP is a common cause of serious illness, hospitalization, and death in persons with HIV/AIDS, especially in those individuals with a CD4 cell count less than 200. Clinical trials have clearly demonstrated that PCP can be prevented by taking medication, and PCP prophylaxis has been shown to prolong the lives of persons with AIDS. HIV-positive individuals should start PCP prophylaxis when their CD4 cell count drops below 200 or when they have had complications such as thrush or unexplained fever. The major medications available for PCP prophylaxis include trimethoprimsulfamethoxazole (TMP-SMX), daspone, and aerosol pentamidine. The fact sheet identifies how these medications and others are administered and their side effects. HIV-positive individuals whose CD4 cell count was below 200 but rises above this benchmark should discuss the continuance of PCP prophylaxis with their physician. A table is provided that compares commonly used drugs for PCP prophylaxis in categories such as efficacy, toxicity, cost, toxoplasmosis protection, bacterial infection protection, and risk of extrapulmonary PCP.

•

Pneumocystis Carinii Pneumonia (PCP) Contact: National AIDS Treatment Information Project, Beth Israel Deaconess Medical Center, Beth Israel Hospital, 330 Brookline Ave Libby Bldg 317, Boston, MA, 02215, (617) 667-5520, http://www.natip.org. Summary: This fact sheet, written for individuals with the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), presents information about pneumocystis carinii pneumonia (PCP). PCP is a protozoal organism that often attacks the lungs of people with damaged immune systems, such as those with HIV/AIDS. PCP, though an organism that is difficult to avoid, is not likely to be transmitted from person to person. Individuals with HIV who are in the advanced stages of infection and

428 Pneumonia

exhibiting symptoms such as thrush or persistent fever are at risk for PCP. The symptoms of PCP are persistent fever, fatigue, shortness of breath, and a dry cough. PCP may be determined by physical examination, a chest x-ray, an oximeter, a measure of arterial blood gases, an induced sputum test, a bronchoscopy with lavage, a pulmonary function test, and a gallium scan. PCP is treated with oral or intravenous medications over a course of three weeks. Taking daily oral prophylactic medication such as TMP-SMX, daspone, atovaquone, and aerosol pentamidine can prevent PCP. A table identifies the treatments available for PCP.

The National Guideline Clearinghouse™ The National Guideline Clearinghouse™ offers hundreds of evidence-based clinical practice guidelines published in the United States and other countries. You can search this site located at http://www.guideline.gov/ by using the keyword “pneumonia” (or synonyms). The following was recently posted: •

Clinical policy for the management and risk stratification of community-acquired pneumonia in adults in the emergency department Source: American College of Emergency Physicians - Medical Specialty Society; 2001; 7 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3301&nbr=2527&a mp;string=pneumonia

•

Community-acquired pneumonia in adults Source: Institute for Clinical Systems Improvement - Private Nonprofit Organization; 1999 August (revised 2002 May); 41 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3351&nbr=2577&a mp;string=pneumonia

•

Evidence-based assessment of diagnostic tests for ventilator-associated pneumonia Source: American College of Chest Physicians - Medical Specialty Society; 2000 April; 42 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2718&nbr=1944&a mp;string=pneumonia

•

Evidence-based clinical practice guideline of community-acquired pneumonia in children 60 days to 17 years of age Source: Cincinnati Children's Hospital Medical Center - Hospital/Medical Center; 2000 July; 11 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2654&nbr=1880&a mp;string=pneumonia


•

Practice guidelines for the management of community-acquired pneumonia in adults Source: Infectious Diseases Society of America - Medical Specialty Society; 2000 February; 36 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2665&nbr=1891&a mp;string=pneumonia Healthfinder™

Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: •

Fight Flu and Pneumonia Summary: This publication describes the flu, explains which groups of people should get the flu shot and why, directs people on when to get the shot, and informs people on Medicare where they can go to get flu Source: Centers for Medicare and Medicaid Services (CMS), formerly the Health Care Financing Administration http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=3187

•

Severe Acute Respiratory Syndrome (SARS) Information from WHO Summary: Severe Acute Respiratory Syndrome (SARS), an atypical pneumonia of unknown etiology, was recognized at the end of February 2003. Source: World Health Organization http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=7349

•

Test Your Pneumonia I.Q. Summary: Test your knowledge of pneumonia. Answer true or false to the statements online and find out what you know about this respiratory disease. Source: American Association for Respiratory Care http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=6171

•

Warden Notice: Guidance about Severe Acute Respiratory Syndrome for Americans Living Abroad Summary: The Centers for Disease Control and Prevention, HHS, has received reports of outbreaks of a severe form of pneumonia (also being referred to as Severe Acute Respiratory Syndrome, or SARS) in Hong Kong Source: National Center for Infectious Diseases, Centers for Disease Control and Prevention http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=7347

430 Pneumonia

The NIH Search Utility The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to pneumonia. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources

A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats

•

Family Village: http://www.familyvillage.wisc.edu/specific.htm

•

Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/

•

Med Help International: http://www.medhelp.org/HealthTopics/A.html

•

Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/

•

Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/

•

WebMDHealth: http://my.webmd.com/health_topics

Associations and Pneumonia The following is a list of associations that provide information on and resources relating to pneumonia: •

Sarcoidosis Center Telephone: (901) 761-5877 Toll-free: (877) 727-2643 Fax: (901) 761-2280 Email: [email protected] Web Site: http://www.sarcoidcenter.com Background: The Sarcoidosis Center provides a broad range of services for sarcoidosis patients. Sarcoidosis is a multisystem disorder that most often affects individuals between 20 and 40 years of age and is characterized by the abnormal formation of inflammatory masses or nodules of white blood cells in certain organs of the body. Organs or systems that may be affected include the lungs, liver, bone marrow, spleen, musculoskeletal system, heart, salivary glands, and/or nervous system. The center exists as a virtual entity on the Internet and as a real establishment in Memphis, Tenn. Areas to be addressed by the center include coordinating the exchange of information internationally. The center provides disability advice, innovative educational materials, and a toll-free number for support and information. It also hosts workshops and


Internet discussions. Although the major focus is on providing services for patients and their families, funding for research will be provided depending on the availability of funds.

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to pneumonia. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with pneumonia. The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about pneumonia. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “pneumonia” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “pneumonia”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “pneumonia” (or synonyms) into the “For

432 Pneumonia

these words:” box. You should check back periodically with this database since it is updated every three months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “pneumonia” (or a synonym) into the search box, and click “Submit Query.”

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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.

Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.26

Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.

Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of

26

Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.

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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)27: •

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

•

Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)

•

Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

•

California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html

•

California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html

•

California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/

•

California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp

•

California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

•

California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/

•

California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/

•

California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/

•

California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html

•

California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/

•

Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/

•

Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/

•

Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/

27

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

Finding Medical Libraries 435

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Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml

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Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm

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Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html

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Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

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Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp

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Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/

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Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm

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Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html

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Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/

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Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm

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Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/

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Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/

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Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/

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Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm

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Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html

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Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

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Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

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Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

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Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

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Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/

436 Pneumonia

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Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

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Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

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Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

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Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

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Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html

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Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

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Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

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Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

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Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

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Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

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Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

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Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

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Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

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Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

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Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

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Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

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National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

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National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

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National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

Finding Medical Libraries 437

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Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm

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New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

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New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

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New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

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New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

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New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

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New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

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New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

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New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

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Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

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Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

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Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

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Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

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Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

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Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

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Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

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Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

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Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

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Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

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Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/

438 Pneumonia

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South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

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Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

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Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

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Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

439

ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

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MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

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Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

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Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

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On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

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Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

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Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on pneumonia: •

Basic Guidelines for Pneumonia Hospital-acquired pneumonia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000146.htm Mycoplasma pneumonia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000082.htm Pneumonia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000145.htm Pneumonia in immunocompromised host Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000093.htm Pneumonia with lung abscess Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000121.htm

440 Pneumonia

•

Signs & Symptoms for Pneumonia Abdominal pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003120.htm Abnormal (high pitched) breathing sounds Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003074.htm Anxiety, stress, and tension Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm Bluish discoloration of the skin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm Bone pain or tenderness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003180.htm Breath odor Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003058.htm Breath sounds Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003323.htm Breathing, rapid Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003071.htm Chest pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003079.htm Coma Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003202.htm Cough Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003072.htm Coughing Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003072.htm Coughing up blood Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003073.htm Easy fatigue Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Fatigue Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Fever Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003090.htm

Online Glossaries 441

Glands, swollen Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003097.htm Headache Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003024.htm Joint stiffness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003261.htm Joint swelling Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003262.htm Leukemia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001299.htm Loss of appetite Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003121.htm Low blood pressure Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003083.htm Malaise Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003089.htm Muscular stiffness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003178.htm Nail abnormalities Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003247.htm Nasal flaring Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003055.htm Nausea and vomiting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003117.htm Rales Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003323.htm Rapid pulse Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003077.htm Shortness of breath Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003075.htm Skin, clammy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003216.htm Stress Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm

442 Pneumonia

Swallowing difficulty Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003115.htm Sweating, excessive Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003218.htm Tension Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm Vomit Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003117.htm Vomiting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003117.htm Weight loss Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003107.htm Wheezing Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003070.htm •

Diagnostics and Tests for Pneumonia ALT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003473.htm Arterial blood gas Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003855.htm Arterial blood gases Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003855.htm Biopsy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003416.htm Blood culture Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003744.htm Blood gases Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003855.htm Bronchoscopy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003857.htm CBC Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003642.htm Chest X-ray Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm

Online Glossaries 443

CT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm Heart rate Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003399.htm Lung needle biopsy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003860.htm Open lung biopsy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003861.htm Pleural fluid culture Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003725.htm Pulmonary ventilation/perfusion scan Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003828.htm Routine sputum culture Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003723.htm Sputum culture Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003723.htm Sputum gram stain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003765.htm Thoracic CT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003788.htm X-ray Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003337.htm •

Background Topics for Pneumonia Acute Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002215.htm Aerobic bacteria Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003437.htm Alcohol consumption Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001944.htm Anaerobic bacteria Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003439.htm Aspiration Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002216.htm

444 Pneumonia

Auscultation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002226.htm Dental hygiene Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001957.htm Flu vaccine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002025.htm Immune response Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000821.htm Incidence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002387.htm Physical examination Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002274.htm Respiratory Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002290.htm Shock Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000039.htm Unconscious Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000022.htm

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

•

MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

•

Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

•

Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

445

PNEUMONIA DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 3-dimensional: 3-D. A graphic display of depth, width, and height. Three-dimensional radiation therapy uses computers to create a 3-dimensional picture of the tumor. This allows doctors to give the highest possible dose of radiation to the tumor, while sparing the normal tissue as much as possible. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Abscess: Accumulation of purulent material in tissues, organs, or circumscribed spaces, usually associated with signs of infection. [NIH] Academic Medical Centers: Medical complexes consisting of medical school, hospitals, clinics, libraries, administrative facilities, etc. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acetylcysteine: The N-acetyl derivative of cysteine. It is used as a mucolytic agent to reduce the viscosity of mucous secretions. It has also been shown to have antiviral effects in patients with HIV due to inhibition of viral stimulation by reactive oxygen intermediates. [NIH] Acidosis: A pathologic condition resulting from accumulation of acid or depletion of the alkaline reserve (bicarbonate content) in the blood and body tissues, and characterized by an increase in hydrogen ion concentration. [EU] Acinetobacter: A genus of gram-negative bacteria of the family Neisseriaceae, found in soil and water and of uncertain pathogenicity. [NIH] Acne: A disorder of the skin marked by inflammation of oil glands and hair glands. [NIH] Acoustic: Having to do with sound or hearing. [NIH] Acquired Immunodeficiency Syndrome: An acquired defect of cellular immunity associated with infection by the human immunodeficiency virus (HIV), a CD4-positive Tlymphocyte count under 200 cells/microliter or less than 14% of total lymphocytes, and increased susceptibility to opportunistic infections and malignant neoplasms. Clinical manifestations also include emaciation (wasting) and dementia. These elements reflect criteria for AIDS as defined by the CDC in 1993. [NIH] Actin: Essential component of the cell skeleton. [NIH]

446 Pneumonia

Acute Disease: Disease having a short and relatively severe course. [NIH] Acute leukemia: A rapidly progressing cancer of the blood-forming tissue (bone marrow). [NIH]

Acute lymphoblastic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphocytic leukemia. [NIH] Acute lymphocytic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphoblastic leukemia. [NIH] Acute myelogenous leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute nonlymphocytic leukemia. [NIH] Acute myeloid leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myelogenous leukemia or acute nonlymphocytic leukemia. [NIH] Acute nonlymphocytic leukemia: A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute myelogenous leukemia. [NIH] Acute renal: A condition in which the kidneys suddenly stop working. In most cases, kidneys can recover from almost complete loss of function. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenoma: A benign epithelial tumor with a glandular organization. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adhesions: Pathological processes consisting of the union of the opposing surfaces of a wound. [NIH] Adjunctive Therapy: Another treatment used together with the primary treatment. Its purpose is to assist the primary treatment. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adolescence: The period of life beginning with the appearance of secondary sex

Dictionary 447

characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adoptive Transfer: Form of passive immunization where previously sensitized immunologic agents (cells or serum) are transferred to non-immune recipients. When transfer of cells is used as a therapy for the treatment of neoplasms, it is called adoptive immunotherapy (immunotherapy, adoptive). [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]

Aetiology: Study of the causes of disease. [EU] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agammaglobulinemia: An immunologic deficiency state characterized by an extremely low level of generally all classes of gamma-globulin in the blood. [NIH] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]

Age Groups: Persons classified by age from birth (infant, newborn) to octogenarians and older (aged, 80 and over). [NIH] Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Aged, 80 and Over: A person 80 years of age and older. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Air Sacs: Thin-walled sacs or spaces which function as a part of the respiratory system in birds, fishes, insects, and mammals. [NIH]

448 Pneumonia

Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Alanine: A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system. [NIH] Alertness: A state of readiness to detect and respond to certain specified small changes occurring at random intervals in the environment. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkaline Phosphatase: An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. EC 3.1.3.1. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allogeneic: Taken from different individuals of the same species. [NIH] Allogeneic bone marrow transplantation: A procedure in which a person receives stem cells, the cells from which all blood cells develop, from a compatible, though not genetically identical, donor. [NIH] Allylamine: Possesses an unusual and selective cytotoxicity for vascular smooth muscle cells in dogs and rats. Useful for experiments dealing with arterial injury, myocardial fibrosis or cardiac decompensation. [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Alum: A type of immune adjuvant (a substance used to help boost the immune response to a vaccine). Also called aluminum sulfate. [NIH] Aluminum: A metallic element that has the atomic number 13, atomic symbol Al, and atomic weight 26.98. [NIH] Alveoli: Tiny air sacs at the end of the bronchioles in the lungs. [NIH] Amantadine: An antiviral that is used in the prophylactic or symptomatic treatment of Influenza A. It is also used as an antiparkinsonian agent, to treat extrapyramidal reactions, and for postherpetic neuralgia. The mechanisms of its effects in movement disorders are not well understood but probably reflect an increase in synthesis and release of dopamine, with

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perhaps some inhibition of dopamine uptake. [NIH] Ameliorated: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] Amino acid: Any organic compound containing an amino (-NH2 and a carboxyl (- COOH) group. The 20 a-amino acids listed in the accompanying table are the amino acids from which proteins are synthesized by formation of peptide bonds during ribosomal translation of messenger RNA; all except glycine, which is not optically active, have the L configuration. Other amino acids occurring in proteins, such as hydroxyproline in collagen, are formed by posttranslational enzymatic modification of amino acids residues in polypeptide chains. There are also several important amino acids, such as the neurotransmitter y-aminobutyric acid, that have no relation to proteins. Abbreviated AA. [EU] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Aminoquinolines: Quinolines substituted in any position by one or more amino groups. [NIH]

Amitriptyline: Tricyclic antidepressant with anticholinergic and sedative properties. It appears to prevent the re-uptake of norepinephrine and serotonin at nerve terminals, thus potentiating the action of these neurotransmitters. Amitriptyline also appears to antaganize cholinergic and alpha-1 adrenergic responses to bioactive amines. [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amoxicillin: A broad-spectrum semisynthetic antibiotic similar to ampicillin except that its resistance to gastric acid permits higher serum levels with oral administration. [NIH] Ampicillin: Semi-synthetic derivative of penicillin that functions as an orally active broadspectrum antibiotic. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH] Anaerobic: 1. Lacking molecular oxygen. 2. Growing, living, or occurring in the absence of molecular oxygen; pertaining to an anaerobe. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU]

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Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Analysis of Variance: A statistical technique that isolates and assesses the contributions of categorical independent variables to variation in the mean of a continuous dependent variable. [NIH] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Ankle: That part of the lower limb directly above the foot. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]

Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Antiangiogenic: Having to do with reducing the growth of new blood vessels. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibiotic Prophylaxis: Use of antibiotics before, during, or after a diagnostic, therapeutic,

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or surgical procedure to prevent infectious complications. [NIH] Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticholinergic: An agent that blocks the parasympathetic nerves. Called also parasympatholytic. [EU] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Anticonvulsant: An agent that prevents or relieves convulsions. [EU] Antidepressant: A drug used to treat depression. [NIH] Antidote: A remedy for counteracting a poison. [EU] Antifungal: Destructive to fungi, or suppressing their reproduction or growth; effective against fungal infections. [EU] Antifungal Agents: Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from fungicides, industrial because they defend against fungi present in human or animal tissues. [NIH] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH] Anti-infective: An agent that so acts. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antineoplastic Agents: Substances that inhibit or prevent the proliferation of neoplasms. [NIH]

Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are

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split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiproliferative: Counteracting a process of proliferation. [EU] Antipsychotic: Effective in the treatment of psychosis. Antipsychotic drugs (called also neuroleptic drugs and major tranquilizers) are a chemically diverse (including phenothiazines, thioxanthenes, butyrophenones, dibenzoxazepines, dibenzodiazepines, and diphenylbutylpiperidines) but pharmacologically similar class of drugs used to treat schizophrenic, paranoid, schizoaffective, and other psychotic disorders; acute delirium and dementia, and manic episodes (during induction of lithium therapy); to control the movement disorders associated with Huntington's chorea, Gilles de la Tourette's syndrome, and ballismus; and to treat intractable hiccups and severe nausea and vomiting. Antipsychotic agents bind to dopamine, histamine, muscarinic cholinergic, a-adrenergic, and serotonin receptors. Blockade of dopaminergic transmission in various areas is thought to be responsible for their major effects : antipsychotic action by blockade in the mesolimbic and mesocortical areas; extrapyramidal side effects (dystonia, akathisia, parkinsonism, and tardive dyskinesia) by blockade in the basal ganglia; and antiemetic effects by blockade in the chemoreceptor trigger zone of the medulla. Sedation and autonomic side effects (orthostatic hypotension, blurred vision, dry mouth, nasal congestion and constipation) are caused by blockade of histamine, cholinergic, and adrenergic receptors. [EU] Antiserum: The blood serum obtained from an animal after it has been immunized with a particular antigen. It will contain antibodies which are specific for that antigen as well as antibodies specific for any other antigen with which the animal has previously been immunized. [NIH] Antithrombotic: Preventing or interfering with the formation of thrombi; an agent that so acts. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Aorta: The main trunk of the systemic arteries. [NIH] Aortic Aneurysm: Aneurysm of the aorta. [NIH] Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Appendicitis: Acute inflammation of the vermiform appendix. [NIH] Applicability: A list of the commodities to which the candidate method can be applied as presented or with minor modifications. [NIH] Approximate: Approximal [EU] Aqueous: Having to do with water. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat

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as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Archaea: One of the three domains of life (the others being bacteria and Eucarya), formerly called Archaebacteria under the taxon Bacteria, but now considered separate and distinct. They are characterized by: 1) the presence of characteristic tRNAs and ribosomal RNAs; 2) the absence of peptidoglycan cell walls; 3) the presence of ether-linked lipids built from branched-chain subunits; and 4) their occurrence in unusual habitats. While archaea resemble bacteria in morphology and genomic organization, they resemble eukarya in their method of genomic replication. The domain contains at least three kingdoms: crenarchaeota, euryarchaeota, and korarchaeota. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Arteriosus: Circle composed of anastomosing arteries derived from two long posterior ciliary and seven anterior ciliary arteries, located in the ciliary body about the root of the iris. [NIH]

Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Arteriovenous Fistula: An abnormal communication between an artery and a vein. [NIH] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Arthralgia: Pain in the joint. [NIH] Aspergillus: A genus of mitosporic fungi containing about 100 species and eleven different teleomorphs in the family Trichocomaceae. [NIH] Asphyxia: A pathological condition caused by lack of oxygen, manifested in impending or actual cessation of life. [NIH] Aspirate: Fluid withdrawn from a lump, often a cyst, or a nipple. [NIH] Aspiration: The act of inhaling. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atelectasis: Incomplete expansion of the lung. [NIH]

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Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Auditory: Pertaining to the sense of hearing. [EU] Auscultation: Act of listening for sounds within the body. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autologous bone marrow transplantation: A procedure in which bone marrow is removed from a person, stored, and then given back to the person after intensive treatment. [NIH] Autolysis: The spontaneous disintegration of tissues or cells by the action of their own autogenous enzymes. [NIH] Autopsy: Postmortem examination of the body. [NIH] Avidity: The strength of the interaction of an antiserum with a multivalent antigen. [NIH] Axenic: Not contaminated by or, associated with any foreign organisms. [NIH] Azithromycin: A semi-synthetic macrolide antibiotic structurally related to erythromycin. It has been used in the treatment of Mycobacterium avium intracellulare infections, toxoplasmosis, and cryptosporidiosis. [NIH] Bacillus: A genus of Bacillaceae that are spore-forming, rod-shaped cells. Most species are saprophytic soil forms with only a few species being pathogenic. [NIH] Bacteraemia: The presence of bacteria in the blood. [EU] Bacteremia: The presence of viable bacteria circulating in the blood. Fever, chills, tachycardia, and tachypnea are common acute manifestations of bacteremia. The majority of cases are seen in already hospitalized patients, most of whom have underlying diseases or procedures which render their bloodstreams susceptible to invasion. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Adhesion: Physicochemical property of fimbriated and non-fimbriated bacteria of attaching to cells, tissue, and nonbiological surfaces. It is a factor in bacterial colonization and pathogenicity. [NIH] Bacterial Infections: Infections by bacteria, general or unspecified. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bacterial Proteins: Proteins found in any species of bacterium. [NIH] Bacterial toxin: A toxic substance, made by bacteria, that can be modified to kill specific tumor cells without harming normal cells. [NIH] Bacterial Translocation: The passage of viable bacteria from the gastrointestinal tract to extra-intestinal sites, such as the mesenteric lymph node complex, liver, spleen, kidney, and blood. Factors that promote bacterial translocation include overgrowth with gram-negative

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enteric bacilli, impaired host immune defenses, and injury to the intestinal mucosa resulting in increased intestinal permeability. These mechanisms can act in concert to promote synergistically the systemic spread of indigenous translocating bacteria to cause lethal sepsis. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Bacteriostatic: 1. Inhibiting the growth or multiplication of bacteria. 2. An agent that inhibits the growth or multiplication of bacteria. [EU] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Bacteriuria: The presence of bacteria in the urine with or without consequent urinary tract infection. Since bacteriuria is a clinical entity, the term does not preclude the use of urine/microbiology for technical discussions on the isolation and segregation of bacteria in the urine. [NIH] Barium: An element of the alkaline earth group of metals. It has an atomic symbol Ba, atomic number 56, and atomic weight 138. All of its acid-soluble salts are poisonous. [NIH] Barium swallow: A series of x-rays of the esophagus. The x-ray pictures are taken after the person drinks a solution that contains barium. The barium coats and outlines the esophagus on the x-ray. Also called an esophagram. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Bereavement: Refers to the whole process of grieving and mourning and is associated with a deep sense of loss and sadness. [NIH] Beta-glucans: Polysaccharides made by several types of mushrooms. Beta-glucans have been used to treat patients with gastric cancer and colorectal cancer. They may be able to stimulate the immune system. [NIH]

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Beta-Lactamases: Enzymes found in many bacteria which catalyze the hydrolysis of the amide bond in the beta-lactam ring. Well known antibiotics destroyed by these enzymes are penicillins and cephalosporins. EC 3.5.2.6. [NIH] Beta-pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile duct: A tube through which bile passes in and out of the liver. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioassay: Determination of the relative effective strength of a substance (as a vitamin, hormone, or drug) by comparing its effect on a test organism with that of a standard preparation. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biochemical reactions: In living cells, chemical reactions that help sustain life and allow cells to grow. [NIH] Biogenesis: The origin of life. It includes studies of the potential basis for life in organic compounds but excludes studies of the development of altered forms of life through mutation and natural selection, which is evolution. [NIH] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biological Warfare: Warfare involving the use of living organisms or their products as disease etiologic agents against people, animals, or plants. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biophysics: The science of physical phenomena and processes in living organisms. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biopsy specimen: Tissue removed from the body and examined under a microscope to determine whether disease is present. [NIH] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic

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engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Bioterrorism: The use of biological agents in terrorism. This includes the malevolent use of bacteria, viruses, or toxins against people, animals, or plants. [NIH] Biotype: A group of individuals having the same genotype. [NIH] Biphasic: Having two phases; having both a sporophytic and a gametophytic phase in the life cycle. [EU] Bladder: The organ that stores urine. [NIH] Blood Cell Count: A count of the number of leukocytes and erythrocytes per unit volume in a sample of venous blood. A complete blood count (CBC) also includes measurement of the hemoglobin, hematocrit, and erythrocyte indices. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood transfusion: The administration of blood or blood products into a blood vessel. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Body Composition: The relative amounts of various components in the body, such as percent body fat. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [NIH] Bolus: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus infusion. [NIH] Bolus infusion: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus. [NIH] Bombesin: A tetradecapeptide originally obtained from the skins of toads Bombina bombina and B. variegata. It is also an endogenous neurotransmitter in many animals including mammals. Bombesin affects vascular and other smooth muscle, gastric secretion, and renal circulation and function. [NIH] Bone Density: The amount of mineral per square centimeter of bone. This is the definition used in clinical practice. Actual bone density would be expressed in grams per milliliter. It is most frequently measured by photon absorptiometry or x-ray computed tomography. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and

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is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone Marrow Cells: Cells contained in the bone marrow including fat cells, stromal cells, megakaryocytes, and the immediate precursors of most blood cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Breakdown: A physical, metal, or nervous collapse. [NIH] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Bronchiectasis: Persistent abnormal dilatation of the bronchi. [NIH] Bronchioles: The tiny branches of air tubes in the lungs. [NIH] Bronchiolitis: Inflammation of the bronchioles. [NIH] Bronchiolitis Obliterans: Inflammation of the bronchioles with obstruction by fibrous granulation tissue or bronchial exudate. It may follow inhalation of irritating gases or foreign bodies and it complicates pneumonia. [NIH] Bronchiolitis Obliterans Organizing Pneumonia: Inflammation of the bronchioles. [NIH] Bronchiseptica: A small, gram-negative, motile bacillus. A normal inhabitant of the respiratory tract in man, dogs, and pigs, but is also associated with canine infectious tracheobronchitis and atrophic rhinitis in pigs. [NIH] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH] Bronchoalveolar Lavage: Washing out of the lungs with saline or mucolytic agents for diagnostic or therapeutic purposes. It is very useful in the diagnosis of diffuse pulmonary infiltrates in immunosuppressed patients. [NIH] Bronchoalveolar Lavage Fluid: Fluid obtained by washout of the alveolar compartment of the lung. It is used to assess biochemical and inflammatory changes in and effects of therapy on the interstitial lung tissue. [NIH] Bronchoconstriction: Diminution of the caliber of a bronchus physiologically or as a result

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of pharmacological intervention. [NIH] Bronchoscope: A thin, lighted tube used to examine the inside of the trachea and bronchi, the air passages that lead into the lungs. [NIH] Bronchoscopy: Endoscopic examination, therapy or surgery of the bronchi. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Burns: Injuries to tissues caused by contact with heat, steam, chemicals (burns, chemical), electricity (burns, electric), or the like. [NIH] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Cachexia: General ill health, malnutrition, and weight loss, usually associated with chronic disease. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Caloric intake: Refers to the number of calories (energy content) consumed. [NIH] Candidiasis: Infection with a fungus of the genus Candida. It is usually a superficial infection of the moist cutaneous areas of the body, and is generally caused by C. albicans; it most commonly involves the skin (dermatocandidiasis), oral mucous membranes (thrush, def. 1), respiratory tract (bronchocandidiasis), and vagina (vaginitis). Rarely there is a systemic infection or endocarditis. Called also moniliasis, candidosis, oidiomycosis, and formerly blastodendriosis. [EU] Candidosis: An infection caused by an opportunistic yeasts that tends to proliferate and become pathologic when the environment is favorable and the host resistance is weakened. [NIH]

Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capsid: The outer protein protective shell of a virus, which protects the viral nucleic acid. [NIH]

Capsular: Cataract which is initiated by an opacification at the surface of the lens. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbamazepine: An anticonvulsant used to control grand mal and psychomotor or focal seizures. Its mode of action is not fully understood, but some of its actions resemble those of phenytoin; although there is little chemical resemblance between the two compounds, their three-dimensional structure is similar. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH]

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Carboxy: Cannabinoid. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinogens: Substances that increase the risk of neoplasms in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. [NIH] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Cardiac: Having to do with the heart. [NIH] Cardiogenic: Originating in the heart; caused by abnormal function of the heart. [EU] Cardiopulmonary: Having to do with the heart and lungs. [NIH] Cardiopulmonary Resuscitation: The artificial substitution of heart and lung action as indicated for heart arrest resulting from electric shock, drowning, respiratory arrest, or other causes. The two major components of cardiopulmonary resuscitation are artificial ventilation and closed-chest cardiac massage. [NIH] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Carrier State: The condition of harboring an infective organism without manifesting symptoms of infection. The organism must be readily transmissable to another susceptible host. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] Case-Control Studies: Studies which start with the identification of persons with a disease of interest and a control (comparison, referent) group without the disease. The relationship of an attribute to the disease is examined by comparing diseased and non-diseased persons with regard to the frequency or levels of the attribute in each group. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Catalyse: To speed up a chemical reaction. [EU] Catheter: A flexible tube used to deliver fluids into or withdraw fluids from the body. [NIH] Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ, or body cavity for injecting or withdrawing fluids for diagnostic or therapeutic purposes. It differs from intubation in that the tube here is used to restore or maintain patency in obstructions. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Causal: Pertaining to a cause; directed against a cause. [EU]

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Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Caveolae: Endocytic/exocytic cell membrane structures rich in glycosphingolipids, cholesterol, and lipid-anchored membrane proteins that function in endocytosis (potocytosis), transcytosis, and signal transduction. Caveolae assume various shapes from open pits to closed vesicles. Caveolar coats are composed of caveolins. [NIH] Caveolins: The main structural proteins of caveolae. Several distinct genes for caveolins have been identified. [NIH] Cefaclor: Semisynthetic, broad-spectrum antibiotic derivative of cephalexin. [NIH] Cefotaxime: Semisynthetic broad-spectrum cephalosporin. [NIH] Ceftazidime: Semisynthetic, broad-spectrum antibacterial derived from cephaloridine and used especially for Pseudomonas and other gram-negative infections in debilitated patients. [NIH]

Ceftriaxone: Broad-spectrum cephalosporin antibiotic with a very long half-life and high penetrability to usually inaccessible infections, including those involving the meninges, eyes, inner ears, and urinary tract. [NIH] Cefuroxime: Broad-spectrum cephalosporin antibiotic resistant to beta-lactamase. It has been proposed for infections with gram-negative and gram-positive organisms, gonorrhea, and haemophilus. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Adhesion Molecules: Surface ligands, usually glycoproteins, that mediate cell-to-cell adhesion. Their functions include the assembly and interconnection of various vertebrate systems, as well as maintenance of tissue integration, wound healing, morphogenic movements, cellular migrations, and metastasis. [NIH] Cell Count: A count of the number of cells of a specific kind, usually measured per unit volume of sample. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell Membrane Structures: Structures which are part of the cell membrane or have cell membrane as a major part of their structure. [NIH] Cell motility: The ability of a cell to move. [NIH] Cell Physiology: Characteristics and physiological processes of cells from cell division to cell death. [NIH] Cell Polarity: Orientation of intracellular structures especially with respect to the apical and basolateral domains of the plasma membrane. Polarized cells must direct proteins from the Golgi apparatus to the appropriate domain since tight junctions prevent proteins from

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diffusing between the two domains. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [NIH] Cellular metabolism: The sum of all chemical changes that take place in a cell through which energy and basic components are provided for essential processes, including the synthesis of new molecules and the breakdown and removal of others. [NIH] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Central Nervous System Infections: Pathogenic infections of the brain, spinal cord, and meninges. DNA virus infections; RNA virus infections; bacterial infections; mycoplasma infections; Spirochaetales infections; fungal infections; protozoan infections; helminthiasis; and prion diseases may involve the central nervous system as a primary or secondary process. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Cephalexin: A semisynthetic cephalosporin antibiotic with antimicrobial activity similar to that of cephaloridine or cephalothin, but somewhat less potent. It is effective against both gram-positive and gram-negative organisms. [NIH] Cephaloridine: A cephalosporin antibiotic. [NIH] Cephalosporins: A group of broad-spectrum antibiotics first isolated from the Mediterranean fungus Acremonium (Cephalosporium acremonium). They contain the betalactam moiety thia-azabicyclo-octenecarboxylic acid also called 7-aminocephalosporanic acid. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] Cerebral Palsy: Refers to a motor disability caused by a brain dysfunction. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH]

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Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Chemical Warfare: Tactical warfare using incendiary mixtures, smokes, or irritant, burning, or asphyxiating gases. [NIH] Chemical Warfare Agents: Chemicals that are used to cause the disturbance, disease, or death of humans during war. [NIH] Chemokines: Class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. They can be divided into at least three structural branches: C (chemokines, C), CC (chemokines, CC), and CXC (chemokines, CXC), according to variations in a shared cysteine motif. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotaxis: The movement of cells or organisms toward or away from a substance in response to its concentration gradient. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chest Pain: Pressure, burning, or numbness in the chest. [NIH] Chest wall: The ribs and muscles, bones, and joints that make up the area of the body between the neck and the abdomen. [NIH] Chickenpox: A mild, highly contagious virus characterized by itchy blisters all over the body. [NIH] Chimera: An individual that contains cell populations derived from different zygotes. [NIH] Chimeric Proteins: Proteins in individuals that are derived from genetically different zygotes. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Chlorhexidine: Disinfectant and topical anti-infective agent used also as mouthwash to prevent oral plaque. [NIH] Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [NIH] Cholera: An acute diarrheal disease endemic in India and Southeast Asia whose causative agent is vibrio cholerae. This condition can lead to severe dehydration in a matter of hours unless quickly treated. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU]

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Cholinesterase Inhibitors: Drugs that inhibit cholinesterases. The neurotransmitter acetylcholine is rapidly hydrolyzed, and thereby inactivated, by cholinesterases. When cholinesterases are inhibited, the action of endogenously released acetylcholine at cholinergic synapses is potentiated. Cholinesterase inhibitors are widely used clinically for their potentiation of cholinergic inputs to the gastrointestinal tract and urinary bladder, the eye, and skeletal muscles; they are also used for their effects on the heart and the central nervous system. [NIH] Chondrocytes: Polymorphic cells that form cartilage. [NIH] Chorea: Involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement. Hypotonia and pendular reflexes are often associated. Conditions which feature recurrent or persistent episodes of chorea as a primary manifestation of disease are referred to as choreatic disorders. Chorea is also a frequent manifestation of basal ganglia diseases. [NIH] Chorioretinitis: Inflammation of the choroid in which the sensory retina becomes edematous and opaque. The inflammatory cells and exudate may burst through the sensory retina to cloud the vitreous body. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic granulocytic leukemia: A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myelogenous leukemia or chronic myeloid leukemia. [NIH] Chronic lymphocytic leukemia: A slowly progressing disease in which too many white blood cells (called lymphocytes) are found in the body. [NIH] Chronic myelogenous leukemia: CML. A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myeloid leukemia or chronic granulocytic leukemia. [NIH] Chronic Obstructive Pulmonary Disease: Collective term for chronic bronchitis and emphysema. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Cilastatin: A renal dehydropeptidase-I and leukotriene D4 dipeptidase inhibitor. Since the antibiotic, imipenem, is hydrolyzed by dehydropeptidase-I, which resides in the brush border of the renal tubule, cilastatin is administered with imipenem to increase its effectiveness. The drug also inhibits the metabolism of leukotriene D4 to leukeotriene E4. [NIH]

Ciliary: Inflammation or infection of the glands of the margins of the eyelids. [NIH]

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Ciprofloxacin: A carboxyfluoroquinoline antimicrobial agent that is effective against a wide range of microorganisms. It has been successfully and safely used in the treatment of resistant respiratory, skin, bone, joint, gastrointestinal, urinary, and genital infections. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Clarithromycin: A semisynthetic macrolide antibiotic derived from erythromycin that is active against a variety of microorganisms. It can inhibit protein synthesis in bacteria by reversibly binding to the 50S ribosomal subunits. This inhibits the translocation of aminoacyl transfer-RNA and prevents peptide chain elongation. [NIH] Claudication: Limping or lameness. [EU] Cleave: A double-stranded cut in DNA with a restriction endonuclease. [NIH] Clindamycin: An antibacterial agent that is a semisynthetic analog of lincomycin. [NIH] Clinical Protocols: Precise and detailed plans for the study of a medical or biomedical problem and/or plans for a regimen of therapy. [NIH] Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]

Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Clot Retraction: Retraction of a clot resulting from contraction of platelet pseudopods attached to fibrin strands that is dependent on the contractile protein thrombosthenin. Used as a measure of platelet function. [NIH] Clozapine: A tricylic dibenzodiazepine, classified as an atypical antipsychotic agent. It binds several types of central nervous system receptors, and displays a unique pharmacological profile. Clozapine is a serotonin antagonist, with strong binding to 5-HT 2A/2C receptor subtype. It also displays strong affinity to several dopaminergic receptors, but shows only weak antagonism at the dopamine D2 receptor, a receptor commonly thought to modulate neuroleptic activity. Agranulocytosis is a major adverse effect associated with administration of this agent. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH]

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Cohort Studies: Studies in which subsets of a defined population are identified. These groups may or may not be exposed to factors hypothesized to influence the probability of the occurrence of a particular disease or other outcome. Cohorts are defined populations which, as a whole, are followed in an attempt to determine distinguishing subgroup characteristics. [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Combined Modality Therapy: The treatment of a disease or condition by several different means simultaneously or sequentially. Chemoimmunotherapy, radioimmunotherapy, chemoradiotherapy, cryochemotherapy, and salvage therapy are seen most frequently, but their combinations with each other and surgery are also used. [NIH] Common Variable Immunodeficiency: Heterogeneous group of immunodeficiency syndromes characterized by hypogammaglobulinemia of most isotypes, variable B-cell defects, and the presence of recurrent bacterial infections. [NIH] Community Health Centers: Facilities which administer the delivery of health care services to people living in a community or neighborhood. [NIH] Community-Acquired Infections: Any infection acquired in the community, that is, contrasted with those acquired in a health care facility (cross infection). An infection would be classified as community-acquired if the patient had not recently been in a health care facility or been in contact with someone who had been recently in a health care facility. [NIH] Comorbidity: The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. [NIH] Compassionate: A process for providing experimental drugs to very sick patients who have no treatment options. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire

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functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complete remission: The disappearance of all signs of cancer. Also called a complete response. [NIH] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Concomitant: Accompanying; accessory; joined with another. [EU] Confidence Intervals: A range of values for a variable of interest, e.g., a rate, constructed so

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that this range has a specified probability of including the true value of the variable. [NIH] Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the "true" effect of an intervention. [NIH] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjugation: 1. The act of joining together or the state of being conjugated. 2. A sexual process seen in bacteria, ciliate protozoa, and certain fungi in which nuclear material is exchanged during the temporary fusion of two cells (conjugants). In bacterial genetics a form of sexual reproduction in which a donor bacterium (male) contributes some, or all, of its DNA (in the form of a replicated set) to a recipient (female) which then incorporates differing genetic information into its own chromosome by recombination and passes the recombined set on to its progeny by replication. In ciliate protozoa, two conjugants of separate mating types exchange micronuclear material and then separate, each now being a fertilized cell. In certain fungi, the process involves fusion of two gametes, resulting in union of their nuclei and formation of a zygote. 3. In chemistry, the joining together of two compounds to produce another compound, such as the combination of a toxic product with some substance in the body to form a detoxified product, which is then eliminated. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Constriction: The act of constricting. [NIH] Consumption: Pulmonary tuberculosis. [NIH] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Continuous infusion: The administration of a fluid into a blood vessel, usually over a prolonged period of time. [NIH] Continuum: An area over which the vegetation or animal population is of constantly changing composition so that homogeneous, separate communities cannot be distinguished. [NIH]

Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH]

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Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]

Conus: A large, circular, white patch around the optic disk due to the exposing of the sclera as a result of degenerative change or congenital abnormality in the choroid and retina. [NIH] Conventional therapy: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional treatment. [NIH] Conventional treatment: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional therapy. [NIH] Cooperative group: A group of physicians, hospitals, or both formed to treat a large number of persons in the same way so that new treatment can be evaluated quickly. Clinical trials of new cancer treatments often require many more people than a single physician or hospital can care for. [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Artery Bypass: Surgical therapy of ischemic coronary artery disease achieved by grafting a section of saphenous vein, internal mammary artery, or other substitute between the aorta and the obstructed coronary artery distal to the obstructive lesion. [NIH] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Coronavirus: A genus of the family Coronaviridae which causes respiratory or gastrointestinal disease in a variety of vertebrates. [NIH] Corpus: The body of the uterus. [NIH] Corpuscle: A small mass or body; a sensory nerve end bulb; a cell, especially that of the blood or the lymph. [NIH] Corticosteroid: Any of the steroids elaborated by the adrenal cortex (excluding the sex hormones of adrenal origin) in response to the release of corticotrophin (adrenocorticotropic hormone) by the pituitary gland, to any of the synthetic equivalents of these steroids, or to angiotensin II. They are divided, according to their predominant biological activity, into three major groups: glucocorticoids, chiefly influencing carbohydrate, fat, and protein metabolism; mineralocorticoids, affecting the regulation of electrolyte and water balance; and C19 androgens. Some corticosteroids exhibit both types of activity in varying degrees, and others exert only one type of effect. The corticosteroids are used clinically for hormonal replacement therapy, for suppression of ACTH secretion by the anterior pituitary, as antineoplastic, antiallergic, and anti-inflammatory agents, and to suppress the immune response. Called also adrenocortical hormone and corticoid. [EU]

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Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Cost Savings: Reductions in all or any portion of the costs of providing goods or services. Savings may be incurred by the provider or the consumer. [NIH] Co-trimoxazole: A combination of two anti-infection drugs, sulfamethoxazole and trimethoprim. It is used to fight bacterial and protozoal infections. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH] C-Reactive Protein: A plasma protein that circulates in increased amounts during inflammation and after tissue damage. [NIH] Critical Care: Health care provided to a critically ill patient during a medical emergency or crisis. [NIH] Critical Illness: A disease or state in which death is possible or imminent. [NIH] Cross Infection: Any infection which a patient contracts in a healthcare institution. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Croup: A condition characterized by resonant barking cough, hoarseness and persistant stridor and caused by allergy, foreign body, infection, or neoplasm. It occurs chiefly in infants and children. [NIH] Cryptosporidiosis: Parasitic intestinal infection with severe diarrhea caused by a protozoan, Cryptosporidium. It occurs in both animals and humans. [NIH] Cryptosporidium: A genus of coccidian parasites of the family Cryptosporidiidae, found in the intestinal epithelium of many vertebrates including humans. [NIH] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH] Cyst: A sac or capsule filled with fluid. [NIH] Cystitis: Inflammation of the urinary bladder. [EU] Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as

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cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytochrome b: Cytochromes (electron-transporting proteins) with protoheme or a related heme as the prosthetic group. The prosthetic group is not covalently bound to the protein moiety. [NIH] Cytogenetics: A branch of genetics which deals with the cytological and molecular behavior of genes and chromosomes during cell division. [NIH] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytomegalovirus: A genus of the family Herpesviridae, subfamily Betaherpesvirinae, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS. [NIH] Cytomegalovirus Infections: Infection with Cytomegalovirus, characterized by enlarged cells bearing intranuclear inclusions. Infection may be in almost any organ, but the salivary glands are the most common site in children, as are the lungs in adults. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytostatic: An agent that suppresses cell growth and multiplication. [EU] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Data Collection: Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Death Certificates: Official records of individual deaths including the cause of death certified by a physician, and any other required identifying information. [NIH] Decision Making: The process of making a selective intellectual judgment when presented with several complex alternatives consisting of several variables, and usually defining a course of action or an idea. [NIH] Decision Trees: A graphic device used in decision analysis, series of decision options are represented as branches (hierarchical). [NIH] Decontamination: The removal of contaminating material, such as radioactive materials, biological materials, or chemical warfare agents, from a person or object. [NIH] Defense Mechanisms: Unconscious process used by an individual or a group of individuals

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in order to cope with impulses, feelings or ideas which are not acceptable at their conscious level; various types include reaction formation, projection and self reversal. [NIH] Deferoxamine: Natural product isolated from Streptomyces pilosus. It forms iron complexes and is used as a chelating agent, particularly in the form of its mesylate. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Deglutition: The process or the act of swallowing. [NIH] Dehydration: The condition that results from excessive loss of body water. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Delirium: (DSM III-R) an acute, reversible organic mental disorder characterized by reduced ability to maintain attention to external stimuli and disorganized thinking as manifested by rambling, irrelevant, or incoherent speech; there are also a reduced level of consciousness, sensory misperceptions, disturbance of the sleep-wakefulness cycle and level of psychomotor activity, disorientation to time, place, or person, and memory impairment. Delirium may be caused by a large number of conditions resulting in derangement of cerebral metabolism, including systemic infection, poisoning, drug intoxication or withdrawal, seizures or head trauma, and metabolic disturbances such as hypoxia, hypoglycaemia, fluid, electrolyte, or acid-base imbalances, or hepatic or renal failure. Called also acute confusional state and acute brain syndrome. [EU] Delivery of Health Care: The concept concerned with all aspects of providing and distributing health services to a patient population. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dendritic cell: A special type of antigen-presenting cell (APC) that activates T lymphocytes. [NIH]

Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dental Caries: Localized destruction of the tooth surface initiated by decalcification of the enamel followed by enzymatic lysis of organic structures and leading to cavity formation. If left unchecked, the cavity may penetrate the enamel and dentin and reach the pulp. The three most prominent theories used to explain the etiology of the disase are that acids produced by bacteria lead to decalcification; that micro-organisms destroy the enamel protein; or that keratolytic micro-organisms produce chelates that lead to decalcification. [NIH]

Dental Plaque: A film that attaches to teeth, often causing dental caries and gingivitis. It is composed of mucins, secreted from salivary glands, and microorganisms. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU]

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Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] Dermatology: A medical specialty concerned with the skin, its structure, functions, diseases, and treatment. [NIH] Dermis: A layer of vascular connective tissue underneath the epidermis. The surface of the dermis contains sensitive papillae. Embedded in or beneath the dermis are sweat glands, hair follicles, and sebaceous glands. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Desquamation: The shedding of epithelial elements, chiefly of the skin, in scales or small sheets; exfoliation. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Developing Countries: Countries in the process of change directed toward economic growth, that is, an increase in production, per capita consumption, and income. The process of economic growth involves better utilization of natural and human resources, which results in a change in the social, political, and economic structures. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diabetic Ketoacidosis: Complication of diabetes resulting from severe insulin deficiency coupled with an absolute or relative increase in glucagon concentration. The metabolic acidosis is caused by the breakdown of adipose stores and resulting increased levels of free fatty acids. Glucagon accelerates the oxidation of the free fatty acids producing excess ketone bodies (ketosis). [NIH] Diagnostic Errors: Incorrect diagnoses after clinical examination or technical diagnostic procedures. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diaphragm: The musculofibrous partition that separates the thoracic cavity from the abdominal cavity. Contraction of the diaphragm increases the volume of the thoracic cavity aiding inspiration. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diarrhoea: Abnormal frequency and liquidity of faecal discharges. [EU] Diastolic: Of or pertaining to the diastole. [EU] Difluoromethylornithine: DFMO. An anticancer drug that has been shown to reduce the risk of cancer in animals. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH]

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Dihydrotestosterone: Anabolic agent. [NIH] Dilatation: The act of dilating. [NIH] Diphtheria: A localized infection of mucous membranes or skin caused by toxigenic strains of Corynebacterium diphtheriae. It is characterized by the presence of a pseudomembrane at the site of infection. Diphtheria toxin, produced by C. diphtheriae, can cause myocarditis, polyneuritis, and other systemic toxic effects. [NIH] Diphtheria Toxin: A 60 kD single chain protein elaborated by Corynebacterium diphtheriae that causes the sign and symptoms of diphtheria; it can be broken into two unequal fragments, the smaller (A fragment) inhibits protein synthesis and is the lethal moiety that needs the larger (B fragment) for entry into cells. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [EU] Disposition: A tendency either physical or mental toward certain diseases. [EU] Dissection: Cutting up of an organism for study. [NIH] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Domesticated: Species in which the evolutionary process has been influenced by humans to meet their needs. [NIH] Donepezil: A drug used in the treatment of Alzheimer's disease. It belongs to the family of drugs called cholinesterase inhibitors. It is being studied as a treatment for side effects caused by radiation therapy to the brain. [NIH] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for

Dictionary 475

its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dormancy: The period when an organism (i. e., a virus or a bacterium) is in the body but not producing any ill effects. [NIH] Dose-dependent: Refers to the effects of treatment with a drug. If the effects change when the dose of the drug is changed, the effects are said to be dose dependent. [NIH] Dose-limiting: Describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. [NIH] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Double-blinded: A clinical trial in which neither the medical staff nor the person knows which of several possible therapies the person is receiving. [NIH] Drug Combinations: Single preparations containing two or more active agents, for the purpose of their concurrent administration as a fixed dose mixture. It is differentiated from combination drug therapy in which two or more drugs are administered separately for a combined effect. [NIH] Drug Design: The molecular designing of drugs for specific purposes (such as DNAbinding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dura mater: The outermost, toughest, and most fibrous of the three membranes (meninges) covering the brain and spinal cord; called also pachymeninx. [EU] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dyspareunia: Painful sexual intercourse. [NIH] Dysphagia: Difficulty in swallowing. [EU] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dyspnea: Difficult or labored breathing. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular

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dystrophies. [EU] Ectopic: Pertaining to or characterized by ectopia. [EU] Ectopic Pregnancy: The pregnancy occurring elsewhere than in the cavity of the uterus. [NIH]

Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efferent: Nerve fibers which conduct impulses from the central nervous system to muscles and glands. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Effusion: The escape of fluid into a part or tissue, as an exudation or a transudation. [EU] Elastic: Susceptible of resisting and recovering from stretching, compression or distortion applied by a force. [EU] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electric shock: A dangerous patho-physiological effect resulting from an electric current passing through the body of a human or animal. [NIH] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]

Elementary Particles: Individual components of atoms, usually subatomic; subnuclear particles are usually detected only when the atomic nucleus decays and then only transiently, as most of them are unstable, often yielding pure energy without substance, i.e., radiation. [NIH] Emaciation: Clinical manifestation of excessive leanness usually caused by disease or a lack of nutrition. [NIH] Embolism: Blocking of a blood vessel by a blood clot or foreign matter that has been transported from a distant site by the blood stream. [NIH] Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Emesis: Vomiting; an act of vomiting. Also used as a word termination, as in haematemesis. [EU]

Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Empiric: Empirical; depending upon experience or observation alone, without using

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scientific method or theory. [EU] Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] Empyema: Presence of pus in a hollow organ or body cavity. [NIH] Emulsions: Colloids of two immiscible liquids where either phase may be either fatty or aqueous; lipid-in-water emulsions are usually liquid, like milk or lotion and water-in-lipid emulsions tend to be creams. [NIH] Enamel: A very hard whitish substance which covers the dentine of the anatomical crown of a tooth. [NIH] Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]

Encephalitis: Inflammation of the brain due to infection, autoimmune processes, toxins, and other conditions. Viral infections (see encephalitis, viral) are a relatively frequent cause of this condition. [NIH] Encephalitis, Viral: Inflammation of brain parenchymal tissue as a result of viral infection. Encephalitis may occur as primary or secondary manifestation of Togaviridae infections; Herpesviridae infections; Adenoviridae infections; Flaviviridae infections; Bunyaviridae infections; Picornaviridae infections; Paramyxoviridae infections; Orthomyxoviridae infections; Retroviridae infections; and Arenaviridae infections. [NIH] Encephalomyelitis: A general term indicating inflammation of the brain and spinal cord, often used to indicate an infectious process, but also applicable to a variety of autoimmune and toxic-metabolic conditions. There is significant overlap regarding the usage of this term and encephalitis in the literature. [NIH] Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocarditis: Exudative and proliferative inflammatory alterations of the endocardium, characterized by the presence of vegetations on the surface of the endocardium or in the endocardium itself, and most commonly involving a heart valve, but sometimes affecting the inner lining of the cardiac chambers or the endocardium elsewhere. It may occur as a primary disorder or as a complication of or in association with another disease. [EU] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endocrinology: A subspecialty of internal medicine concerned with the metabolism, physiology, and disorders of the endocrine system. [NIH] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endopeptidases: A subclass of peptide hydrolases. They are classified primarily by their catalytic mechanism. Specificity is used only for identification of individual enzymes. They comprise the serine endopeptidases, EC 3.4.21; cysteine endopeptidases, EC 3.4.22; aspartic endopeptidases, EC 3.4.23, metalloendopeptidases, EC 3.4.24; and a group of enzymes yet to be assigned to any of the above sub-classes, EC 3.4.99. EC 3.4.-. [NIH] Endophthalmitis: Suppurative inflammation of the tissues of the internal structures of the eye; not all layers of the uvea are affected. Fungi, necrosis of intraocular tumors, and retained intraocular foreign bodies often cause a purulent endophthalmitis. [NIH]

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Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxemia: A condition characterized by the presence of endotoxins in the blood. If endotoxemia is the result of gram-negative rod-shaped bacteria, shock may occur. [NIH] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enteral Nutrition: Nutritional support given via the alimentary canal or any route connected to the gastrointestinal system (i.e., the enteral route). This includes oral feeding, sip feeding, and tube feeding using nasogastric, gastrostomy, and jejunostomy tubes. [NIH] Enteric Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] Eosinophil: A polymorphonuclear leucocyte with large eosinophilic granules in its cytoplasm, which plays a role in hypersensitivity reactions. [NIH] Eosinophilic: A condition found primarily in grinding workers caused by a reaction of the pulmonary tissue, in particular the eosinophilic cells, to dust that has entered the lung. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiological: Relating to, or involving epidemiology. [EU] Epidemiology, Molecular: The application of molecular biology to the answering of

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epidemiological questions. The examination of patterns of changes in DNA to implicate particular carcinogens and the use of molecular markers to predict which individuals are at highest risk for a disease are common examples. [NIH] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermal Growth Factor: A 6 kD polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. epidermal growth factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and epithelial cells. [NIH] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Episode of Care: An interval of care by a health care facility or provider for a specific medical problem or condition. It may be continuous or it may consist of a series of intervals marked by one or more brief separations from care, and can also identify the sequence of care (e.g., emergency, inpatient, outpatient), thus serving as one measure of health care provided. [NIH] Epistaxis: Bleeding from the nose. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]

Erythema: Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of causes. [NIH] Erythema Nodosum: An erythematous eruption commonly associated with drug reactions or infection and characterized by inflammatory nodules that are usually tender, multiple, and bilateral. These nodules are located predominantly on the shins with less common occurrence on the thighs and forearms. They undergo characteristic color changes ending in temporary bruise-like areas. This condition usually subsides in 3-6 weeks without scarring or atrophy. [NIH] Erythrocyte Membrane: The semipermeable outer portion of the red corpuscle. It is known as a 'ghost' after hemolysis. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythromycin: A bacteriostatic antibiotic substance produced by Streptomyces erythreus. Erythromycin A is considered its major active component. In sensitive organisms, it inhibits protein synthesis by binding to 50S ribosomal subunits. This binding process inhibits

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peptidyl transferase activity and interferes with translocation of amino acids during translation and assembly of proteins. [NIH] Escalation: Progressive use of more harmful drugs. [NIH] Esophageal: Having to do with the esophagus, the muscular tube through which food passes from the throat to the stomach. [NIH] Esophageal Stricture: A narrowing of the esophagus often caused by acid flowing back from the stomach. This condition may require surgery. [NIH] Esophagitis: Inflammation, acute or chronic, of the esophagus caused by bacteria, chemicals, or trauma. [NIH] Esophagram: A series of x-rays of the esophagus. The x-ray pictures are taken after the person drinks a solution that contains barium. The barium coats and outlines the esophagus on the x-ray. Also called a barium swallow. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [NIH] Estrogen: One of the two female sex hormones. [NIH] Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [NIH] Etoposide: A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evacuation: An emptying, as of the bowels. [EU] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excipients: Usually inert substances added to a prescription in order to provide suitable consistency to the dosage form; a binder, matrix, base or diluent in pills, tablets, creams, salves, etc. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Exercise Test: Controlled physical activity, more strenuous than at rest, which is performed in order to allow assessment of physiological functions, particularly cardiovascular and pulmonary, but also aerobic capacity. Maximal (most intense) exercise is usually required but submaximal exercise is also used. The intensity of exercise is often graded, using criteria such as rate of work done, oxygen consumption, and heart rate. Physiological data obtained from an exercise test may be used for diagnosis, prognosis, and evaluation of disease severity, and to evaluate therapy. Data may also be used in prescribing exercise by

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determining a person's exercise capacity. [NIH] Exfoliation: A falling off in scales or layers. [EU] Exhaustion: The feeling of weariness of mind and body. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Expiration: The act of breathing out, or expelling air from the lungs. [EU] Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [NIH]

External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH] Extracorporeal: Situated or occurring outside the body. [EU] Extracorporeal Membrane Oxygenation: Application of a life support system that circulates the blood through an oxygenating system, which may consist of a pump, a membrane oxygenator, and a heat exchanger. Examples of its use are to assist victims of smoke inhalation injury, respiratory failure, and cardiac failure. [NIH] Extrapyramidal: Outside of the pyramidal tracts. [EU] Extravasation: A discharge or escape, as of blood, from a vessel into the tissues. [EU] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Exudate: Material, such as fluid, cells, or cellular debris, which has escaped from blood vessels and has been deposited in tissues or on tissue surfaces, usually as a result of inflammation. An exudate, in contrast to a transudate, is characterized by a high content of protein, cells, or solid materials derived from cells. [EU] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] Faecal: Pertaining to or of the nature of feces. [EU] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

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Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Febrile: Pertaining to or characterized by fever. [EU] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Femoral: Pertaining to the femur, or to the thigh. [EU] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [NIH] Fermentation: An enzyme-induced chemical change in organic compounds that takes place in the absence of oxygen. The change usually results in the production of ethanol or lactic acid, and the production of energy. [NIH] Fever of Unknown Origin: Fever in which the etiology cannot be ascertained. [NIH] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibrinolysis: The natural enzymatic dissolution of fibrin. [NIH] Fibroblast Growth Factor: Peptide isolated from the pituitary gland and from the brain. It is a potent mitogen which stimulates growth of a variety of mesodermal cells including chondrocytes, granulosa, and endothelial cells. The peptide may be active in wound healing and animal limb regeneration. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Filgrastim: A colony-stimulating factor that stimulates the production of neutrophils (a type of white blood cell). It is a cytokine that belongs to the family of drugs called hematopoietic (blood-forming) agents. Also called granulocyte colony-stimulating factor (G-CSF). [NIH] Fine-needle aspiration: The removal of tissue or fluid with a needle for examination under a microscope. Also called needle biopsy. [NIH] Fistula: Abnormal communication most commonly seen between two internal organs, or between an internal organ and the surface of the body. [NIH] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in

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carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Flagellin: A protein with a molecular weight of 40,000 isolated from bacterial flagella. At appropriate pH and salt concentration, three flagellin monomers can spontaneously reaggregate to form structures which appear identical to intact flagella. [NIH] Flatus: Gas passed through the rectum. [NIH] Flow Cytometry: Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. [NIH] Fludarabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]

Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorescent Dyes: Dyes that emit light when exposed to light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags. They are used as markers in biochemistry and immunology. [NIH] Foam Cells: Lipid-laden macrophages originating from monocytes or from smooth muscle cells. [NIH] Focus Groups: A method of data collection and a qualitative research tool in which a small group of individuals are brought together and allowed to interact in a discussion of their opinions about topics, issues, or questions. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Foramen: A natural hole of perforation, especially one in a bone. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Formulary: A book containing a list of pharmaceutical products with their formulas and means of preparation. [NIH] Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free

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radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [NIH] Fungicides, Industrial: Chemicals that kill or inhibit the growth of fungi in agricultural applications, on wood, plastics, or other materials, in swimming pools, etc. [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] Galactose Oxidase: An enzyme that oxidizes galactose in the presence of molecular oxygen to D-galacto-hexodialdose. It is a copper protein. EC 1.1.3.9. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gallium: A rare, metallic element designated by the symbol, Ga, atomic number 31, and atomic weight 69.72. [NIH] Gallstones: The solid masses or stones made of cholesterol or bilirubin that form in the gallbladder or bile ducts. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Gamma-interferon: Interferon produced by T-lymphocytes in response to various mitogens and antigens. Gamma interferon appears to have potent antineoplastic, immunoregulatory and antiviral activity. [NIH] Ganciclovir: Acyclovir analog that is a potent inhibitor of the Herpesvirus family including cytomegalovirus. Ganciclovir is used to treat complications from AIDS-associated cytomegalovirus infections. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] Ganglioside: Protein kinase C's inhibitor which reduces ischemia-related brain damage. [NIH]

Gangrene: Death and putrefaction of tissue usually due to a loss of blood supply. [NIH] Gangrenous: A circumscribed, deep-seated, suppurative inflammation of the subcutaneous tissue of the eyelid discharging pus from several points. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body

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through the rectum (flatus) or the mouth (burp). [NIH] Gas exchange: Primary function of the lungs; transfer of oxygen from inhaled air into the blood and of carbon dioxide from the blood into the lungs. [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Juices: Liquids produced in the stomach to help break down food and kill bacteria. [NIH]

Gastric Mucosa: Surface epithelium in the stomach that invaginates into the lamina propria, forming gastric pits. Tubular glands, characteristic of each region of the stomach (cardiac, gastric, and pyloric), empty into the gastric pits. The gastric mucosa is made up of several different kinds of cells. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastritis: Inflammation of the stomach. [EU] Gastroenteritis: An acute inflammation of the lining of the stomach and intestines, characterized by anorexia, nausea, diarrhoea, abdominal pain, and weakness, which has various causes, including food poisoning due to infection with such organisms as Escherichia coli, Staphylococcus aureus, and Salmonella species; consumption of irritating food or drink; or psychological factors such as anger, stress, and fear. Called also enterogastritis. [EU] Gastroesophageal Reflux: Reflux of gastric juice and/or duodenal contents (bile acids, pancreatic juice) into the distal esophagus, commonly due to incompetence of the lower esophageal sphincter. Gastric regurgitation is an extension of this process with entry of fluid into the pharynx or mouth. [NIH] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gastrostomy: Creation of an artificial external opening into the stomach for nutritional support or gastrointestinal compression. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] General practitioner: A medical practitioner who does not specialize in a particular branch of medicine or limit his practice to a specific class of diseases. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH]

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Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]

Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Giant Cells: Multinucleated masses produced by the fusion of many cells; often associated with viral infections. In AIDS, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium leads to cell death and thus may account for the cytopathic effect of the virus. [NIH] Gingivitis: Inflammation of the gingivae. Gingivitis associated with bony changes is referred to as periodontitis. Called also oulitis and ulitis. [EU] Ginseng: An araliaceous genus of plants that contains a number of pharmacologically active agents used as stimulants, sedatives, and tonics, especially in traditional medicine. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Glomeruli: Plural of glomerulus. [NIH] Glomerulonephritis: Glomerular disease characterized by an inflammatory reaction, with leukocyte infiltration and cellular proliferation of the glomeruli, or that appears to be the result of immune glomerular injury. [NIH] Glucans: Polysaccharides composed of repeating glucose units. They can consist of branched or unbranched chains in any linkages. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

Glutamine: A non-essential amino acid present abundantly throught the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. [NIH] Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9.

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[NIH]

Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]

Glycerophospholipids: Derivatives of phosphatidic acid in which the hydrophobic regions are composed of two fatty acids and a polar alcohol is joined to the C-3 position of glycerol through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. [NIH] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycolysis: The pathway by which glucose is catabolized into two molecules of pyruvic acid with the generation of ATP. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] Goblet Cells: Cells of the epithelial lining that produce and secrete mucins. [NIH] Gonadal: Pertaining to a gonad. [EU] Gonorrhea: Acute infectious disease characterized by primary invasion of the urogenital tract. The etiologic agent, Neisseria gonorrhoeae, was isolated by Neisser in 1879. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]

Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Graft-versus-host disease: GVHD. A reaction of donated bone marrow or peripheral stem cells against a person's tissue. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Gram-Negative Bacteria: Bacteria which lose crystal violet stain but are stained pink when treated by Gram's method. [NIH] Gram-positive: Retaining the stain or resisting decolorization by alcohol in Gram's method of staining, a primary characteristic of bacteria whose cell wall is composed of a thick layer of peptidologlycan with attached teichoic acids. [EU] Gram-Positive Bacteria: Bacteria which retain the crystal violet stain when treated by Gram's method. [NIH]

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Granulation Tissue: A vascular connective tissue formed on the surface of a healing wound, ulcer, or inflamed tissue. It consists of new capillaries and an infiltrate containing lymphoid cells, macrophages, and plasma cells. [NIH] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [NIH] Granuloma: A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanine: One of the four DNA bases. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Guideline Adherence: Conformity in fulfilling or following official, recognized, or institutional requirements, guidelines, recommendations, protocols, pathways, or other standards. [NIH] Guinea Pigs: A common name used for the family Caviidae. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research. [NIH]

Gynecology: A medical-surgical specialty concerned with the physiology and disorders primarily of the female genital tract, as well as female endocrinology and reproductive physiology. [NIH] Gyrase: An enzyme that causes negative supercoiling of E. coli DNA during replication. [NIH]

Habitat: An area considered in terms of its environment, particularly as this determines the type and quality of the vegetation the area can carry. [NIH] Haematemesis: The vomiting of blood. [EU] Haematological: Relating to haematology, that is that branch of medical science which treats of the morphology of the blood and blood-forming tissues. [EU] Haematology: The science of the blood, its nature, functions, and diseases. [NIH] Haemophilus: A genus of Pasteurellaceae that consists of several species occurring in animals and humans. Its organisms are described as gram-negative, facultatively anaerobic, coccobacillus or rod-shaped, and nonmotile. [NIH] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Hantavirus: A genus of the family Bunyaviridae causing Hantavirus infections, first identified during the Korean war. Infection is found primarily in rodents and humans. Transmission does not appear to involve arthropods. The genus has one recognized group (Hantaan group) consisting of several species including Dobrava-Belgrade virus, Seoul virus, Prospect Hill virus, Puumala virus, Thottapalayam virus, and Hantaan virus, the type species. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH]

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Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Headache Disorders: Common conditions characterized by persistent or recurrent headaches. Headache syndrome classification systems may be based on etiology (e.g., vascular headache, post-traumatic headaches, etc.), temporal pattern (e.g., cluster headache, paroxysmal hemicrania, etc.), and precipitating factors (e.g., cough headache). [NIH] Health Care Costs: The actual costs of providing services related to the delivery of health care, including the costs of procedures, therapies, and medications. It is differentiated from health expenditures, which refers to the amount of money paid for the services, and from fees, which refers to the amount charged, regardless of cost. [NIH] Health Expenditures: The amounts spent by individuals, groups, nations, or private or public organizations for total health care and/or its various components. These amounts may or may not be equivalent to the actual costs (health care costs) and may or may not be shared among the patient, insurers, and/or employers. [NIH] Health Services: Services for the diagnosis and treatment of disease and the maintenance of health. [NIH] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [NIH] Heart Arrest: Sudden and usually momentary cessation of the heart beat. This sudden cessation may, but not usually, lead to death, sudden, cardiac. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heartburn: Substernal pain or burning sensation, usually associated with regurgitation of gastric juice into the esophagus. [NIH] Hematocrit: Measurement of the volume of packed red cells in a blood specimen by centrifugation. The procedure is performed using a tube with graduated markings or with automated blood cell counters. It is used as an indicator of erythrocyte status in disease. For example, anemia shows a low hematocrit, polycythemia, high values. [NIH] Hematogenous: Originating in the blood or spread through the bloodstream. [NIH] Hematologic malignancies: Cancers of the blood or bone marrow, including leukemia and lymphoma. Also called hematologic cancers. [NIH] Hematopoiesis: The development and formation of various types of blood cells. [NIH] Hematopoietic Stem Cell Transplantation: The transference of stem cells from one animal or human to another (allogeneic), or within the same individual (autologous). The source for the stem cells may be the bone marrow or peripheral blood. Stem cell transplantation has been used as an alternative to autologous bone marrow transplantation in the treatment of a variety of neoplasms. [NIH] Hematuria: Presence of blood in the urine. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the

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prosthetic group in many hemeproteins. [NIH] Hemodiafiltration: The combination of hemodialysis and hemofiltration either simultaneously or sequentially. Convective transport (hemofiltration) may be better for removal of larger molecular weight substances and diffusive transport (hemodialysis) for smaller molecular weight solutes. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemofiltration: Extracorporeal ultrafiltration technique without hemodialysis for treatment of fluid overload and electrolyte disturbances affecting renal, cardiac, or pulmonary function. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemolysis: The destruction of erythrocytes by many different causal agents such as antibodies, bacteria, chemicals, temperature, and changes in tonicity. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]

Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatocyte: A liver cell. [NIH] Hepatocyte Growth Factor: Multifunctional growth factor which regulates both cell growth and cell motility. It exerts a strong mitogenic effect on hepatocytes and primary epithelial cells. Its receptor is proto-oncogene protein C-met. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Herpes: Any inflammatory skin disease caused by a herpesvirus and characterized by the

Dictionary 491

formation of clusters of small vesicles. When used alone, the term may refer to herpes simplex or to herpes zoster. [EU] Herpes virus: A member of the herpes family of viruses. [NIH] Herpes Zoster: Acute vesicular inflammation. [NIH] Herpes Zoster Oticus: A virus infection of the Gasserian ganglion and its nerve branches, characterized by discrete areas of vesiculation of the epithelium of the forehead, the nose, the eyelids, and the cornea together with subepithelial infiltration. [NIH] Heterodimers: Zippered pair of nonidentical proteins. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]

Heterotrophic: Pertaining to organisms that are consumers and dependent on other organisms for their source of energy (food). [NIH] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] HIV: Human immunodeficiency virus. Species of lentivirus, subgenus primate lentiviruses, formerly designated T-cell lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV). It is acknowledged to be the agent responsible for the acute infectious manifestations, neurologic disorders, and immunologic abnormalities linked to the acquired immunodeficiency syndrome. [NIH] HIV-1: The type species of Lentivirus and widely recognized as the etiologic agent of acquired immunodeficiency syndrome (AIDS). It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. [NIH] Hoarseness: An unnaturally deep or rough quality of voice. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homogenate: A suspension of animal tissue that is ground in the all-glass "homogenizer" described by Potter and Elvehjem in 1936. [NIH] Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hormone Replacement Therapy: Therapeutic use of hormones to alleviate the effects of hormone deficiency. [NIH] Hospice: Institution dedicated to caring for the terminally ill. [NIH] Hospital Charges: The prices a hospital sets for its services. Hospital costs (the direct and indirect expenses incurred by the hospital in providing the services) are one factor in the determination of hospital charges. Other factors may include, for example, profits, competition, and the necessity of recouping the costs of uncompensated care. [NIH]

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Hospital Costs: The expenses incurred by a hospital in providing care. The hospital costs attributed to a particular patient care episode include the direct costs plus an appropriate proportion of the overhead for administration, personnel, building maintenance, equipment, etc. Hospital costs are one of the factors which determine hospital charges (the price the hospital sets for its services). [NIH] Hospital Mortality: A vital statistic measuring or recording the rate of death from any cause in hospitalized populations. [NIH] Hospitalists: Physicians who are employed to work exclusively in hospital settings, primarily for managed care organizations. They are the attending or primary responsible physician for the patient during hospitalization. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hybridoma: A hybrid cell resulting from the fusion of a specific antibody-producing spleen cell with a myeloma cell. [NIH] Hydration: Combining with water. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Bonding: A low-energy attractive force between hydrogen and another element. It plays a major role in determining the properties of water, proteins, and other compounds. [NIH]

Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrogenation: Specific method of reduction in which hydrogen is added to a substance by the direct use of gaseous hydrogen. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hyperglycemia: Abnormally high blood sugar. [NIH]

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Hyperoxia: An abnormal increase in the amount of oxygen in the tissues and organs. [NIH] Hyperreflexia: Exaggeration of reflexes. [EU] Hypersecretion: Excessive secretion. [EU] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hypogammaglobulinemia: The most common primary immunodeficiency in which antibody production is deficient. [NIH] Hypoglycaemia: An abnormally diminished concentration of glucose in the blood, which may lead to tremulousness, cold sweat, piloerection, hypothermia, and headache, accompanied by irritability, confusion, hallucinations, bizarre behaviour, and ultimately, convulsions and coma. [EU] Hypotension: Abnormally low blood pressure. [NIH] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypothermia: Lower than normal body temperature, especially in warm-blooded animals; in man usually accidental or unintentional. [NIH] Hypotrophy: Abiotrophy. [EU] Hypoxanthine: A purine and a reaction intermediate in the metabolism of adenosine and in the formation of nucleic acids by the salvage pathway. [NIH] Hypoxemia: Deficient oxygenation of the blood; hypoxia. [EU] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Hypoxic: Having too little oxygen. [NIH] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Imipenem: Semisynthetic thienamycin that has a wide spectrum of antibacterial activity against gram-negative and gram-positive aerobic and anaerobic bacteria, including many multiresistant strains. It is stable to beta-lactamases. Clinical studies have demonstrated high efficacy in the treatment of infections of various body systems. Its effectiveness is enhanced when it is administered in combination with cilastatin, a renal dipeptidase inhibitor. [NIH] Immune adjuvant: A drug that stimulates the immune system to respond to disease. [NIH] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH]

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Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunocompromised: Having a weakened immune system caused by certain diseases or treatments. [NIH] Immunocompromised Host: A human or animal whose immunologic mechanism is deficient because of an immunodeficiency disorder or other disease or as the result of the administration of immunosuppressive drugs or radiation. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunodeficiency syndrome: The inability of the body to produce an immune response. [NIH]

Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incompetence: Physical or mental inadequacy or insufficiency. [EU]

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Incubated: Grown in the laboratory under controlled conditions. (For instance, white blood cells can be grown in special conditions so that they attack specific cancer cells when returned to the body.) [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Indigestion: Poor digestion. Symptoms include heartburn, nausea, bloating, and gas. Also called dyspepsia. [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Induction therapy: Treatment designed to be used as a first step toward shrinking the cancer and in evaluating response to drugs and other agents. Induction therapy is followed by additional therapy to eliminate whatever cancer remains. [NIH] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infant Mortality: Perinatal, neonatal, and infant deaths in a given population. [NIH] Infant, Newborn: An infant during the first month after birth. [NIH] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Infection Control: Programs of disease surveillance, generally within health care facilities, designed to investigate, prevent, and control the spread of infections and their causative microorganisms. [NIH] Infectious Bovine Rhinotracheitis: A herpesvirus infection of cattle characterized by inflammation and necrosis of the mucous membranes of the upper respiratory tract. [NIH] Infectious Diarrhea: Diarrhea caused by infection from bacteria, viruses, or parasites. [NIH] Infectious Mononucleosis: A common, acute infection usually caused by the Epstein-Barr virus (Human herpesvirus 4). There is an increase in mononuclear white blood cells and other atypical lymphocytes, generalized lymphadenopathy, splenomegaly, and occasionally hepatomegaly with hepatitis. [NIH] Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU]

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Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Inflammatory bowel disease: A general term that refers to the inflammation of the colon and rectum. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. [NIH]

Influenza: An acute viral infection involving the respiratory tract. It is marked by inflammation of the nasal mucosa, the pharynx, and conjunctiva, and by headache and severe, often generalized, myalgia. [NIH] Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inlay: In dentistry, a filling first made to correspond with the form of a dental cavity and then cemented into the cavity. [NIH] Inner ear: The labyrinth, comprising the vestibule, cochlea, and semicircular canals. [NIH] Innervation: 1. The distribution or supply of nerves to a part. 2. The supply of nervous energy or of nerve stimulus sent to a part. [EU] Inoperable: Not suitable to be operated upon. [EU] Inorganic: Pertaining to substances not of organic origin. [EU] Insertional: A technique in which foreign DNA is cloned into a restriction site which occupies a position within the coding sequence of a gene in the cloning vector molecule. Insertion interrupts the gene's sequence such that its original function is no longer expressed. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Integrins: A family of transmembrane glycoproteins consisting of noncovalent heterodimers. They interact with a wide variety of ligands including extracellular matrix glycoproteins, complement, and other cells, while their intracellular domains interact with the cytoskeleton. The integrins consist of at least three identified families: the cytoadhesin receptors, the leukocyte adhesion receptors, and the very-late-antigen receptors. Each family contains a common beta-subunit combined with one or more distinct alpha-subunits. These receptors participate in cell-matrix and cell-cell adhesion in many physiologically important processes, including embryological development, hemostasis, thrombosis, wound healing,

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immune and nonimmune defense mechanisms, and oncogenic transformation. [NIH] Intensive Care: Advanced and highly specialized care provided to medical or surgical patients whose conditions are life-threatening and require comprehensive care and constant monitoring. It is usually administered in specially equipped units of a health care facility. [NIH]

Intensive Care Units: Hospital units providing continuous surveillance and care to acutely ill patients. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-18: Cytokine which resembles IL-1 structurally and IL-12 functionally. It enhances the cytotoxic activity of NK cells and CTLs, and appears to play a role both as neuroimmunomodulator and in the induction of mucosal immunity. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Interleukin-4: Soluble factor produced by activated T-lymphocytes that causes proliferation and differentiation of B-cells. Interleukin-4 induces the expression of class II major histocompatibility complex and Fc receptors on B-cells. It also acts on T-lymphocytes, mast cell lines, and several other hematopoietic lineage cells including granulocyte, megakaryocyte, and erythroid precursors, as well as macrophages. [NIH] Interleukin-5: Factor promoting eosinophil differentiation and activation in hematopoiesis. It also triggers activated B-cells for a terminal differentiation into Ig-secreting cells. [NIH] Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intervention Studies: Epidemiologic investigations designed to test a hypothesized causeeffect relation by modifying the supposed causal factor(s) in the study population. [NIH] Intestinal: Having to do with the intestines. [NIH]

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Intestinal Mucosa: The surface lining of the intestines where the cells absorb nutrients. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intramuscular injection: IM. Injection into a muscle. [NIH] Intraocular: Within the eye. [EU] Intraperitoneal: IP. Within the peritoneal cavity (the area that contains the abdominal organs). [NIH] Intravascular: Within a vessel or vessels. [EU] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Intubation: Introduction of a tube into a hollow organ to restore or maintain patency if obstructed. It is differentiated from catheterization in that the insertion of a catheter is usually performed for the introducing or withdrawing of fluids from the body. [NIH] Invalidate: To weaken or make valueless : to discredit. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Involuntary: Reaction occurring without intention or volition. [NIH] Iodine: A nonmetallic element of the halogen group that is represented by the atomic symbol I, atomic number 53, and atomic weight of 126.90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective properties and is used topically. [NIH] Ionization: 1. Any process by which a neutral atom gains or loses electrons, thus acquiring a net charge, as the dissociation of a substance in solution into ions or ion production by the passage of radioactive particles. 2. Iontophoresis. [EU] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isoflurane: A stable, non-explosive inhalation anesthetic, relatively free from significant side

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effects. [NIH] Jejunostomy: Surgical formation of an opening through the abdominal wall into the jejunum, usually for enteral hyperalimentation. [NIH] Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Kava: Dried rhizome and roots of Piper methysticum, a shrub native to Oceania and known for its anti-anxiety and sedative properties. Heavy usage results in some adverse effects. It contains alkaloids, lactones, kawain, methysticin, mucilage, starch, and yangonin. Kava is also the name of the pungent beverage prepared from the plant's roots. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Keratinocyte growth factor: A substance that stimulates the growth of epithelial cells that line the surface of the mouth and intestinal tract. [NIH] Keratolytic: An agent that promotes keratolysis. [EU] Keto: It consists of 8 carbon atoms and within the endotoxins, it connects poysaccharide and lipid A. [NIH] Ketone Bodies: Chemicals that the body makes when there is not enough insulin in the blood and it must break down fat for its energy. Ketone bodies can poison and even kill body cells. When the body does not have the help of insulin, the ketones build up in the blood and then "spill" over into the urine so that the body can get rid of them. The body can also rid itself of one type of ketone, called acetone, through the lungs. This gives the breath a fruity odor. Ketones that build up in the body for a long time lead to serious illness and coma. [NIH] Ketosis: A condition of having ketone bodies build up in body tissues and fluids. The signs of ketosis are nausea, vomiting, and stomach pain. Ketosis can lead to ketoacidosis. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Pelvis: The flattened, funnel-shaped expansion connecting the ureter to the kidney calices. [NIH] Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Laceration: 1. The act of tearing. 2. A torn, ragged, mangled wound. [EU] Lactose Intolerance: The disease state resulting from the absence of lactase enzyme in the musocal cells of the gastrointestinal tract, and therefore an inability to break down the disaccharide lactose in milk for absorption from the gastrointestinal tract. It is manifested by indigestion of a mild nature to severe diarrhea. It may be due to inborn defect genetically conditioned or may be acquired. [NIH] Laminin: Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion. [NIH] Laparotomy: A surgical incision made in the wall of the abdomen. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called

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colon. [NIH] Laryngitis: Inflammation of the larynx. This condition presents itself with dryness and soreness of the throat, difficulty in swallowing, cough, and hoarseness. [NIH] Larynx: An irregularly shaped, musculocartilaginous tubular structure, lined with mucous membrane, located at the top of the trachea and below the root of the tongue and the hyoid bone. It is the essential sphincter guarding the entrance into the trachea and functioning secondarily as the organ of voice. [NIH] Latency: The period of apparent inactivity between the time when a stimulus is presented and the moment a response occurs. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Lavage: A cleaning of the stomach and colon. Uses a special drink and enemas. [NIH] Least-Squares Analysis: A principle of estimation in which the estimates of a set of parameters in a statistical model are those quantities minimizing the sum of squared differences between the observed values of a dependent variable and the values predicted by the model. [NIH] Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] Legionella: Gram-negative aerobic rods, isolated from surface water, mud, or thermally polluted lakes or streams. It is pathogenic for man and it has no known soil or animal sources. [NIH] Legionellaceae: A family of gram-negative, aerobic bacteria that do not form endospores or microcysts. [NIH] Leishmaniasis: A disease caused by any of a number of species of protozoa in the genus Leishmania. There are four major clinical types of this infection: cutaneous (Old and New World), diffuse cutaneous, mucocutaneous, and visceral leishmaniasis. [NIH] Length of Stay: The period of confinement of a patient to a hospital or other health facility. [NIH]

Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Lentivirus: A genus of the family Retroviridae consisting of non-oncogenic retroviruses that produce multi-organ diseases characterized by long incubation periods and persistent infection. Lentiviruses are unique in that they contain open reading frames (ORFs) between the pol and env genes and in the 3' env region. Five serogroups are recognized, reflecting the mammalian hosts with which they are associated. HIV-1 is the type species. [NIH] Lethal: Deadly, fatal. [EU] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]

Leucovorin: The active metabolite of folic acid. Leucovorin is used principally as its calcium salt as an antidote to folic acid antagonists which block the conversion of folic acid to folinic acid. [NIH] Leukaemia: An acute or chronic disease of unknown cause in man and other warm-blooded animals that involves the blood-forming organs, is characterized by an abnormal increase in the number of leucocytes in the tissues of the body with or without a corresponding increase of those in the circulating blood, and is classified according of the type leucocyte most

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prominently involved. [EU] Leukemia: Cancer of blood-forming tissue. [NIH] Leukocyte Count: A count of the number of white blood cells per unit volume in venous blood. A differential leukocyte count measures the relative numbers of the different types of white cells. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Leukocytosis: A transient increase in the number of leukocytes in a body fluid. [NIH] Leukoencephalopathy: A condition with spongy holes in the brain's white matter. [NIH] Leukopenia: A condition in which the number of leukocytes (white blood cells) in the blood is reduced. [NIH] Leukoplakia: A white patch that may develop on mucous membranes such as the cheek, gums, or tongue and may become cancerous. [NIH] Levofloxacin: A substance used to treat bacterial infections. It belongs to the family of drugs called quinolone antibiotics. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Life Expectancy: A figure representing the number of years, based on known statistics, to which any person of a given age may reasonably expect to live. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Likelihood Functions: Functions constructed from a statistical model and a set of observed data which give the probability of that data for various values of the unknown model parameters. Those parameter values that maximize the probability are the maximum likelihood estimates of the parameters. [NIH] Lincomycin: (2S-trans)-Methyl 6,8-dideoxy-6-(((1-methyl-4-propyl-2pyrrolidinyl)carbonyl)amino)-1-thio-D-erythro-alpha-D-galacto-octopyranoside. An antibiotic produced by Streptomyces lincolnensis var. lincolnensis. It has been used in the treatment of staphylococcal, streptococcal, and Bacteroides fragilis infections. [NIH] Linear Models: Statistical models in which the value of a parameter for a given value of a factor is assumed to be equal to a + bx, where a and b are constants. The models predict a linear regression. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] Lipopolysaccharide: Substance consisting of polysaccaride and lipid. [NIH]

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Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Liposomal: A drug preparation that contains the active drug in very tiny fat particles. This fat-encapsulated drug is absorbed better, and its distribution to the tumor site is improved. [NIH]

Liposomes: Artificial, single or multilaminar vesicles (made from lecithins or other lipids) that are used for the delivery of a variety of biological molecules or molecular complexes to cells, for example, drug delivery and gene transfer. They are also used to study membranes and membrane proteins. [NIH] Liquor: 1. A liquid, especially an aqueous solution containing a medicinal substance. 2. A general term used in anatomical nomenclature for certain fluids of the body. [EU] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver Cirrhosis: Liver disease in which the normal microcirculation, the gross vascular anatomy, and the hepatic architecture have been variably destroyed and altered with fibrous septa surrounding regenerated or regenerating parenchymal nodules. [NIH] Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another. [NIH] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Logistic Models: Statistical models which describe the relationship between a qualitative dependent variable (that is, one which can take only certain discrete values, such as the presence or absence of a disease) and an independent variable. A common application is in epidemiology for estimating an individual's risk (probability of a disease) as a function of a given risk factor. [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Long-Term Care: Care over an extended period, usually for a chronic condition or disability, requiring periodic, intermittent, or continuous care. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lower Esophageal Sphincter: The muscle between the esophagus and stomach. When a

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person swallows, this muscle relaxes to let food pass from the esophagus to the stomach. It stays closed at other times to keep stomach contents from flowing back into the esophagus. [NIH]

Lumen: The cavity or channel within a tube or tubular organ. [EU] Lung Ta: Deposition of iron dust in the lungs while grinding cutlery. [NIH] Lung Transplantation: The transference of either one or both of the lungs from one human or animal to another. [NIH] Lung volume: The amount of air the lungs hold. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphadenopathy: Disease or swelling of the lymph nodes. [NIH] Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphoblastic: One of the most aggressive types of non-Hodgkin lymphoma. [NIH] Lymphoblasts: Interferon produced predominantly by leucocyte cells. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphocyte Count: A count of the number of lymphocytes in the blood. [NIH] Lymphocytic: Referring to lymphocytes, a type of white blood cell. [NIH] Lymphocytosis: Excess of normal lymphocytes in the blood or in any effusion. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphokines: Soluble protein factors generated by activated lymphocytes that affect other cells, primarily those involved in cellular immunity. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lymphoproliferative: Disorders characterized by proliferation of lymphoid tissue, general or unspecified. [NIH] Lymphoproliferative Disorders: Disorders characterized by proliferation of lymphoid tissue, general or unspecified. [NIH] Lysosome: A sac-like compartment inside a cell that has enzymes that can break down cellular components that need to be destroyed. [NIH] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] Macrolides: A group of organic compounds that contain a macrocyclic lactone ring linked

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glycosidically to one or more sugar moieties. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Macrophage Activation: The process of altering the morphology and functional activity of macrophages so that they become avidly phagocytic. It is initiated by lymphokines, such as the macrophage activation factor (MAF) and the macrophage migration-inhibitory factor (MMIF), immune complexes, C3b, and various peptides, polysaccharides, and immunologic adjuvants. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Magnetic Resonance Spectroscopy: Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (magnetic resonance imaging). [NIH] Maintenance therapy: Treatment that is given to help a primary (original) treatment keep working. Maintenance therapy is often given to help keep cancer in remission. [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malaria: A protozoan disease caused in humans by four species of the genus Plasmodium (P. falciparum (malaria, falciparum), P. vivax (malaria, vivax), P. ovale, and P. malariae) and transmitted by the bite of an infected female mosquito of the genus Anopheles. Malaria is endemic in parts of Asia, Africa, Central and South America, Oceania, and certain Caribbean islands. It is characterized by extreme exhaustion associated with paroxysms of high fever, sweating, shaking chills, and anemia. Malaria in animals is caused by other species of plasmodia. [NIH] Malaria, Falciparum: Malaria caused by Plasmodium falciparum. This is the severest form of malaria and is associated with the highest levels of parasites in the blood. This disease is characterized by irregularly recurring febrile paroxysms that in extreme cases occur with acute cerebral, renal, or gastrointestinal manifestations. [NIH] Malaria, Vivax: Malaria caused by Plasmodium vivax. This form of malaria is less severe than malaria, falciparum, but there is a higher probability for relapses to occur. Febrile paroxysms often occur every other day. [NIH] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Mammary: Pertaining to the mamma, or breast. [EU] Mandible: The largest and strongest bone of the face constituting the lower jaw. It supports

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the lower teeth. [NIH] Mania: Excitement of psychotic proportions manifested by mental and physical hyperactivity, disorganization of behaviour, and elevation of mood. [EU] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Mannans: Polysaccharides consisting of mannose units. [NIH] Mastitis: Inflammatory disease of the breast, or mammary gland. [NIH] Matrix metalloproteinase: A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis. [NIH] Measles Virus: The type species of morbillivirus and the cause of the highly infectious human disease measles, which affects mostly children. [NIH] Mechanical ventilation: Use of a machine called a ventilator or respirator to improve the exchange of air between the lungs and the atmosphere. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medical Errors: Errors or mistakes committed by health professionals which result in harm to the patient. They include errors in diagnosis (diagnostic errors), errors in the administration of drugs and other medications (medication errors), errors in the performance of surgical procedures, in the use of other types of therapy, in the use of equipment, and in the interpretation of laboratory findings. Medical errors are differentiated from malpractice in that the former are regarded as honest mistakes or accidents while the latter is the result of negligence, reprehensible ignorance, or criminal intent. [NIH] Medical Staff: Professional medical personnel who provide care to patients in an organized facility, institution or agency. [NIH] Medication Errors: Errors in prescribing, dispensing, or administering medication with the result that the patient fails to receive the correct drug or the indicated proper drug dosage. [NIH]

MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Megakaryocytes: Very large bone marrow cells which release mature blood platelets. [NIH] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment.

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Melanoma usually begins in a mole. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Fusion: The adherence of cell membranes, intracellular membranes, or artifical membrane models of either to each other or to viruses, parasites, or interstitial particles through a variety of chemical and physical processes. [NIH] Membrane Lipids: Lipids, predominantly phospholipids, cholesterol and small amounts of glycolipids found in membranes including cellular and intracellular membranes. These lipids may be arranged in bilayers in the membranes with integral proteins between the layers and peripheral proteins attached to the outside. Membrane lipids are required for active transport, several enzymatic activities and membrane formation. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Meningitis: Inflammation of the meninges. When it affects the dura mater, the disease is termed pachymeningitis; when the arachnoid and pia mater are involved, it is called leptomeningitis, or meningitis proper. [EU] Menopause: Permanent cessation of menstruation. [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesenteric: Pertaining to the mesentery : a membranous fold attaching various organs to the body wall. [EU] Mesentery: A layer of the peritoneum which attaches the abdominal viscera to the abdominal wall and conveys their blood vessels and nerves. [NIH] Mesothelial: It lines the peritonealla and pleural cavities. [NIH]

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Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metaplasia: A condition in which there is a change of one adult cell type to another similar adult cell type. [NIH] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Metastasize: To spread from one part of the body to another. When cancer cells metastasize and form secondary tumors, the cells in the metastatic tumor are like those in the original (primary) tumor. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] Methotrexate: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of dihydrofolate reductase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [NIH] Methylprednisolone: (6 alpha,11 beta)-11,17,21-Trihydroxy-6-methylpregna-1,4-diene-3,2dione. A prednisolone derivative which has pharmacological actions similar to prednisolone. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiological: Pertaining to microbiology : the science that deals with microorganisms, including algae, bacteria, fungi, protozoa and viruses. [EU] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microcirculation: The vascular network lying between the arterioles and venules; includes capillaries, metarterioles and arteriovenous anastomoses. Also, the flow of blood through this network. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Micro-organism: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH]

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Milliliter: A measure of volume for a liquid. A milliliter is approximately 950-times smaller than a quart and 30-times smaller than a fluid ounce. A milliliter of liquid and a cubic centimeter (cc) of liquid are the same. [NIH] Mineralization: The action of mineralizing; the state of being mineralized. [EU] Mineralocorticoids: A group of corticosteroids primarily associated with the regulation of water and electrolyte balance. This is accomplished through the effect on ion transport in renal tubules, resulting in retention of sodium and loss of potassium. Mineralocorticoid secretion is itself regulated by plasma volume, serum potassium, and angiotensin II. [NIH] Minority Groups: A subgroup having special characteristics within a larger group, often bound together by special ties which distinguish it from the larger group. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitosporic Fungi: A large and heterogenous group of fungi whose common characteristic is the absence of a sexual state. Many of the pathogenic fungi in humans belong to this group. [NIH]

Mitotic: Cell resulting from mitosis. [NIH] Mobility: Capability of movement, of being moved, or of flowing freely. [EU] Mobilization: The process of making a fixed part or stored substance mobile, as by separating a part from surrounding structures to make it accessible for an operative procedure or by causing release into the circulation for body use of a substance stored in the body. [EU] Mode of Transmission: Hepatitis A [NIH] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocyte: A type of white blood cell. [NIH] Monocyte Chemoattractant Protein-1: A chemokine that is a chemoattractant for human monocytes and may also cause cellular activation of specific functions related to host defense. It is produced by leukocytes of both monocyte and lymphocyte lineage and by

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fibroblasts during tissue injury. [NIH] Mononuclear: A cell with one nucleus. [NIH] Mononucleosis: The presence of an abnormally large number of mononuclear leucocytes (monocytes) in the blood. The term is often used alone to refer to infectious mononucleosis. [EU]

Monotherapy: A therapy which uses only one drug. [EU] Morbillivirus: A genus of the family Paramyxoviridae (subfamily Paramyxovirinae) where all the virions have hemagglutinin but not neuraminidase activity. All members produce both cytoplasmic and intranuclear inclusion bodies. MEASLES VIRUS is the type species. [NIH]

Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Motility: The ability to move spontaneously. [EU] Motion Sickness: Sickness caused by motion, as sea sickness, train sickness, car sickness, and air sickness. [NIH] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucociliary: Pertaining to or affecting the mucus membrane and hairs (including eyelashes, nose hair, .): mucociliary clearing: the clearance of mucus by ciliary movement ( particularly in the respiratory system). [EU] Mucociliary Clearance: Rate of ciliary and secretory activity of the respiratory submucosal glands. It is a non-specific host defense mechanism, measurable in vivo by mucus transfer, ciliary beat frequency, and clearance of radioactive tracers. [NIH] Mucocutaneous: Pertaining to or affecting the mucous membrane and the skin. [EU] Mucolytic: Destroying or dissolving mucin; an agent that so acts : a mucopolysaccharide or glycoprotein, the chief constituent of mucus. [EU] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] Multicenter study: A clinical trial that is carried out at more than one medical institution. [NIH]

Multidrug resistance: Adaptation of tumor cells to anticancer drugs in ways that make the drugs less effective. [NIH] Multiple Myeloma: A malignant tumor of plasma cells usually arising in the bone marrow; characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria, and anemia. [NIH] Multiple Organ Failure: A progressive condition usually characterized by combined failure of several organs such as the lungs, liver, kidney, along with some clotting mechanisms, usually postinjury or postoperative. [NIH] Multiple Trauma: Physical insults or injuries occurring simultaneously in several parts of the body. [NIH] Multivalent: Pertaining to a group of 5 or more homologous or partly homologous

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chromosomes during the zygotene stage of prophase to first metaphasis in meiosis. [NIH] Multivariate Analysis: A set of techniques used when variation in several variables has to be studied simultaneously. In statistics, multivariate analysis is interpreted as any analytic method that allows simultaneous study of two or more dependent variables. [NIH] Mupirocin: A topically used antibiotic from a strain of Pseudomonas fluorescens. It has shown excellent activity against gram-positive staphylococci and streptococci. The antibiotic is used primarily for the treatment of primary and secondary skin disorders, nasal infections, and wound healing. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Musculoskeletal System: Themuscles, bones, and cartilage of the body. [NIH] Myalgia: Pain in a muscle or muscles. [EU] Mycobacterium: A genus of gram-positive, aerobic bacteria. Most species are free-living in soil and water, but the major habitat for some is the diseased tissue of warm-blooded hosts. [NIH]

Mycobacterium avium: A bacterium causing tuberculosis in domestic fowl and other birds. In pigs, it may cause localized and sometimes disseminated disease. The organism occurs occasionally in sheep and cattle. It should be distinguished from the M. avium complex, which infects primarily humans. [NIH] Mycoplasma: A genus of gram-negative, facultatively anaerobic bacteria bounded by a plasma membrane only. Its organisms are parasites and pathogens, found on the mucous membranes of humans, animals, and birds. [NIH] Mycoplasma Infections: Infections with species of the genus Mycoplasma. [NIH] Mycoplasma pneumoniae: Short filamentous organism of the genus Mycoplasma, which binds firmly to the cells of the respiratory epithelium. It is one of the etiologic agents of nonviral primary atypical pneumonia in man. [NIH] Mycosis: Any disease caused by a fungus. [EU] Myelogenous: Produced by, or originating in, the bone marrow. [NIH] Myeloma: Cancer that arises in plasma cells, a type of white blood cell. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocarditis: Inflammation of the myocardium; inflammation of the muscular walls of the heart. [EU] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myopathy: Any disease of a muscle. [EU] Myositis: Inflammation of a voluntary muscle. [EU] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be

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progressive. [NIH] Nadir: The lowest point; point of greatest adversity or despair. [EU] Naive: Used to describe an individual who has never taken a certain drug or class of drugs (e. g., AZT-naive, antiretroviral-naive), or to refer to an undifferentiated immune system cell. [NIH] Naloxone: A specific opiate antagonist that has no agonist activity. It is a competitive antagonist at mu, delta, and kappa opioid receptors. [NIH] Narcotic: 1. Pertaining to or producing narcosis. 2. An agent that produces insensibility or stupor, applied especially to the opioids, i.e. to any natural or synthetic drug that has morphine-like actions. [EU] Nasal Mucosa: The mucous membrane lining the nasal cavity. [NIH] Nasogastric: The process of passing a small, flexible plastic tube through the nose or mouth into the stomach or small intestine. [NIH] Nasopharynx: The nasal part of the pharynx, lying above the level of the soft palate. [NIH] Natural selection: A part of the evolutionary process resulting in the survival and reproduction of the best adapted individuals. [NIH] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Nebulizer: A device used to turn liquid into a fine spray. [NIH] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Needle biopsy: The removal of tissue or fluid with a needle for examination under a microscope. Also called fine-needle aspiration. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neonatology: A subspecialty of pediatrics concerned with the newborn infant. [NIH] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephropathy: Disease of the kidneys. [EU] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU]

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Neuraminidase: An enzyme that catalyzes the hydrolysis of alpha-2,3, alpha-2,6-, and alpha-2,8-glycosidic linkages (at a decreasing rate, respectively) of terminal sialic residues in oligosaccharides, glycoproteins, glycolipids, colominic acid, and synthetic substrate. (From Enzyme Nomenclature, 1992) EC 3.2.1.18. [NIH] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neuroleptic: A term coined to refer to the effects on cognition and behaviour of antipsychotic drugs, which produce a state of apathy, lack of initiative, and limited range of emotion and in psychotic patients cause a reduction in confusion and agitation and normalization of psychomotor activity. [EU] Neurologic: Having to do with nerves or the nervous system. [NIH] Neurologic Manifestations: Clinical signs and symptoms caused by nervous system injury or dysfunction. [NIH] Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of the nervous system. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH] Neuroretinitis: Inflammation of the optic nerve head and adjacent retina. [NIH] Neurosyphilis: A late form of syphilis that affects the brain and may lead to dementia and death. [NIH] Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotoxins: Toxic substances from microorganisms, plants or animals that interfere with the functions of the nervous system. Most venoms contain neurotoxic substances. Myotoxins are included in this concept. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutralization: An act or process of neutralizing. [EU] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophil: A type of white blood cell. [NIH]

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Neutrophil Infiltration: The diffusion or accumulation of neutrophils in tissues or cells in response to a wide variety of substances released at the sites of inflammatory reactions. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]

Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Nitrous Oxide: Nitrogen oxide (N2O). A colorless, odorless gas that is used as an anesthetic and analgesic. High concentrations cause a narcotic effect and may replace oxygen, causing death by asphyxia. It is also used as a food aerosol in the preparation of whipping cream. [NIH]

Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nosocomial: Pertaining to or originating in the hospital, said of an infection not present or incubating prior to admittance to the hospital, but generally occurring 72 hours after admittance; the term is usually used to refer to patient disease, but hospital personnel may also acquire nosocomial infection. [EU] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclear magnetic resonance imaging: NMRI. A procedure in which a magnet linked to a computer is used to create detailed pictures of areas inside the body. Also called magnetic resonance imaging (MRI). [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nutritional Status: State of the body in relation to the consumption and utilization of nutrients. [NIH] Nutritional Support: The administration of nutrients for assimilation and utilization by a patient by means other than normal eating. It does not include fluid therapy which normalizes body fluids to restore water-electrolyte balance. [NIH]

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Observational study: An epidemiologic study that does not involve any intervention, experimental or otherwise. Such a study may be one in which nature is allowed to take its course, with changes in one characteristic being studied in relation to changes in other characteristics. Analytical epidemiologic methods, such as case-control and cohort study designs, are properly called observational epidemiology because the investigator is observing without intervention other than to record, classify, count, and statistically analyze results. [NIH] Occult: Obscure; concealed from observation, difficult to understand. [EU] Occult Blood: Chemical, spectroscopic, or microscopic detection of extremely small amounts of blood. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Odds Ratio: The ratio of two odds. The exposure-odds ratio for case control data is the ratio of the odds in favor of exposure among cases to the odds in favor of exposure among noncases. The disease-odds ratio for a cohort or cross section is the ratio of the odds in favor of disease among the exposed to the odds in favor of disease among the unexposed. The prevalence-odds ratio refers to an odds ratio derived cross-sectionally from studies of prevalent cases. [NIH] Ointments: Semisolid preparations used topically for protective emollient effects or as a vehicle for local administration of medications. Ointment bases are various mixtures of fats, waxes, animal and plant oils and solid and liquid hydrocarbons. [NIH] Oligosaccharides: Carbohydrates consisting of between two and ten monosaccharides connected by either an alpha- or beta-glycosidic link. They are found throughout nature in both the free and bound form. [NIH] Omeprazole: A highly effective inhibitor of gastric acid secretion used in the therapy of gastric ulcers and Zollinger-Ellison syndrome. The drug inhibits the H(+)-K(+)-ATPase (H(+)-K(+)-exchanging ATPase) in a pH-dependent manner. This ATPase is considered the proton pump in the secretory membrane of the parietal cell. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] Oncology: The study of cancer. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Ophthalmology: A surgical specialty concerned with the structure and function of the eye and the medical and surgical treatment of its defects and diseases. [NIH] Opiate: A remedy containing or derived from opium; also any drug that induces sleep. [EU] Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [NIH] Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the

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suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Oral Health: The optimal state of the mouth and normal functioning of the organs of the mouth without evidence of disease. [NIH] Oral Hygiene: The practice of personal hygiene of the mouth. It includes the maintenance of oral cleanliness, tissue tone, and general preservation of oral health. [NIH] Oral Manifestations: Disorders of the mouth attendant upon non-oral disease or injury. [NIH]

Organ Transplantation: Transference of an organ between individuals of the same species or between individuals of different species. [NIH] Orofacial: Of or relating to the mouth and face. [EU] Oropharynx: Oral part of the pharynx. [NIH] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Otitis: Inflammation of the ear, which may be marked by pain, fever, abnormalities of hearing, hearing loss, tinnitus, and vertigo. [EU] Otitis Media: Inflammation of the middle ear. [NIH] Otolaryngology: A surgical specialty concerned with the study and treatment of disorders of the ear, nose, and throat. [NIH] Otorhinolaryngology: That branch of medicine concerned with medical and surgical treatment of the head and neck, including the ears, nose and throat. [EU] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] Overexpress: An excess of a particular protein on the surface of a cell. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxidants: Oxidizing agents or electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (oxidation-reduction). In vivo, it appears that phagocyte-generated oxidants function as tumor promoters or cocarcinogens rather than as complete carcinogens perhaps because of the high levels of endogenous antioxidant defenses. It is also thought that oxidative damage in joints may trigger the autoimmune response that characterizes the persistence of the rheumatoid disease process. [NIH]

Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative Phosphorylation: Electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds. [NIH]

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Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oximetry: The determination of oxygen-hemoglobin saturation of blood either by withdrawing a sample and passing it through a classical photoelectric oximeter or by electrodes attached to some translucent part of the body like finger, earlobe, or skin fold. It includes non-invasive oxygen monitoring by pulse oximetry. [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] Oxygenator: An apparatus by which oxygen is introduced into the blood during circulation outside the body, as during open heart surgery. [NIH] Pachymeningitis: Inflammation of the dura mater of the brain, the spinal cord or the optic nerve. [NIH] Paclitaxel: Antineoplastic agent isolated from the bark of the Pacific yew tree, Taxus brevifolia. Paclitaxel stabilizes microtubules in their polymerized form and thus mimics the action of the proto-oncogene proteins c-mos. [NIH] Paediatric: Of or relating to the care and medical treatment of children; belonging to or concerned with paediatrics. [EU] Palate: The structure that forms the roof of the mouth. It consists of the anterior hard palate and the posterior soft palate. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Pancreatic Juice: The fluid containing digestive enzymes secreted by the pancreas in response to food in the duodenum. [NIH] Panic: A state of extreme acute, intense anxiety and unreasoning fear accompanied by disorganization of personality function. [NIH] Paraffin: A mixture of solid hydrocarbons obtained from petroleum. It has a wide range of uses including as a stiffening agent in ointments, as a lubricant, and as a topical antiinflammatory. It is also commonly used as an embedding material in histology. [NIH] Paranasal Sinuses: Air-filled extensions of the respiratory part of the nasal cavity into the frontal, ethmoid, sphenoid, and maxillary cranial bones. They vary in size and form in different individuals and are lined by the ciliated mucous membranes of the nasal cavity. [NIH]

Parasite: An animal or a plant that lives on or in an organism of another species and gets at least some of its nutrition from that other organism. [NIH] Parasitic: Having to do with or being a parasite. A parasite is an animal or a plant that lives on or in an organism of another species and gets at least some of its nutrients from it. [NIH] Parasitic Diseases: Infections or infestations with parasitic organisms. They are often

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contracted through contact with an intermediate vector, but may occur as the result of direct exposure. [NIH] Parasitism: A) The mode of life of a parasite; b) The relationship between an organism (parasite) that derives benefits from, and at the expense of, another organism (host). [NIH] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Parietal: 1. Of or pertaining to the walls of a cavity. 2. Pertaining to or located near the parietal bone, as the parietal lobe. [EU] Parotid: The space that contains the parotid gland, the facial nerve, the external carotid artery, and the retromandibular vein. [NIH] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Pastoral Care: Counseling or comfort given by ministers, priests, rabbis, etc., to those in need of help with emotional problems or stressful situations. [NIH] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathologist: A doctor who identifies diseases by studying cells and tissues under a microscope. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Patient Selection: Criteria and standards used for the determination of the appropriateness of the inclusion of patients with specific conditions in proposed treatment plans and the criteria used for the inclusion of subjects in various clinical trials and other research protocols. [NIH] Pediatrics: A medical specialty concerned with maintaining health and providing medical care to children from birth to adolescence. [NIH] Pelvic: Pertaining to the pelvis. [EU] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Penicillin: An antibiotic drug used to treat infection. [NIH] Penicillin Resistance: Nonsusceptibility of an organism to the action of penicillins. [NIH] Pentamidine: Antiprotozoal agent effective in trypanosomiasis, leishmaniasis, and some fungal infections; used in treatment of Pneumocystis carinii pneumonia in HIV-infected patients. It may cause diabetes mellitus, central nervous system damage, and other toxic

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effects. [NIH] Pepsin: An enzyme made in the stomach that breaks down proteins. [NIH] Pepsin A: Formed from pig pepsinogen by cleavage of one peptide bond. The enzyme is a single polypeptide chain and is inhibited by methyl 2-diaazoacetamidohexanoate. It cleaves peptides preferentially at the carbonyl linkages of phenylalanine or leucine and acts as the principal digestive enzyme of gastric juice. [NIH] Peptic: Pertaining to pepsin or to digestion; related to the action of gastric juices. [EU] Peptic Ulcer: Ulcer that occurs in those portions of the alimentary tract which come into contact with gastric juice containing pepsin and acid. It occurs when the amount of acid and pepsin is sufficient to overcome the gastric mucosal barrier. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide Chain Elongation: The process whereby an amino acid is joined through a substituted amide linkage to a chain of peptides. [NIH] Peptide Fragments: Partial proteins formed by partial hydrolysis of complete proteins. [NIH] Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [NIH] Perceived risk: Estimate or evaluation of risk as observed through personal experience or personal study, and personal evaluation of consequences. [NIH] Perception: The ability quickly and accurately to recognize similarities and differences among presented objects, whether these be pairs of words, pairs of number series, or multiple sets of these or other symbols such as geometric figures. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Pericarditis: Inflammation of the pericardium. [EU] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]

Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Periodontics: A dental specialty concerned with the histology, physiology, and pathology of the tissues that support, attach, and surround the teeth, and of the treatment and prevention of disease affecting these tissues. [NIH] Periodontitis: Inflammation of the periodontal membrane; also called periodontitis simplex. [NIH]

Perioperative: Around the time of surgery; usually lasts from the time of going into the

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hospital or doctor's office for surgery until the time the patient goes home. [NIH] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peripheral Neuropathy: Nerve damage, usually affecting the feet and legs; causing pain, numbness, or a tingling feeling. Also called "somatic neuropathy" or "distal sensory polyneuropathy." [NIH] Peripheral stem cell transplantation: A method of replacing blood-forming cells destroyed by cancer treatment. Immature blood cells (stem cells) in the circulating blood that are similar to those in the bone marrow are given after treatment to help the bone marrow recover and continue producing healthy blood cells. Transplantation may be autologous (an individual's own blood cells saved earlier), allogeneic (blood cells donated by someone else), or syngeneic (blood cells donated by an identical twin). Also called peripheral stem cell support. [NIH] Peripheral stem cells: Immature cells found circulating in the bloodstream. New blood cells develop from peripheral stem cells. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH] Peritoneal Dialysis: Dialysis fluid being introduced into and removed from the peritoneal cavity as either a continuous or an intermittent procedure. [NIH] Peritoneum: Endothelial lining of the abdominal cavity, the parietal peritoneum covering the inside of the abdominal wall and the visceral peritoneum covering the bowel, the mesentery, and certain of the organs. The portion that covers the bowel becomes the serosal layer of the bowel wall. [NIH] Peritonitis: Inflammation of the peritoneum; a condition marked by exudations in the peritoneum of serum, fibrin, cells, and pus. It is attended by abdominal pain and tenderness, constipation, vomiting, and moderate fever. [EU] Permissiveness: The attitude that grants freedom of expression and activity to another individual, but not necessarily with sanction or approval. [NIH] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Petroleum: Naturally occurring complex liquid hydrocarbons which, after distillation, yield combustible fuels, petrochemicals, and lubricants. [NIH] P-Glycoprotein: A 170 kD transmembrane glycoprotein from the superfamily of ABC transporters. It serves as an ATP-dependent efflux pump for a variety of chemicals, including many antineoplastic agents. Overexpression of this glycoprotein is associated with multidrug resistance. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU]

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Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH] Pharmacists: Those persons legally qualified by education and training to engage in the practice of pharmacy. [NIH] Pharmacodynamics: The study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the correlation of actions and effects of drugs with their chemical structure; also, such effects on the actions of a particular drug or drugs. [EU] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phenytoin: An anticonvulsant that is used in a wide variety of seizures. It is also an antiarrhythmic and a muscle relaxant. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. The mechanism of its muscle relaxant effect appears to involve a reduction in the sensitivity of muscle spindles to stretch. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. [NIH] Pheromone: A substance secreted externally by certain animal species, especially insects, to affect the behavior or development of other members of the species. [NIH] Phorbol: Class of chemicals that promotes the development of tumors. [NIH] Phorbol Esters: Tumor-promoting compounds obtained from croton oil (Croton tiglium). Some of these are used in cell biological experiments as activators of protein kinase C. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylates: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Phosphorylcholine: Calcium and magnesium salts used therapeutically in hepatobiliary

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dysfunction. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Picornavirus: Any of a group of tiny RNA-containing viruses including the enteroviruses and rhinoviruses. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [NIH] Plasmin: A product of the lysis of plasminogen (profibrinolysin) by plasminogen activators. It is composed of two polypeptide chains, light (B) and heavy (A), with a molecular weight of 75,000. It is the major proteolytic enzyme involved in blood clot retraction or the lysis of fibrin and quickly inactivated by antiplasmins. EC 3.4.21.7. [NIH] Plasminogen: Precursor of fibrinolysin (plasmin). It is a single-chain beta-globulin of molecular weight 80-90,000 found mostly in association with fibrinogen in plasma; plasminogen activators change it to fibrinolysin. It is used in wound debriding and has been investigated as a thrombolytic agent. [NIH] Plasminogen Activators: A heterogeneous group of proteolytic enzymes that convert plasminogen to plasmin. They are concentrated in the lysosomes of most cells and in the vascular endothelium, particularly in the vessels of the microcirculation. EC 3.4.21.-. [NIH] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene

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changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] Platelet Activating Factor: A phospholipid derivative formed by platelets, basophils, neutrophils, monocytes, and macrophages. It is a potent platelet aggregating agent and inducer of systemic anaphylactic symptoms, including hypotension, thrombocytopenia, neutropenia, and bronchoconstriction. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [NIH]

Pleura: The thin serous membrane enveloping the lungs and lining the thoracic cavity. [NIH] Pleural: A circumscribed area of hyaline whorled fibrous tissue which appears on the surface of the parietal pleura, on the fibrous part of the diaphragm or on the pleura in the interlobar fissures. [NIH] Pleural cavity: A space enclosed by the pleura (thin tissue covering the lungs and lining the interior wall of the chest cavity). It is bound by thin membranes. [NIH] Pleural Effusion: Presence of fluid in the pleural cavity resulting from excessive transudation or exudation from the pleural surfaces. It is a sign of disease and not a diagnosis in itself. [NIH] Pleurisy: Inflammation of the pleura, with exudation into its cavity and upon its surface. It may occur as either an acute or a chronic process. In acute pleurisy the pleura becomes reddened, then covered with an exudate of lymph, fibrin, and cellular elements (the dry stage); the disease may progress to the second stage, in which a copious exudation of serum occurs (stage of liquid effusion). The inflamed surfaces of the pleura tend to become united by adhesions, which are usually permanent. The symptoms are a stitch in the side, a chill, followed by fever and a dry cough. As effusion occurs there is an onset of dyspnea and a diminution of pain. The patient lies on the affected side. [EU] Pneumonia: Inflammation of the lungs. [NIH] Pneumonitis: A disease caused by inhaling a wide variety of substances such as dusts and molds. Also called "farmer's disease". [NIH] Pneumothorax: Accumulation of air or gas in the space between the lung and chest wall, resulting in partial or complete collapse of the lung. [NIH] Podophyllotoxin: The main active constituent of the resin from the roots of may apple or mandrake (Podophyllum peltatum and P. emodi). It is a potent spindle poison, toxic if taken internally, and has been used as a cathartic. It is very irritating to skin and mucous membranes, has keratolytic actions, has been used to treat warts and keratoses, and may have antineoplastic properties, as do some of its congeners and derivatives. [NIH]

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Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polyneuritis: Inflammation of several peripheral nerves at the same time. [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Positron emission tomography scan: PET scan. A computerized image of the metabolic activity of body tissues used to determine the presence of disease. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postherpetic Neuralgia: Variety of neuralgia associated with migraine in which pain is felt in or behind the eye. [NIH] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postoperative: After surgery. [NIH] Postoperative Complications: Pathologic processes that affect patients after a surgical procedure. They may or may not be related to the disease for which the surgery was done, and they may or may not be direct results of the surgery. [NIH] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-traumatic: Occurring as a result of or after injury. [EU] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH]

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Potentiating: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Prednisolone: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. [NIH] Prednisone: A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. [NIH] Preoperative: Preceding an operation. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Primary endpoint: The main result that is measured at the end of a study to see if a given treatment worked (e.g., the number of deaths or the difference in survival between the treatment group and the control group). What the primary endpoint will be is decided before the study begins. [NIH] Primary Prevention: Prevention of disease or mental disorders in susceptible individuals or populations through promotion of health, including mental health, and specific protection, as in immunization, as distinguished from the prevention of complications or after-effects of existing disease. [NIH] Primary tumor: The original tumor. [NIH] Private Sector: That distinct portion of the institutional, industrial, or economic structure of a country that is controlled or owned by non-governmental, private interests. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Progeny: The offspring produced in any generation. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH]

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Prognostic factor: A situation or condition, or a characteristic of a patient, that can be used to estimate the chance of recovery from a disease, or the chance of the disease recurring (coming back). [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Promotor: In an operon, a nucleotide sequence located at the operator end which contains all the signals for the correct initiation of genetic transcription by the RNA polymerase holoenzyme and determines the maximal rate of RNA synthesis. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Prospective Payment System: A system wherein reimbursement rates are set, for a given period of time, prior to the circumstances giving rise to actual reimbursement claims. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandin: Any of a group of components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway that are extremely potent mediators of a diverse group of physiologic processes. The abbreviation for prostaglandin is PG; specific compounds are designated by adding one of the letters A through I to indicate the type of substituents found on the hydrocarbon skeleton and a subscript (1, 2 or 3) to indicate the number of double bonds in the hydrocarbon skeleton e.g., PGE2. The predominant naturally occurring prostaglandins all have two double bonds and are synthesized from arachidonic acid (5,8,11,14-eicosatetraenoic acid) by the pathway shown in the illustration. The 1 series and 3 series are produced by the same pathway with fatty acids having one fewer double bond (8,11,14-eicosatrienoic acid or one more double bond (5,8,11,14,17-eicosapentaenoic acid) than arachidonic acid. The subscript a or ß indicates the configuration at C-9 (a denotes a substituent below the plane of the ring, ß, above the plane). The naturally occurring PGF's have the a configuration, e.g., PGF2a. All of the prostaglandins act by binding to specific cell-surface receptors causing an increase in the level of the intracellular second messenger cyclic AMP (and in some cases cyclic GMP also). The effect produced by the cyclic AMP increase depends on the specific cell type. In some cases there is also a positive feedback effect. Increased cyclic AMP increases prostaglandin synthesis leading to further increases in cyclic AMP. [EU] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH]

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Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). [NIH] Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein Kinase C: An enzyme that phosphorylates proteins on serine or threonine residues in the presence of physiological concentrations of calcium and membrane phospholipids. The additional presence of diacylglycerols markedly increases its sensitivity to both calcium and phospholipids. The sensitivity of the enzyme can also be increased by phorbol esters and it is believed that protein kinase C is the receptor protein of tumor-promoting phorbol esters. EC 2.7.1.-. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proteoglycans: Glycoproteins which have a very high polysaccharide content. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Proton Pump: Integral membrane proteins that transport protons across a membrane against a concentration gradient. This transport is driven by hydrolysis of ATP by H(+)transporting ATP synthase. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proto-Oncogene Proteins: Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity. [NIH] Proto-Oncogene Proteins c-mos: Cellular proteins encoded by the c-mos genes. They function in the cell cycle to maintain maturation promoting factor in the active state and have protein-serine/threonine kinase activity. Oncogenic transformation can take place when c-mos proteins are expressed at the wrong time. [NIH]

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Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Protozoal: Having to do with the simplest organisms in the animal kingdom. Protozoa are single-cell organisms, such as ameba, and are different from bacteria, which are not members of the animal kingdom. Some protozoa can be seen without a microscope. [NIH] Protozoan: 1. Any individual of the protozoa; protozoon. 2. Of or pertaining to the protozoa; protozoal. [EU] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Proxy: A person authorized to decide or act for another person, for example, a person having durable power of attorney. [NIH] Pseudomonas: A genus of gram-negative, aerobic, rod-shaped bacteria widely distributed in nature. Some species are pathogenic for humans, animals, and plants. [NIH] Pseudomonas aeruginosa: A species of gram-negative, aerobic, rod-shaped bacteria commonly isolated from clinical specimens (wound, burn, and urinary tract infections). It is also found widely distributed in soil and water. P. aeruginosa is a major agent of nosocomial infection. [NIH] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Psychomotor: Pertaining to motor effects of cerebral or psychic activity. [EU] Psychotherapy: A generic term for the treatment of mental illness or emotional disturbances primarily by verbal or nonverbal communication. [NIH] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulmonary Embolism: Embolism in the pulmonary artery or one of its branches. [NIH] Pulmonary Fibrosis: Chronic inflammation and progressive fibrosis of the pulmonary

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alveolar walls, with steadily progressive dyspnea, resulting finally in death from oxygen lack or right heart failure. [NIH] Pulmonary Ventilation: The total volume of gas per minute inspired or expired measured in liters per minute. [NIH] Pulsation: A throb or rhythmical beat, as of the heart. [EU] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Purulent: Consisting of or containing pus; associated with the formation of or caused by pus. [EU] Putrefaction: The process of decomposition of animal and vegetable matter by living organisms. [NIH] Pyelonephritis: Inflammation of the kidney and its pelvis, beginning in the interstitium and rapidly extending to involve the tubules, glomeruli, and blood vessels; due to bacterial infection. [EU] Pyoderma: Any purulent skin disease (Dorland, 27th ed). [NIH] Pyoderma Gangrenosum: An idiopathic, rapidly evolving, and severely debilitating disease occurring most commonly in association with chronic ulcerative colitis. It is characterized by the presence of boggy, purplish ulcers with undermined borders, appearing mostly on the legs. The majority of cases are in people between 40 and 60 years old. Its etiology is unknown. [NIH] Pyogenic: Producing pus; pyopoietic (= liquid inflammation product made up of cells and a thin fluid called liquor puris). [EU] Pyridoxal: 3-Hydroxy-5-(hydroxymethyl)-2-methyl-4- pyridinecarboxaldehyde. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quinolones: Quinolines which are substituted in any position by one or more oxo groups. These compounds can have any degree of hydrogenation, any substituents, and fused ring systems. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH]

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Radiography: Examination of any part of the body for diagnostic purposes by means of roentgen rays, recording the image on a sensitized surface (such as photographic film). [NIH] Radioimmunotherapy: Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (immunotoxins) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (radiotherapy). [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Random Allocation: A process involving chance used in therapeutic trials or other research endeavor for allocating experimental subjects, human or animal, between treatment and control groups, or among treatment groups. It may also apply to experiments on inanimate objects. [NIH] Randomization: Also called random allocation. Is allocation of individuals to groups, e.g., for experimental and control regimens, by chance. Within the limits of chance variation, random allocation should make the control and experimental groups similar at the start of an investigation and ensure that personal judgment and prejudices of the investigator do not influence allocation. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Randomized Controlled Trials: Clinical trials that involve at least one test treatment and one control treatment, concurrent enrollment and follow-up of the test- and control-treated groups, and in which the treatments to be administered are selected by a random process, such as the use of a random-numbers table. Treatment allocations using coin flips, odd-even numbers, patient social security numbers, days of the week, medical record numbers, or other such pseudo- or quasi-random processes, are not truly randomized and trials employing any of these techniques for patient assignment are designated simply controlled clinical trials. [NIH] Ranitidine: A non-imidazole blocker of those histamine receptors that mediate gastric secretion (H2 receptors). It is used to treat gastrointestinal ulcers. [NIH] Reactivation: The restoration of activity to something that has been inactivated. [EU] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and

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non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reassurance: A procedure in psychotherapy that seeks to give the client confidence in a favorable outcome. It makes use of suggestion, of the prestige of the therapist. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Receptors, Chemokine: Cell surface glycoproteins that bind to chemokines and thus mediate the migration of pro-inflammatory molecules. The receptors are members of the seven-transmembrane G protein-coupled receptor family. Like the chemokines themselves, the receptors can be divided into at least three structural branches: CR, CCR, and CXCR, according to variations in a shared cysteine motif. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Reconstitution: 1. A type of regeneration in which a new organ forms by the rearrangement of tissues rather than from new formation at an injured surface. 2. The restoration to original form of a substance previously altered for preservation and storage, as the restoration to a liquid state of blood serum or plasma that has been dried and stored. [EU] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reference Values: The range or frequency distribution of a measurement in a population (of organisms, organs or things) that has not been selected for the presence of disease or abnormality. [NIH] Reflective: Capable of throwing back light, images, sound waves : reflecting. [EU] Reflex: An involuntary movement or exercise of function in a part, excited in response to a stimulus applied to the periphery and transmitted to the brain or spinal cord. [NIH] Reflux: The term used when liquid backs up into the esophagus from the stomach. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractory: Not readily yielding to treatment. [EU] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH]

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Regional lymph node: In oncology, a lymph node that drains lymph from the region around a tumor. [NIH] Regression Analysis: Procedures for finding the mathematical function which best describes the relationship between a dependent variable and one or more independent variables. In linear regression (see linear models) the relationship is constrained to be a straight line and least-squares analysis is used to determine the best fit. In logistic regression (see logistic models) the dependent variable is qualitative rather than continuously variable and likelihood functions are used to find the best relationship. In multiple regression the dependent variable is considered to depend on more than a single independent variable. [NIH]

Regurgitation: A backward flowing, as the casting up of undigested food, or the backward flowing of blood into the heart, or between the chambers of the heart when a valve is incompetent. [EU] Rehabilitative: Instruction of incapacitated individuals or of those affected with some mental disorder, so that some or all of their lost ability may be regained. [NIH] Reinfection: A second infection by the same pathogenic agent, or a second infection of an organ such as the kidney by a different pathogenic agent. [EU] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Relative risk: The ratio of the incidence rate of a disease among individuals exposed to a specific risk factor to the incidence rate among unexposed individuals; synonymous with risk ratio. Alternatively, the ratio of the cumulative incidence rate in the exposed to the cumulative incidence rate in the unexposed (cumulative incidence ratio). The term relative risk has also been used synonymously with odds ratio. This is because the odds ratio and relative risk approach each other if the disease is rare ( 5 percent of population) and the number of subjects is large. [NIH] Reliability: Used technically, in a statistical sense, of consistency of a test with itself, i. e. the extent to which we can assume that it will yield the same result if repeated a second time. [NIH]

Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal Circulation: The circulation of the blood through the vessels of the kidney. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Renal pelvis: The area at the center of the kidney. Urine collects here and is funneled into the ureter, the tube that connects the kidney to the bladder. [NIH] Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH] Repressor: Any of the specific allosteric protein molecules, products of regulator genes, which bind to the operator of operons and prevent RNA polymerase from proceeding into

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the operon to transcribe messenger RNA. [NIH] Research Design: A plan for collecting and utilizing data so that desired information can be obtained with sufficient precision or so that an hypothesis can be tested properly. [NIH] Research Support: Financial support of research activities. [NIH] Resection: Removal of tissue or part or all of an organ by surgery. [NIH] Residual Volume: The volume of air remaining in the lungs at the end of a maximal expiration. Common abbreviation is RV. [NIH] Resolving: The ability of the eye or of a lens to make small objects that are close together, separately visible; thus revealing the structure of an object. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respirator: A mechanical device that helps a patient breathe; a mechanical ventilator. [NIH] Respiratory distress syndrome: A lung disease that occurs primarily in premature infants; the newborn must struggle for each breath and blueing of its skin reflects the baby's inability to get enough oxygen. [NIH] Respiratory failure: Inability of the lungs to conduct gas exchange. [NIH] Respiratory Physiology: Functions and activities of the respiratory tract as a whole or of any of its parts. [NIH] Respiratory syncytial virus: RSV. A virus that causes respiratory infections with cold-like symptoms. [NIH] Respiratory System: The tubular and cavernous organs and structures, by means of which pulmonary ventilation and gas exchange between ambient air and the blood are brought about. [NIH] Response Elements: Nucleotide sequences, usually upstream, which are recognized by specific regulatory transcription factors, thereby causing gene response to various regulatory agents. These elements may be found in both promotor and enhancer regions. [NIH]

Response rate: The percentage of patients whose cancer shrinks or disappears after treatment. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinitis: Inflammation of the retina. It is rarely limited to the retina, but is commonly associated with diseases of the choroid (chorioretinitis) and of the optic nerve (neuroretinitis). The disease may be confined to one eye, but since it is generally dependent on a constitutional factor, it is almost always bilateral. It may be acute in course, but as a rule it lasts many weeks or even several months. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoids: Derivatives of vitamin A. Used clinically in the treatment of severe cystic acne,

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psoriasis, and other disorders of keratinization. Their possible use in the prophylaxis and treatment of cancer is being actively explored. [NIH] Retrograde: 1. Moving backward or against the usual direction of flow. 2. Degenerating, deteriorating, or catabolic. [EU] Retrospective: Looking back at events that have already taken place. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Retrovirus: A member of a group of RNA viruses, the RNA of which is copied during viral replication into DNA by reverse transcriptase. The viral DNA is then able to be integrated into the host chromosomal DNA. [NIH] Rhabdomyolysis: Necrosis or disintegration of skeletal muscle often followed by myoglobinuria. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rhinitis: Inflammation of the mucous membrane of the nose. [NIH] Rhinovirus: A genus of Picornaviridae inhabiting primarily the respiratory tract of mammalian hosts. It includes the human strains associated with common colds. [NIH] Ribavirin: 1-beta-D-Ribofuranosyl-1H-1,2,4-triazole-3-carboxamide. A nucleoside antimetabolite antiviral agent that blocks nucleic acid synthesis and is used against both RNA and DNA viruses. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Risk patient: Patient who is at risk, because of his/her behaviour or because of the type of person he/she is. [EU] Ristocetin: An antibiotic mixture of two components, A and B, obtained from Nocardia lurida (or the same substance produced by any other means). It is no longer used clinically because of its toxicity. It causes platelet agglutination and blood coagulation and is used to assay those functions in vitro. [NIH] Rod: A reception for vision, located in the retina. [NIH] Rotavirus: A genus of Reoviridae, causing acute gastroenteritis in birds and mammals, including humans. Transmission is horizontal and by environmental contamination. [NIH] Rubber: A high-molecular-weight polymeric elastomer derived from the milk juice (latex) of Hevea brasiliensis and other trees. It is a substance that can be stretched at room temperature to atleast twice its original length and after releasing the stress, retractrapidly, and recover its original dimensions fully. Synthetic rubber is made from many different chemicals, including styrene, acrylonitrile, ethylene, propylene, and isoprene. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Salmonella: A genus of gram-negative, facultatively anaerobic, rod-shaped bacteria that utilizes citrate as a sole carbon source. It is pathogenic for humans, causing enteric fevers, gastroenteritis, and bacteremia. Food poisoning is the most common clinical manifestation. Organisms within this genus are separated on the basis of antigenic characteristics, sugar

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fermentation patterns, and bacteriophage susceptibility. [NIH] Salvage Therapy: A therapeutic approach, involving chemotherapy, radiation therapy, or surgery, after initial regimens have failed to lead to improvement in a patient's condition. Salvage therapy is most often used for neoplastic diseases. [NIH] Saphenous: Applied to certain structures in the leg, e. g. nerve vein. [NIH] Saphenous Vein: The vein which drains the foot and leg. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Sarcoid: A cutaneus lesion occurring as a manifestation of sarcoidosis. [NIH] Sarcoidosis: An idiopathic systemic inflammatory granulomatous disorder comprised of epithelioid and multinucleated giant cells with little necrosis. It usually invades the lungs with fibrosis and may also involve lymph nodes, skin, liver, spleen, eyes, phalangeal bones, and parotid glands. [NIH] Sarcoma: A connective tissue neoplasm formed by proliferation of mesodermal cells; it is usually highly malignant. [NIH] Satellite: Applied to a vein which closely accompanies an artery for some distance; in cytogenetics, a chromosomal agent separated by a secondary constriction from the main body of the chromosome. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [EU] Sediment: A precipitate, especially one that is formed spontaneously. [EU] Sedimentation: The act of causing the deposit of sediment, especially by the use of a

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centrifugal machine. [EU] Segmental: Describing or pertaining to a structure which is repeated in similar form in successive segments of an organism, or which is undergoing segmentation. [NIH] Segmentation: The process by which muscles in the intestines move food and wastes through the body. [NIH] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selection Bias: The introduction of error due to systematic differences in the characteristics between those selected and those not selected for a given study. In sampling bias, error is the result of failure to ensure that all members of the reference population have a known chance of selection in the sample. [NIH] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Senescence: The bodily and mental state associated with advancing age. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU] Sepsis: The presence of bacteria in the bloodstream. [NIH] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU] Septicaemia: A term originally used to denote a putrefactive process in the body, but now usually referring to infection with pyogenic micro-organisms; a genus of Diptera; the severe type of infection in which the blood stream is invaded by large numbers of the causal. [NIH] Septicemia: Systemic disease associated with the presence and persistence of pathogenic microorganisms or their toxins in the blood. Called also blood poisoning. [EU] Sequence Analysis: A multistage process that includes the determination of a sequence (protein, carbohydrate, etc.), its fragmentation and analysis, and the interpretation of the resulting sequence information. [NIH] Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines,

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pyrimidines, and other amino acids. [NIH] Seroconversion: The change of a serologic test from negative to positive, indicating the development of antibodies in response to infection or immunization. [EU] Seroepidemiologic Studies: Epidemiologic studies based on the detection through serological testing of characteristic change in the serum level of specific antibodies. Latent subclinical infections and carrier states can thus be detected in addition to clinically overt cases. [NIH] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serology: The study of serum, especially of antigen-antibody reactions in vitro. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serotypes: A cause of haemorrhagic septicaemia (in cattle, sheep and pigs), fowl cholera of birds, pasteurellosis of rabbits, and gangrenous mastitis of ewes. It is also commonly found in atrophic rhinitis of pigs. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Shedding: Release of infectious particles (e. g., bacteria, viruses) into the environment, for example by sneezing, by fecal excretion, or from an open lesion. [NIH] Ships: Large vessels propelled by power or sail used for transportation on rivers, seas, oceans, or other navigable waters. Boats are smaller vessels propelled by oars, paddles, sail, or power; they may or may not have a deck. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet

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activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Sinusitis: An inflammatory process of the mucous membranes of the paranasal sinuses that occurs in three stages: acute, subacute, and chronic. Sinusitis results from any condition causing ostial obstruction or from pathophysiologic changes in the mucociliary transport mechanism. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skin test: A test for an immune response to a compound by placing it on or under the skin. [NIH]

Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small cell lung cancer: A type of lung cancer in which the cells appear small and round when viewed under the microscope. Also called oat cell lung cancer. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smoke Inhalation Injury: Pulmonary injury following the breathing in of toxic smoke from burning materials such as plastics, synthetics, building materials, etc. This injury is the most frequent cause of death in burn patients. [NIH] Smoking Cessation: Discontinuation of the habit of smoking, the inhaling and exhaling of tobacco smoke. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Sneezing: Sudden, forceful, involuntary expulsion of air from the nose and mouth caused by irritation to the mucous membranes of the upper respiratory tract. [NIH] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Social Security: Government sponsored social insurance programs. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatic cells: All the body cells except the reproductive (germ) cells. [NIH]

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Somatostatin: A polypeptide hormone produced in the hypothalamus, and other tissues and organs. It inhibits the release of human growth hormone, and also modulates important physiological functions of the kidney, pancreas, and gastrointestinal tract. Somatostatin receptors are widely expressed throughout the body. Somatostatin also acts as a neurotransmitter in the central and peripheral nervous systems. [NIH] Sound wave: An alteration of properties of an elastic medium, such as pressure, particle displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectroscopic: The recognition of elements through their emission spectra. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sphincter: A ringlike band of muscle fibres that constricts a passage or closes a natural orifice; called also musculus sphincter. [EU] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Splenectomy: An operation to remove the spleen. [NIH] Spondylitis: Inflammation of the vertebrae. [EU] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Sputum: The material expelled from the respiratory passages by coughing or clearing the throat. [NIH] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Standard therapy: A currently accepted and widely used treatment for a certain type of cancer, based on the results of past research. [NIH] Statistically significant: Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. [NIH] Steady state: Dynamic equilibrium. [EU] Stem cell transplantation: A method of replacing immature blood-forming cells that were destroyed by cancer treatment. The stem cells are given to the person after treatment to help

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the bone marrow recover and continue producing healthy blood cells. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stenosis: Narrowing or stricture of a duct or canal. [EU] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Steroid therapy: Treatment with corticosteroid drugs to reduce swelling, pain, and other symptoms of inflammation. [NIH] Stethoscope: An instrument used for the detection and study of sounds within the body that conveyed to the ears of the observer through rubber tubing. [NIH] Stimulants: Any drug or agent which causes stimulation. [NIH] Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Streptococcal: Caused by infection due to any species of streptococcus. [NIH] Streptococci: A genus of spherical Gram-positive bacteria occurring in chains or pairs. They are widely distributed in nature, being important pathogens but often found as normal commensals in the mouth, skin, and intestine of humans and other animals. [NIH] Streptococcus: A genus of gram-positive, coccoid bacteria whose organisms occur in pairs or chains. No endospores are produced. Many species exist as commensals or parasites on man or animals with some being highly pathogenic. A few species are saprophytes and occur in the natural environment. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stress Ulcer: An upper GI ulcer from physical injury such as surgery, major burns, or critical head injury. [NIH] Striatum: A higher brain's domain thus called because of its stripes. [NIH] Stricture: The abnormal narrowing of a body opening. Also called stenosis. [NIH] Stridor: The loud, harsh, vibrating sound produced by partial obstruction of the larynx or trachea. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the

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hematopoietic system and elsewhere. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Submaxillary: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts. [NIH] Sucralfate: A basic aluminum complex of sulfated sucrose. It is advocated in the therapy of peptic, duodenal, and prepyloric ulcers, gastritis, reflux esophagitis, and other gastrointestinal irritations. It acts primarily at the ulcer site, where it has cytoprotective, pepsinostatic, antacid, and bile acid-binding properties. The drug is only slightly absorbed by the digestive mucosa, which explains the absence of systemic effects and toxicity. [NIH] Suction: The removal of secretions, gas or fluid from hollow or tubular organs or cavities by means of a tube and a device that acts on negative pressure. [NIH] Sulbactam: A beta-lactamase inhibitor with very weak antibacterial action. The compound prevents antibiotic destruction of beta-lactam antibiotics by inhibiting beta-lactamases, thus extending their spectrum activity. Combinations of sulbactam with beta-lactam antibiotics have been used successfully for the therapy of infections caused by organisms resistant to the antibiotic alone. [NIH] Sulfadoxine: A long acting sulfonamide that is used, usually in combination with other drugs, for respiratory, urinary tract, and malarial infections. [NIH] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Superinfection: A frequent complication of drug therapy for microbial infection. It may result from opportunistic colonization following immunosuppression by the primary pathogen and can be influenced by the time interval between infections, microbial physiology, or host resistance. Experimental challenge and in vitro models are sometimes used in virulence and infectivity studies. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Supportive care: Treatment given to prevent, control, or relieve complications and side effects and to improve the comfort and quality of life of people who have cancer. [NIH]

Dictionary 541

Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] Surfactant: A fat-containing protein in the respiratory passages which reduces the surface tension of pulmonary fluids and contributes to the elastic properties of pulmonary tissue. [NIH]

Surgical Wound Infection: Infection occurring at the site of a surgical incision. [NIH] Survival Analysis: A class of statistical procedures for estimating the survival function (function of time, starting with a population 100% well at a given time and providing the percentage of the population still well at later times). The survival analysis is then used for making inferences about the effects of treatments, prognostic factors, exposures, and other covariates on the function. [NIH] Survival Rate: The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods. [NIH] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Symptomatic treatment: Therapy that eases symptoms without addressing the cause of disease. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Syncytium: A living nucleated tissue without apparent cellular structure; a tissue composed of a mass of nucleated protoplasm without cell boundaries. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Syphilis: A contagious venereal disease caused by the spirochete Treponema pallidum. [NIH]

Systemic: Affecting the entire body. [NIH] Systemic disease: Disease that affects the whole body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tachycardia: Excessive rapidity in the action of the heart, usually with a heart rate above 100 beats per minute. [NIH] Tachypnea: Rapid breathing. [NIH] Teichoic Acids: Bacterial polysaccharides that are rich in phosphodiester linkages. They are the major components of the cell walls and membranes of many bacteria. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH]

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Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Terminal disease: Disease that cannot be cured and will cause death. [NIH] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetani: Causal agent of tetanus. [NIH] Tetanic: Having the characteristics of, or relating to tetanus. [NIH] Tetanus: A disease caused by tetanospasmin, a powerful protein toxin produced by Clostridium tetani. Tetanus usually occurs after an acute injury, such as a puncture wound or laceration. Generalized tetanus, the most common form, is characterized by tetanic muscular contractions and hyperreflexia. Localized tetanus presents itself as a mild condition with manifestations restricted to muscles near the wound. It may progress to the generalized form. [NIH] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH] Thioredoxin: A hydrogen-carrying protein that participates in a variety of biochemical reactions including ribonucleotide reduction. Thioredoxin is oxidized from a dithiol to a disulfide during ribonucleotide reduction. The disulfide form is then reduced by NADPH in a reaction catalyzed by thioredoxin reductase. [NIH] Thoracic: Having to do with the chest. [NIH] Thorax: A part of the trunk between the neck and the abdomen; the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH]

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Thrombocytopenia: A decrease in the number of blood platelets. [NIH] Thromboembolism: Obstruction of a vessel by a blood clot that has been transported from a distant site by the blood stream. [NIH] Thrombolytic: 1. Dissolving or splitting up a thrombus. 2. A thrombolytic agent. [EU] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thrush: A disease due to infection with species of fungi of the genus Candida. [NIH] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]

Thymidine Kinase: An enzyme that catalyzes the conversion of ATP and thymidine to ADP and thymidine 5'-phosphate. Deoxyuridine can also act as an acceptor and dGTP as a donor. (From Enzyme Nomenclature, 1992) EC 2.7.1.21. [NIH] Thymidylate Synthase: An enzyme of the transferase class that catalyzes the reaction 5,10methylenetetrahydrofolate and dUMP to dihydrofolate and dTMP in the synthesis of thymidine triphosphate. (From Dorland, 27th ed) EC 2.1.1.45. [NIH] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Ticlopidine: Ticlopidine is an effective inhibitor of platelet aggregation. The drug has been found to significantly reduce infarction size in acute myocardial infarcts and is an effective antithrombotic agent in arteriovenous fistulas, aorto-coronary bypass grafts, ischemic heart disease, venous thrombosis, and arteriosclerosis. [NIH] Tin: A trace element that is required in bone formation. It has the atomic symbol Sn, atomic number 50, and atomic weight 118.71. [NIH] Tinnitus: Sounds that are perceived in the absence of any external noise source which may take the form of buzzing, ringing, clicking, pulsations, and other noises. Objective tinnitus refers to noises generated from within the ear or adjacent structures that can be heard by other individuals. The term subjective tinnitus is used when the sound is audible only to the affected individual. Tinnitus may occur as a manifestation of cochlear diseases; vestibulocochlear nerve diseases; intracranial hypertension; craniocerebral trauma; and other conditions. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. [NIH] Titre: The quantity of a substance required to produce a reaction with a given volume of another substance, or the amount of one substance required to correspond with a given

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amount of another substance. [EU] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tonicity: The normal state of muscular tension. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Toxoid: The material resulting from the treatment of toxin in such a way that the toxic properties are inactivated whilst the antigenic potency remains intact. [NIH] Toxoplasma: A genus of protozoa parasitic to birds and mammals. T. gondii is one of the most common infectious pathogenic animal parasites of man. [NIH] Toxoplasmosis: The acquired form of infection by Toxoplasma gondii in animals and man. [NIH]

Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Trachoma: A chronic infection of the conjunctiva and cornea caused by Chlamydia trachomatis. [NIH] Transaminase: Aminotransferase (= a subclass of enzymes of the transferase class that catalyse the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally 2-keto acid). Most of these enzymes are pyridoxal-phosphate-proteins. [EU]

Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case

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of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Transitional cell carcinoma: A type of cancer that develops in the lining of the bladder, ureter, or renal pelvis. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocate: The attachment of a fragment of one chromosome to a non-homologous chromosome. [NIH] Translocating: The attachment of a fragment of one chromosome to a non-homologous chromosome. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Transposons: Discrete genetic elements capable of inserting, in a non-permuted fashion, into the chromosomes of many bacteria. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Treatment Failure: A measure of the quality of health care by assessment of unsuccessful results of management and procedures used in combating disease, in individual cases or series. [NIH] Triad: Trivalent. [NIH] Triage: The sorting out and classification of patients or casualties to determine priority of need and proper place of treatment. [NIH] Trimethoprim-sulfamethoxazole: An antibiotic drug used to treat infection and prevent pneumocystis carinii pneumonia. [NIH] Trimetrexate: A nonclassical folic acid inhibitor through its inhibition of the enzyme dihydrofolate reductase. It is being tested for efficacy as an antineoplastic agent and as an antiparasitic agent against Pneumocystis carinii pneumonia in AIDS patients. Myelosuppression is its dose-limiting toxic effect. [NIH] Trimetrexate glucuronate: A drug that belongs to the family of drugs called antimetabolites. It is used in the treatment of pneumocystis carinii pneumonia and is being studied in the treatment of cancer. [NIH] Tropism: Directed movements and orientations found in plants, such as the turning of the

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sunflower to face the sun. [NIH] Trypanosomiasis: Infection with protozoa of the genus Trypanosoma. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tube-feeding: Feeding by a tube passed into the stomach. [NIH] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tunica: A rather vague term to denote the lining coat of hollow organs, tubes, or cavities. [NIH]

Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ulcerative colitis: Chronic inflammation of the colon that produces ulcers in its lining. This condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and mucus from the bowel. [NIH] Ultrasound test: A test that bounces sound waves off tissues and internal organs and changes the echoes into pictures (sonograms). [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Urban Health: The status of health in urban populations. [NIH] Urban Population: The inhabitants of a city or town, including metropolitan areas and suburban areas. [NIH] Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Ureter: One of a pair of thick-walled tubes that transports urine from the kidney pelvis to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Urinary: Having to do with urine or the organs of the body that produce and get rid of

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urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urinary tract infection: An illness caused by harmful bacteria growing in the urinary tract. [NIH]

Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Uvea: The middle coat of the eyeball, consisting of the choroid in the back of the eye and the ciliary body and iris in the front of the eye. [NIH] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vacuole: A fluid-filled cavity within the cytoplasm of a cell. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vaginal: Of or having to do with the vagina, the birth canal. [NIH] Vaginitis: Inflammation of the vagina characterized by pain and a purulent discharge. [NIH] Vancomycin: Antibacterial obtained from Streptomyces orientalis. It is a glycopeptide related to ristocetin that inhibits bacterial cell wall assembly and is toxic to kidneys and the inner ear. [NIH] Varicella: Chicken pox. [EU] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] Vasculitis: Inflammation of a blood vessel. [NIH] Vasodilators: Any nerve or agent which induces dilatation of the blood vessels. [NIH] VE: The total volume of gas either inspired or expired in one minute. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Vena: A vessel conducting blood from the capillary bed to the heart. [NIH] Venoms: Poisonous animal secretions forming fluid mixtures of many different enzymes, toxins, and other substances. These substances are produced in specialized glands and secreted through specialized delivery systems (nematocysts, spines, fangs, etc.) for disabling prey or predator. [NIH] Venous: Of or pertaining to the veins. [EU] Venous blood: Blood that has given up its oxygen to the tissues and carries carbon dioxide back for gas exchange. [NIH] Venous Thrombosis: The formation or presence of a thrombus within a vein. [NIH] Ventilation: 1. In respiratory physiology, the process of exchange of air between the lungs

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and the ambient air. Pulmonary ventilation (usually measured in litres per minute) refers to the total exchange, whereas alveolar ventilation refers to the effective ventilation of the alveoli, in which gas exchange with the blood takes place. 2. In psychiatry, verbalization of one's emotional problems. [EU] Ventilator: A breathing machine that is used to treat respiratory failure by promoting ventilation; also called a respirator. [NIH] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vertigo: An illusion of movement; a sensation as if the external world were revolving around the patient (objective vertigo) or as if he himself were revolving in space (subjective vertigo). The term is sometimes erroneously used to mean any form of dizziness. [EU] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Vinculin: A cytoskeletal protein associated with cell-cell and cell-matrix interactions. The amino acid sequence of human vinculin has been determined. The protein consists of 1066 amino acid residues and its gene has been assigned to chromosome 10. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Load: The quantity of measurable virus in the blood. Change in viral load, measured in plasma, is used as a surrogate marker in HIV disease progression. [NIH] Viremia: The presence of viruses in the blood. [NIH] Virion: The infective system of a virus, composed of the viral genome, a protein core, and a protein coat called a capsid, which may be naked or enclosed in a lipoprotein envelope called the peplos. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virulent: A virus or bacteriophage capable only of lytic growth, as opposed to temperate phages establishing the lysogenic response. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Virus Activation: The mechanism by which latent viruses, such as genetically transmitted tumor viruses or prophages of lysogenic bacteria, are induced to replicate and are released as infectious viruses. It may be effected by various endogenous and exogenous stimuli, including B-cell lipopolysaccharides, glucocorticoid hormones, halogenated pyrimidines, ionizing radiation, ultraviolet light, and superinfecting viruses. [NIH] Virus Replication: The process of intracellular viral multiplication, consisting of the synthesis of proteins, nucleic acids, and sometimes lipids, and their assembly into a new

Dictionary 549

infectious particle. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Visceral Larva Migrans: Infestation of the dermis by various larvae, characterized by bizarre red irregular lines which are broad at one end and fade at the other, produced by burrowing larvae. [NIH] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] Vital Statistics: Used for general articles concerning statistics of births, deaths, marriages, etc. [NIH] Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Vocal cord: The vocal folds of the larynx. [NIH] Volition: Voluntary activity without external compulsion. [NIH] Vulva: The external female genital organs, including the clitoris, vaginal lips, and the opening to the vagina. [NIH] Vulvovaginitis: Inflammation of the vulva and vagina, or of the vulvovaginal glands. [EU] Wakefulness: A state in which there is an enhanced potential for sensitivity and an efficient responsiveness to external stimuli. [NIH] War: Hostile conflict between organized groups of people. [NIH] Weight Gain: Increase in body weight over existing weight. [NIH] Wheezing: Breathing with a rasp or whistling sound; a sign of airway constriction or obstruction. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Wound Infection: Invasion of the site of trauma by pathogenic microorganisms. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH]

550 Pneumonia

X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zidovudine: A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by an azido group. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA during reverse transcription. It improves immunologic function, partially reverses the HIVinduced neurological dysfunction, and improves certain other clinical abnormalities associated with AIDS. Its principal toxic effect is dose-dependent suppression of bone marrow, resulting in anemia and leukopenia. [NIH] Zoster: A virus infection of the Gasserian ganglion and its nerve branches, characterized by discrete areas of vesiculation of the epithelium of the forehead, the nose, the eyelids, and the cornea together with subepithelial infiltration. [NIH] Zygote: The fertilized ovum. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

551

INDEX 3 3-dimensional, 40, 445, 526 A Abdomen, 382, 445, 458, 463, 498, 499, 502, 516, 517, 519, 538, 539, 542 Abdominal Pain, 228, 258, 381, 382, 445, 485, 519, 546 Aberrant, 84, 445 Abscess, 255, 296, 439, 445 Academic Medical Centers, 7, 445 Acceptor, 445, 501, 515, 543, 544 Acetylcholine, 445, 463, 464, 512, 513 Acetylcysteine, 334, 445 Acidosis, 445, 473 Acinetobacter, 154, 158, 162, 174, 289, 302, 314, 445 Acne, 38, 445, 532 Acoustic, 123, 445 Actin, 65, 66, 126, 445 Acute Disease, 3, 446 Acute leukemia, 282, 292, 446 Acute lymphoblastic leukemia, 310, 446 Acute lymphocytic leukemia, 446 Acute myelogenous leukemia, 228, 446 Acute myeloid leukemia, 446 Acute nonlymphocytic leukemia, 446 Acute renal, 4, 252, 446, 490 Adaptability, 446, 461, 462 Adaptation, 17, 20, 80, 446, 509, 521 Adenine, 364, 369, 370, 446 Adenoma, 190, 446 Adenosine, 446, 493, 520 Adenovirus, 135, 149, 171, 203, 446 Adhesions, 446, 522 Adjunctive Therapy, 101, 446 Adjustment, 126, 446 Adjuvant, 49, 98, 111, 115, 446 Adolescence, 446, 517 Adoptive Transfer, 67, 447 Adrenal Cortex, 447, 469, 524 Adrenergic, 447, 449, 452, 475, 479 Adverse Effect, 14, 53, 340, 343, 400, 447, 465, 499, 520, 536 Aerobic, 363, 443, 447, 480, 493, 500, 510, 527 Aetiology, 181, 226, 260, 308, 320, 447 Afferent, 77, 447 Affinity, 49, 447, 465, 491, 501, 537

Agammaglobulinemia, 171, 291, 447 Agar, 447, 521 Age Groups, 4, 447 Age of Onset, 447, 546 Aged, 80 and Over, 447 Agonist, 26, 164, 447, 475, 511 Air Sacs, 447, 448 Alanine, 94, 448 Alertness, 381, 448 Algorithms, 241, 448, 457 Alimentary, 448, 478, 517, 518 Alkaline, 78, 445, 448, 449, 455, 459 Alkaline Phosphatase, 78, 448 Alleles, 91, 448 Allergen, 158, 448, 473, 535 Allogeneic, 80, 87, 88, 115, 133, 181, 190, 222, 225, 228, 244, 322, 338, 448, 487, 489, 519 Allogeneic bone marrow transplantation, 133, 190, 244, 448 Allylamine, 448, 449 Alopecia, 448, 470 Alpha Particles, 448, 528 Alpha-1, 164, 448, 449 Alternative medicine, 398, 448 Alum, 75, 448 Aluminum, 448, 540 Alveoli, 400, 448, 548 Amantadine, 203, 448 Ameliorated, 146, 449 Ameliorating, 128, 449 Amine, 139, 449, 491 Amino Acid Sequence, 94, 112, 361, 449, 451, 485, 548 Aminoquinolines, 375, 449 Amitriptyline, 179, 449 Ammonia, 449, 486, 546 Amoxicillin, 150, 154, 156, 157, 172, 174, 176, 198, 203, 218, 273, 274, 323, 449 Ampicillin, 157, 202, 314, 449 Amplification, 14, 46, 125, 154, 155, 156, 271, 321, 449 Amyloid, 306, 449 Anaerobic, 60, 363, 443, 449, 488, 493, 510, 533 Anaesthesia, 181, 266, 284, 315, 449, 495 Anal, 449, 482, 502, 510 Analgesic, 449, 513

552 Pneumonia

Analog, 59, 373, 450, 465, 484 Analogous, 450, 475, 545 Analysis of Variance, 61, 104, 450 Anaphylatoxins, 450, 467 Anatomical, 111, 142, 450, 463, 477, 494, 502, 534 Androgens, 447, 450, 469 Anemia, 53, 280, 304, 351, 363, 401, 421, 450, 483, 489, 504, 509, 550 Anesthesia, 26, 66, 119, 360, 368, 448, 450 Aneurysm, 264, 308, 450, 452 Angina, 22, 450 Angiogenesis, 84, 450, 505 Ankle, 384, 450 Annealing, 450, 523 Anorexia, 362, 450, 485 Antagonism, 82, 450, 465 Antiangiogenic, 84, 450 Antibiotic Prophylaxis, 53, 59, 381, 450 Antibody, 14, 18, 20, 24, 26, 28, 33, 49, 51, 62, 70, 73, 86, 100, 101, 129, 130, 131, 150, 151, 163, 167, 168, 173, 175, 203, 207, 269, 388, 390, 447, 451, 466, 479, 489, 491, 492, 493, 494, 495, 498, 505, 508, 528, 529, 535, 536, 538, 550 Anticholinergic, 449, 451 Anticoagulant, 184, 451, 526 Anticonvulsant, 451, 459, 520 Antidepressant, 449, 451 Antidote, 451, 500 Antifungal, 45, 139, 299, 451 Antifungal Agents, 45, 451 Antigen-Antibody Complex, 451, 467 Antigen-presenting cell, 451, 472 Anti-infective, 451, 463, 492, 498 Anti-inflammatory, 68, 101, 107, 114, 115, 127, 133, 253, 451, 469, 486, 516, 524 Anti-Inflammatory Agents, 101, 451, 469 Antimetabolite, 451, 507, 533 Antineoplastic, 451, 469, 470, 484, 507, 516, 519, 522, 545 Antineoplastic Agents, 451, 519 Antioxidant, 16, 89, 133, 451, 515, 516 Antiproliferative, 82, 452 Antipsychotic, 452, 465, 512 Antiserum, 142, 452, 454 Antithrombotic, 452, 543 Antiviral, 5, 12, 65, 376, 388, 391, 445, 448, 452, 484, 497, 518, 533 Anus, 449, 452, 458, 466 Anxiety, 440, 452, 499, 516 Aorta, 264, 272, 385, 452, 469, 548

Aortic Aneurysm, 34, 165, 382, 452 Apolipoproteins, 452, 502 Apoptosis, 62, 83, 96, 225, 452, 460 Appendicitis, 382, 452 Applicability, 45, 452 Approximate, 36, 452 Aqueous, 141, 452, 455, 471, 477, 492, 500, 502 Arachidonic Acid, 452, 525 Archaea, 453, 507 Arginine, 450, 453, 513 Arterial, 428, 442, 448, 453, 463, 493, 526, 541 Arteries, 354, 400, 452, 453, 457, 469, 502, 507, 510 Arterioles, 453, 457, 459, 507 Arteriosclerosis, 453, 543 Arteriosus, 453, 527 Arteriovenous, 453, 507, 543 Arteriovenous Fistula, 453, 543 Artery, 22, 34, 73, 400, 450, 453, 469, 476, 517, 528, 531, 534 Arthralgia, 372, 453 Aspergillus, 292, 309, 453 Asphyxia, 453, 513 Aspirate, 44, 127, 453 Assay, 28, 42, 51, 59, 86, 89, 103, 112, 149, 156, 159, 163, 207, 223, 224, 453, 533 Asymptomatic, 31, 80, 350, 384, 389, 391, 402, 453 Ataxia, 421, 453, 542 Atelectasis, 118, 194, 327, 385, 453 Atrophy, 420, 421, 454, 479 Attenuation, 121, 454 Atypical, 187, 208, 229, 282, 364, 369, 370, 376, 380, 390, 392, 429, 454, 465, 495, 510 Auditory, 381, 454 Auscultation, 123, 444, 454 Autoimmune disease, 454 Autoimmunity, 16, 21, 454 Autologous, 89, 121, 241, 315, 323, 454, 489, 519 Autologous bone marrow transplantation, 454, 489 Autolysis, 150, 454 Autopsy, 18, 37, 62, 156, 454 Avidity, 70, 454 Axenic, 113, 454 Azithromycin, 6, 22, 120, 151, 153, 157, 164, 165, 177, 182, 187, 203, 204, 249, 355, 406, 454

Index 553

B Bacillus, 454, 458 Bacteraemia, 200, 252, 261, 265, 454 Bacteremia, 24, 28, 56, 85, 101, 135, 139, 146, 148, 160, 170, 230, 269, 289, 299, 384, 454, 533 Bacterial Adhesion, 138, 454 Bacterial Infections, 6, 48, 50, 60, 63, 108, 138, 141, 385, 454, 462, 466, 501 Bacterial Physiology, 446, 454 Bacterial Proteins, 26, 454 Bacterial toxin, 26, 454 Bacterial Translocation, 16, 26, 325, 454 Bactericidal, 24, 47, 48, 70, 132, 151, 188, 455, 480 Bacteriophage, 455, 521, 534, 545, 548 Bacteriostatic, 455, 479 Bacterium, 59, 86, 97, 454, 455, 468, 475, 490, 510 Bacteriuria, 384, 455 Barium, 339, 455, 480 Barium swallow, 339, 455, 480 Basal Ganglia, 452, 453, 455, 464, 484 Basal Ganglia Diseases, 453, 455, 464 Base, 19, 35, 98, 110, 122, 446, 455, 471, 472, 480, 485, 499, 542 Basement Membrane, 108, 455, 481, 499 Basophils, 455, 488, 501, 522 Benign, 382, 446, 455, 484, 489, 511, 529 Bereavement, 117, 455 Beta-glucans, 114, 455 Beta-Lactamases, 106, 456, 493, 540 Beta-pleated, 449, 456 Bilateral, 189, 228, 456, 479, 532 Bile, 456, 484, 485, 492, 502, 539, 540 Bile Acids, 456, 485, 539 Bile duct, 456, 484 Bilirubin, 456, 484 Binding Sites, 14, 456 Bioassay, 45, 456 Bioavailability, 82, 137, 456 Biochemical, 28, 57, 59, 83, 290, 448, 451, 456, 458, 483, 500, 520, 536, 542 Biochemical reactions, 456, 542 Biogenesis, 139, 456 Biological response modifier, 456, 497 Biological therapy, 456, 488 Biological Warfare, 6, 456 Biomarkers, 82, 456 Biophysics, 138, 140, 456 Biopsy, 32, 37, 119, 156, 209, 235, 255, 295, 308, 310, 382, 442, 443, 456, 518

Biopsy specimen, 37, 456 Biotechnology, 148, 175, 378, 398, 415, 419, 420, 421, 422, 456 Bioterrorism, 85, 457 Biotype, 94, 457 Biphasic, 44, 457 Bladder, 384, 457, 464, 467, 470, 525, 531, 545, 546, 547 Blood Cell Count, 457, 489 Blood Coagulation, 457, 459, 533, 543 Blood Glucose, 457, 490, 496 Blood Platelets, 457, 505, 536, 543 Blood pressure, 400, 441, 457, 460, 493, 508, 537 Blood transfusion, 53, 382, 390, 457 Blot, 94, 160, 175, 457 Body Composition, 148, 457 Body Fluids, 363, 456, 457, 459, 475, 513, 537, 546 Body Mass Index, 119, 457 Bolus, 79, 457 Bolus infusion, 457 Bombesin, 51, 457 Bone Density, 400, 457 Bone Marrow Cells, 309, 458, 505 Bone Marrow Transplantation, 89, 120, 166, 240, 269, 323, 337, 458 Bowel, 43, 304, 382, 401, 449, 458, 473, 496, 498, 519, 539, 546 Bowel Movement, 458, 473, 539 Brachytherapy, 458, 497, 498, 528, 550 Bradykinin, 458, 513, 521 Branch, 437, 458, 471, 485, 488, 503, 515, 517, 527, 538, 542 Breakdown, 39, 458, 462, 473, 484 Breeding, 45, 360, 369, 458 Broad-spectrum, 101, 204, 449, 458, 461, 462 Bronchi, 458, 459, 479, 544 Bronchial, 19, 83, 150, 158, 190, 207, 208, 458, 491 Bronchiectasis, 26, 458 Bronchioles, 448, 458 Bronchiolitis Obliterans, 83, 163, 198, 210, 228, 244, 246, 290, 300, 309, 311, 324, 337, 458 Bronchiolitis Obliterans Organizing Pneumonia, 83, 210, 244, 246, 290, 300, 309, 311, 324, 458 Bronchiseptica, 152, 169, 458 Bronchitis, 34, 38, 94, 111, 204, 330, 384, 400, 458, 464

554 Pneumonia

Bronchoalveolar Lavage, 30, 37, 89, 95, 113, 133, 134, 155, 207, 209, 212, 219, 235, 244, 253, 266, 272, 299, 458 Bronchoalveolar Lavage Fluid, 95, 113, 133, 134, 155, 207, 219, 235, 244, 253, 458 Bronchoconstriction, 458, 522 Bronchoscope, 19, 121, 459 Bronchoscopy, 229, 428, 442, 459 Buccal, 459, 503 Burns, 321, 459, 539 Bypass, 459, 543 C Cachexia, 98, 459 Calcium, 347, 351, 352, 353, 357, 363, 459, 467, 500, 505, 520, 526, 536 Caloric intake, 43, 459 Candidiasis, 382, 459 Candidosis, 459 Capillary, 30, 132, 153, 458, 459, 547, 548 Capsid, 141, 459, 548 Capsular, 28, 49, 70, 85, 86, 106, 139, 143, 152, 165, 171, 260, 459 Capsules, 106, 332, 459 Carbamazepine, 190, 459 Carbohydrate, 35, 459, 469, 487, 523, 535 Carbon Dioxide, 82, 459, 483, 485, 532, 547 Carboxy, 20, 460 Carcinogenic, 460, 496, 514, 525, 539 Carcinogens, 460, 479, 514, 515 Carcinoma, 84, 192, 205, 384, 460 Cardiac, 13, 34, 234, 290, 298, 448, 460, 477, 479, 481, 485, 489, 490, 510, 539 Cardiogenic, 266, 460 Cardiopulmonary, 120, 219, 460 Cardiopulmonary Resuscitation, 219, 460 Cardiovascular, 22, 33, 45, 53, 97, 134, 139, 189, 291, 399, 402, 460, 480, 536 Cardiovascular disease, 22, 33, 45, 53, 399, 402, 460 Carrier State, 460, 536 Case report, 179, 190, 196, 205, 231, 248, 264, 267, 296, 308, 416, 460, 465 Case series, 191, 460, 465 Case-Control Studies, 118, 460 Caspase, 62, 460 Catalyse, 460, 544 Catheter, 110, 460, 498 Catheterization, 460, 498 Caudal, 121, 460, 493, 523 Causal, 19, 460, 490, 497, 535, 542 Cause of Death, 26, 42, 50, 92, 101, 104, 148, 339, 362, 371, 373, 402, 461, 471, 537

Caveolae, 76, 461 Caveolins, 461 Cefaclor, 154, 461 Cefotaxime, 151, 156, 158, 461 Ceftazidime, 154, 158, 181, 218, 461 Ceftriaxone, 92, 149, 152, 158, 177, 178, 215, 255, 274, 289, 325, 355, 461 Cefuroxime, 149, 152, 204, 274, 461 Cell Adhesion, 65, 112, 461, 496 Cell Adhesion Molecules, 65, 461 Cell Count, 120, 345, 349, 427, 461 Cell Death, 62, 452, 461, 480, 486 Cell Differentiation, 48, 461, 536 Cell Division, 420, 454, 461, 462, 471, 480, 488, 505, 508, 521, 535 Cell membrane, 31, 461, 472, 506, 520 Cell Membrane Structures, 461 Cell motility, 461, 490 Cell Physiology, 113, 461 Cell Polarity, 65, 461 Cell proliferation, 453, 462, 536 Cell Respiration, 462, 532 Cell Size, 462, 483 Cell Survival, 462, 488 Cell Transplantation, 120, 232, 462 Cellular metabolism, 140, 462 Cellulose, 462, 484, 521 Central Nervous System, 12, 18, 399, 445, 448, 462, 464, 465, 476, 484, 486, 489, 515, 517, 536 Central Nervous System Infections, 462, 489 Centrifugation, 462, 489 Cephalexin, 461, 462 Cephaloridine, 461, 462 Cephalosporins, 456, 462 Cerebellar, 453, 462, 530 Cerebral, 117, 270, 297, 453, 455, 462, 463, 472, 479, 480, 504, 527 Cerebral Cortex, 453, 462, 480 Cerebral Palsy, 117, 462 Cerebrospinal, 8, 18, 137, 462 Cerebrospinal fluid, 8, 18, 137, 462 Cerebrovascular, 455, 460, 463, 542 Cerebrum, 462, 463, 546 Chemical Warfare, 463, 471 Chemical Warfare Agents, 463, 471 Chemotactic Factors, 463, 467 Chemotaxis, 99, 105, 463 Chest Pain, 401, 463 Chest wall, 463, 522 Chickenpox, 256, 297, 463

Index 555

Chimera, 5, 463 Chimeric Proteins, 143, 463 Chin, 153, 154, 166, 171, 174, 242, 328, 339, 463, 506 Chlorhexidine, 103, 215, 314, 463 Chlorophyll, 463, 484 Cholera, 463, 536 Cholesterol, 34, 354, 385, 420, 456, 461, 463, 464, 469, 484, 502, 506, 539 Cholesterol Esters, 463, 502 Cholinergic, 449, 452, 463, 464 Cholinesterase Inhibitors, 464, 474 Chondrocytes, 464, 482 Chorea, 381, 452, 464 Chorioretinitis, 464, 532 Choroid, 464, 469, 532, 547 Chromatin, 452, 464 Chromosomal, 449, 464, 521, 533, 534 Chromosome, 464, 468, 488, 501, 534, 535, 545, 548 Chronic Disease, 18, 19, 33, 378, 399, 459, 464, 500 Chronic granulocytic leukemia, 464 Chronic lymphocytic leukemia, 305, 464 Chronic myelogenous leukemia, 191, 464 Chronic Obstructive Pulmonary Disease, 25, 331, 464 Chronic renal, 230, 464, 523 Chylomicrons, 464, 502 Cilastatin, 170, 254, 289, 314, 464, 493 Ciliary, 136, 453, 464, 509, 547 Ciprofloxacin, 111, 156, 161, 169, 252, 254, 321, 465 CIS, 67, 96, 327, 465 Clarithromycin, 169, 170, 176, 177, 182, 288, 289, 465 Claudication, 34, 465 Cleave, 5, 465 Clindamycin, 356, 363, 375, 409, 465 Clinical Protocols, 36, 465 Clinical study, 81, 465, 469 Clone, 56, 112, 122, 126, 151, 465 Cloning, 457, 465, 496 Clot Retraction, 465, 521 Clozapine, 188, 465 Coagulation, 73, 112, 134, 192, 457, 465, 490, 521, 543 Cofactor, 139, 465, 526, 543 Cohort Studies, 145, 466 Colitis, 466 Collagen, 139, 228, 264, 449, 455, 466, 481, 482, 505, 522, 525

Collapse, 108, 458, 466, 522 Colloidal, 466, 476 Colon, 99, 420, 466, 496, 499, 500, 546 Colorectal, 455, 466 Colorectal Cancer, 455, 466 Combination Therapy, 157, 388, 466 Combined Modality Therapy, 40, 466 Common Variable Immunodeficiency, 218, 466 Community Health Centers, 81, 85, 466 Community-Acquired Infections, 72, 466 Comorbidity, 267, 273, 466 Compassionate, 110, 341, 466 Complement, 24, 28, 56, 86, 150, 169, 450, 466, 467, 496, 504, 521, 535 Complementary and alternative medicine, 319, 334, 467 Complementary medicine, 319, 467 Complete remission, 467, 531 Compliance, 10, 12, 17, 105, 109, 467 Computational Biology, 52, 415, 419, 467 Computed tomography, 37, 274, 281, 301, 457, 467 Computerized tomography, 135, 467 Concomitant, 141, 467 Confidence Intervals, 53, 467 Confounding, 73, 103, 127, 468 Congestion, 452, 468, 479 Congestive heart failure, 25, 85, 126, 468 Conjugated, 468, 471 Conjugation, 111, 468 Conjunctiva, 468, 496, 544 Connective Tissue Cells, 468 Consciousness, 449, 468, 472, 474, 527 Constipation, 383, 452, 468, 519 Constitutional, 468, 532 Constriction, 468, 498, 534, 549 Consumption, 292, 315, 443, 468, 473, 485, 513, 516 Contamination, 468, 533 Continuous infusion, 154, 171, 307, 468 Continuum, 80, 468 Contraindications, ii, 468 Control group, 43, 61, 468, 524, 529 Controlled clinical trial, 142, 327, 469, 529 Controlled study, 6, 206, 262, 342, 469 Conus, 469, 527 Conventional therapy, 343, 353, 357, 469 Conventional treatment, 469 Cooperative group, 7, 469 Coordination, 38, 85, 117, 139, 469 Cornea, 469, 491, 544, 550

556 Pneumonia

Coronary, 22, 34, 72, 225, 234, 400, 460, 469, 507, 510, 543 Coronary Artery Bypass, 225, 234, 469 Coronary heart disease, 22, 34, 73, 460, 469 Coronary Thrombosis, 469, 507, 510 Coronavirus, 155, 163, 199, 376, 469 Corpus, 469, 524, 549 Corpuscle, 469, 479 Corticosteroid, 114, 309, 469, 524, 539 Cortisone, 470, 524 Cost Savings, 278, 470 Co-trimoxazole, 166, 470 Cranial, 470, 489, 514, 516, 519 Craniocerebral Trauma, 455, 470, 489, 542, 543 C-Reactive Protein, 72, 470 Critical Illness, 62, 90, 470 Cross Infection, 466, 470 Crossing-over, 470, 530 Croup, 66, 470 Cryptosporidiosis, 391, 454, 470 Cryptosporidium, 389, 390, 470 Cultured cells, 5, 470 Curative, 470, 542 Cutaneous, 290, 390, 459, 470, 500, 503 Cyclic, 470, 488, 513, 525 Cyclophosphamide, 115, 121, 133, 161, 168, 268, 305, 401, 470 Cyclosporine, 401, 470 Cyst, 112, 453, 470 Cystitis, 384, 470 Cytochrome, 113, 470, 471, 515 Cytochrome b, 113, 471 Cytogenetics, 471, 534 Cytokine, 14, 15, 16, 24, 26, 29, 39, 40, 49, 50, 54, 58, 66, 67, 68, 69, 70, 74, 75, 79, 91, 93, 100, 103, 106, 124, 128, 131, 155, 159, 188, 224, 240, 471, 482, 497 Cytomegalovirus Infections, 354, 471, 484 Cytoplasm, 452, 455, 461, 471, 478, 533, 547 Cytosine, 191, 371, 471, 528 Cytoskeleton, 65, 126, 471, 496, 507 Cytostatic, 325, 471 Cytotoxic, 18, 24, 30, 31, 63, 72, 80, 87, 89, 100, 471, 497, 529, 536 Cytotoxicity, 31, 87, 448, 471 D Data Collection, 42, 119, 471, 483 De novo, 51, 471 Death Certificates, 389, 471

Decision Making, 285, 380, 471 Decision Trees, 41, 471 Decontamination, 5, 245, 292, 471 Defense Mechanisms, 48, 100, 135, 471, 497 Deferoxamine, 153, 171, 174, 472 Degenerative, 469, 472, 490 Deglutition, 79, 472 Dehydration, 383, 463, 472 Deletion, 77, 143, 170, 206, 452, 472 Delirium, 53, 399, 452, 472 Delivery of Health Care, 466, 472, 489 Dementia, 8, 12, 13, 79, 90, 205, 303, 339, 380, 399, 445, 452, 472, 512 Denaturation, 99, 472, 523 Dendrites, 472, 512 Dendritic, 77, 472, 505 Dendritic cell, 77, 472 Density, 34, 68, 109, 457, 462, 472, 483, 502, 514, 538 Dental Caries, 4, 472 Dental Plaque, 4, 103, 104, 472 Depolarization, 472, 536 Deprivation, 111, 473 Dermatology, 38, 202, 279, 473 Dermis, 473, 549 Desensitization, 289, 473 Desquamation, 122, 473 Deuterium, 473, 492 Developing Countries, 21, 47, 69, 85, 102, 306, 327, 373, 473 Diabetes Mellitus, 4, 473, 490, 517 Diabetic Ketoacidosis, 386, 473 Diagnostic Errors, 473, 505 Diagnostic procedure, 258, 359, 398, 473 Dialyzer, 473, 490 Diaphragm, 473, 522 Diarrhea, 69, 98, 148, 327, 329, 383, 392, 401, 470, 473, 495, 499 Diarrhoea, 320, 329, 473, 485 Diastolic, 473, 493 Difluoromethylornithine, 154, 473 Digestion, 448, 456, 458, 473, 495, 498, 502, 518, 539 Digestive system, 358, 400, 473, 509 Digestive tract, 473, 537 Dihydrotestosterone, 474, 530 Dilatation, 450, 458, 474, 524, 547 Diphtheria, 84, 406, 474 Diphtheria Toxin, 84, 474 Discrete, 39, 474, 491, 502, 545, 550 Discrimination, 191, 474

Index 557

Disease Progression, 7, 64, 78, 81, 93, 114, 119, 474, 548 Disinfectant, 463, 474, 480 Disorientation, 472, 474 Disposition, 147, 364, 370, 371, 474 Dissection, 385, 474 Dissociation, 447, 474, 498 Distal, 140, 141, 385, 469, 474, 485, 519, 527 Domesticated, 474, 488 Donepezil, 227, 474 Dopamine, 448, 452, 465, 474, 512, 520 Dormancy, 84, 475 Dose-dependent, 133, 475, 550 Dose-limiting, 475, 545 Double-blind, 22, 134, 176, 177, 178, 198, 204, 217, 254, 262, 329, 342, 475 Double-blinded, 342, 475 Drug Combinations, 157, 475 Drug Design, 13, 45, 408, 475 Drug Interactions, 8, 120, 147, 407, 475 Drug Resistance, 20, 130, 220, 308, 475 Drug Tolerance, 475, 544 Duct, 460, 475, 533, 539 Duodenum, 456, 475, 516, 539 Dura mater, 475, 506, 516 Dyes, 449, 455, 475, 483 Dyspareunia, 401, 475 Dysphagia, 54, 80, 185, 285, 315, 381, 475 Dysplasia, 44, 421, 475 Dyspnea, 82, 361, 475, 522, 528 Dystrophy, 326, 420, 475 E Ectopic, 382, 476 Ectopic Pregnancy, 382, 476 Effector, 24, 50, 66, 67, 80, 88, 107, 112, 115, 116, 131, 140, 445, 467, 476 Effector cell, 50, 115, 116, 476 Efferent, 77, 476 Effusion, 476, 503, 522 Elastic, 476, 538, 541 Elastin, 139, 466, 476, 481 Elective, 99, 119, 476 Electric shock, 460, 476 Electrocoagulation, 465, 476 Electrolyte, 383, 469, 472, 476, 490, 508, 513, 523, 537 Electrophoresis, 157, 278, 476 Elementary Particles, 476, 504, 512, 526 Emaciation, 445, 476 Embolism, 287, 476, 527 Embolus, 476, 495 Embryo, 461, 476, 495

Emesis, 401, 476 Emphysema, 47, 464, 476 Empiric, 152, 154, 212, 220, 303, 476 Empirical, 130, 180, 182, 186, 215, 271, 364, 369, 370, 476, 477 Empyema, 11, 203, 276, 477 Emulsions, 341, 447, 477 Enamel, 472, 477 Encapsulated, 6, 28, 151, 173, 477, 502 Encephalitis, 121, 189, 216, 314, 477 Encephalitis, Viral, 477 Encephalomyelitis, 69, 477 Endemic, 70, 463, 477, 504, 538 Endocarditis, 459, 477 Endocrine System, 477, 512 Endocrinology, 477, 488 Endocytosis, 76, 126, 461, 477 Endogenous, 14, 15, 50, 66, 115, 116, 134, 220, 309, 323, 457, 474, 477, 515, 526, 544, 548 Endopeptidases, 477, 526 Endophthalmitis, 220, 477 Endothelial cell, 14, 30, 69, 84, 97, 112, 123, 132, 478, 482, 543 Endothelium, 132, 478, 513, 521 Endothelium, Lymphatic, 478 Endothelium, Vascular, 478 Endothelium-derived, 478, 513 Endotoxemia, 192, 478 Endotoxin, 15, 26, 44, 45, 74, 87, 208, 224, 478, 546 End-stage renal, 464, 478, 523 Enhancer, 478, 532 Enteral Nutrition, 186, 230, 259, 382, 383, 478 Enteric Nervous System, 51, 478 Environmental Exposure, 478, 514 Environmental Health, 73, 414, 416, 478 Enzymatic, 449, 459, 467, 472, 478, 482, 491, 506, 523 Enzyme Inhibitors, 21, 478, 521 Eosinophil, 190, 244, 478, 497 Eosinophilic, 52, 75, 135, 179, 192, 193, 196, 219, 221, 227, 234, 240, 244, 258, 300, 478 Epidemic, 5, 13, 35, 62, 69, 76, 141, 282, 293, 365, 378, 388, 389, 417, 478, 538 Epidemiological, 4, 21, 69, 159, 376, 379, 478, 479 Epidemiology, Molecular, 94, 478 Epidermal, 48, 479, 505 Epidermal Growth Factor, 48, 479

558 Pneumonia

Epidermis, 473, 479 Epinephrine, 447, 474, 479, 512, 513, 546 Episode of Care, 118, 126, 479 Epistaxis, 381, 479 Epithelial, 24, 31, 35, 52, 56, 61, 62, 65, 66, 69, 76, 77, 83, 86, 94, 96, 97, 105, 107, 108, 114, 122, 123, 125, 128, 130, 133, 134, 136, 140, 145, 171, 179, 299, 446, 473, 479, 487, 490, 499 Epitope, 60, 80, 479 Erythema, 34, 331, 381, 479 Erythema Nodosum, 34, 479 Erythrocyte Membrane, 316, 479 Erythrocytes, 94, 450, 457, 458, 479, 490, 530, 535 Erythromycin, 159, 203, 204, 236, 289, 454, 465, 479 Escalation, 236, 480 Esophageal, 401, 480 Esophageal Stricture, 401, 480 Esophagitis, 480, 540 Esophagram, 455, 480 Esophagus, 401, 455, 473, 480, 485, 489, 502, 520, 530, 539 Essential Tremor, 420, 480 Estrogen, 55, 354, 480 Ethanol, 14, 15, 135, 480, 482 Ethnic Groups, 126, 402, 480 Etoposide, 401, 480 Eukaryotic Cells, 26, 58, 126, 480 Evacuation, 468, 480 Evoke, 480, 539 Excipients, 117, 480 Excitation, 480, 483, 512 Exercise Test, 120, 480 Exfoliation, 473, 481 Exhaustion, 450, 481, 504 Exogenous, 15, 29, 31, 133, 225, 323, 477, 481, 526, 546, 548 Expiration, 481, 532 Extensor, 481, 527 External-beam radiation, 481, 498, 528, 550 Extracellular, 76, 96, 160, 449, 468, 477, 481, 482, 496, 505, 537 Extracellular Matrix, 468, 481, 482, 496, 505 Extracellular Matrix Proteins, 481, 505 Extracorporeal, 160, 294, 481, 490 Extracorporeal Membrane Oxygenation, 294, 481 Extrapyramidal, 448, 452, 474, 481

Extravasation, 299, 481 Extremity, 384, 481 Exudate, 458, 464, 481, 522 Eye Infections, 446, 481 F Faecal, 473, 481 Family Planning, 64, 415, 481 Fat, 329, 452, 457, 458, 469, 476, 481, 499, 501, 502, 537, 541 Fatigue, 428, 440, 481, 489 Fatty acids, 473, 482, 487, 525 Febrile, 26, 482, 504 Feces, 468, 481, 482, 539 Femoral, 53, 482 Femur, 482 Fermentation, 482, 534 Fever of Unknown Origin, 172, 482 Fibrin, 457, 465, 482, 519, 521, 522, 542, 543 Fibrinogen, 73, 163, 195, 482, 521, 542 Fibrinolysis, 192, 482 Fibroblast Growth Factor, 89, 482 Fibroblasts, 32, 80, 83, 468, 482, 497, 509 Filgrastim, 228, 262, 482 Fine-needle aspiration, 295, 482, 511 Fistula, 291, 482 Fixation, 150, 482, 535 Flagellin, 101, 483 Flatus, 483, 485 Flow Cytometry, 21, 54, 68, 70, 89, 483 Fludarabine, 221, 227, 305, 315, 323, 483 Fluorescence, 112, 172, 483 Fluorescent Dyes, 483 Foam Cells, 34, 483 Focus Groups, 9, 42, 483 Folate, 323, 375, 483 Fold, 34, 62, 63, 85, 483, 506, 516 Folic Acid, 483, 500, 545 Foramen, 463, 483, 519 Forearm, 457, 483 Formulary, 38, 483 Fractionation, 40, 483 Free Radicals, 451, 474, 483 Fungi, 111, 400, 451, 468, 477, 481, 484, 507, 508, 543, 550 Fungicides, Industrial, 451, 484 Fungus, 70, 136, 427, 459, 462, 484, 510 G Galactose Oxidase, 139, 484 Gallbladder, 382, 445, 473, 484 Gallium, 428, 484 Gallstones, 382, 484 Gamma Rays, 484, 528, 529

Index 559

Gamma-interferon, 14, 484 Ganciclovir, 131, 484 Ganglia, 445, 455, 478, 484, 511, 519 Ganglion, 484, 491, 514, 550 Ganglioside, 94, 484 Gangrene, 384, 484 Gangrenous, 484, 536 Gas, 97, 110, 140, 141, 442, 449, 459, 483, 484, 485, 492, 495, 513, 522, 528, 532, 540, 547, 548 Gas exchange, 110, 140, 141, 485, 532, 547, 548 Gastric, 42, 43, 48, 54, 221, 401, 449, 455, 457, 479, 485, 489, 491, 514, 518, 529 Gastric Juices, 485, 518 Gastric Mucosa, 485, 518 Gastrin, 48, 485, 491 Gastritis, 382, 485, 540 Gastroenteritis, 485, 533 Gastroesophageal Reflux, 401, 485 Gastrointestinal tract, 147, 250, 454, 464, 480, 485, 499, 536, 538, 546 Gastrostomy, 54, 478, 485 Gene Expression, 29, 48, 52, 66, 83, 91, 101, 105, 107, 125, 139, 421, 485 Gene Therapy, 12, 18, 50, 163, 446, 485 General practitioner, 198, 237, 485 Genetic Code, 485, 513 Genetic testing, 486, 523 Genetics, 58, 67, 75, 90, 96, 97, 113, 125, 134, 381, 468, 471, 486 Genital, 465, 486, 488, 549 Genomics, 60, 156, 486 Genotype, 58, 364, 370, 371, 457, 486, 520 Germ Cells, 486, 505 Gestation, 44, 486, 518 Giant Cells, 173, 486, 534 Gingivitis, 472, 486 Ginseng, 158, 161, 322, 324, 333, 486 Gland, 382, 447, 470, 486, 503, 505, 516, 517, 521, 525, 534, 539, 540, 543 Glomerular, 486, 531 Glomeruli, 486, 528 Glomerulonephritis, 112, 486 Glucans, 114, 455, 486 Glucocorticoid, 137, 486, 524, 548 Glucose, 43, 172, 363, 420, 457, 462, 473, 486, 487, 490, 493, 496, 534 Glutamic Acid, 483, 486, 512, 525 Glutamine, 51, 486 Glutathione Peroxidase, 486, 535 Glycerol, 487, 520

Glycerophospholipids, 487, 520 Glycine, 449, 487, 512, 535 Glycolysis, 123, 487 Glycoprotein, 20, 95, 100, 121, 137, 140, 141, 147, 151, 164, 482, 486, 487, 499, 509, 519, 543, 546 Glycosidic, 487, 512, 514 Goblet Cells, 96, 487 Gonadal, 487, 539 Gonorrhea, 461, 487 Governing Board, 487, 524 Gp120, 15, 487, 518 Grade, 385, 487 Graft, 89, 185, 190, 225, 228, 487, 492, 494 Graft Rejection, 487, 494 Grafting, 234, 469, 487, 494 Graft-versus-host disease, 185, 190, 228, 487 Gram-Negative Bacteria, 50, 164, 168, 200, 445, 487 Gram-positive, 50, 56, 60, 77, 127, 132, 242, 292, 315, 461, 462, 487, 493, 510, 539 Gram-Positive Bacteria, 132, 355, 487 Granulation Tissue, 458, 488 Granulocyte, 14, 218, 231, 482, 488, 497 Granuloma, 124, 488 Growth factors, 89, 488 Guanine, 13, 364, 369, 370, 371, 488 Guanylate Cyclase, 488, 513 Guideline Adherence, 61, 488 Guinea Pigs, 149, 156, 161, 162, 164, 488 Gynecology, 10, 64, 78, 488 Gyrase, 149, 488 H Habitat, 488, 510 Haematemesis, 476, 488 Haematological, 280, 488 Haematology, 191, 280, 305, 315, 327, 488 Haemophilus, 23, 60, 93, 138, 164, 260, 289, 292, 461, 488 Half-Life, 92, 101, 461, 488 Hantavirus, 106, 488 Haploid, 112, 488, 521 Haptens, 447, 489 Headache, 389, 441, 489, 493, 496 Headache Disorders, 489 Health Care Costs, 50, 72, 104, 134, 373, 489 Health Expenditures, 489 Health Services, 21, 126, 378, 379, 380, 472, 489 Health Status, 4, 102, 145, 489

560 Pneumonia

Heart Arrest, 460, 489 Heart attack, 22, 126, 460, 489 Heart failure, 61, 124, 233, 489, 528 Heartburn, 401, 489, 495 Hematocrit, 53, 457, 489 Hematogenous, 4, 489 Hematologic malignancies, 288, 489 Hematopoiesis, 489, 497 Hematopoietic Stem Cell Transplantation, 88, 222, 489 Hematuria, 384, 489 Heme, 456, 470, 471, 489 Hemodiafiltration, 187, 314, 490 Hemodialysis, 179, 385, 473, 490 Hemofiltration, 490 Hemoglobin, 53, 450, 457, 479, 489, 490, 516 Hemoglobinopathies, 485, 490 Hemoglobinuria, 420, 490 Hemolysis, 111, 479, 490 Hemolytic, 3, 60, 304, 490 Hemorrhage, 385, 400, 470, 476, 489, 490, 539 Hemostasis, 73, 490, 496, 536 Hepatic, 14, 472, 490, 502 Hepatitis, 8, 12, 53, 73, 78, 90, 150, 383, 385, 389, 490, 495, 508 Hepatocyte, 225, 233, 490 Hepatocyte Growth Factor, 225, 490 Hereditary, 490, 532 Heredity, 485, 486, 490 Herpes, 10, 73, 120, 131, 234, 361, 382, 383, 388, 401, 490, 491 Herpes virus, 10, 361, 491 Herpes Zoster, 120, 382, 491 Herpes Zoster Oticus, 382, 491 Heterodimers, 491, 496 Heterogeneity, 324, 447, 491 Heterotrophic, 484, 491 Histamine, 283, 450, 452, 491, 529 Histology, 46, 260, 491, 516, 518 HIV-1, 7, 11, 14, 90, 125, 130, 147, 234, 258, 278, 304, 363, 491, 500 Hoarseness, 470, 491, 500 Homeostasis, 15, 17, 140, 491 Homogenate, 121, 491 Homogeneous, 57, 91, 468, 491 Homologous, 26, 45, 112, 141, 168, 448, 470, 485, 491, 509, 535, 541, 545 Hormonal, 454, 469, 491 Hormone, 354, 456, 469, 470, 479, 485, 491, 496, 498, 506, 524, 536, 538, 542, 543

Hormone Replacement Therapy, 354, 491 Hospice, 109, 491 Hospital Charges, 491, 492 Hospital Costs, 118, 492 Hospital Mortality, 127, 180, 255, 492 Hospitalists, 203, 492 Humoral, 6, 102, 144, 487, 492 Humour, 492 Hybrid, 465, 492 Hybridization, 107, 492 Hybridoma, 51, 130, 492 Hydration, 54, 492 Hydrogen Bonding, 138, 492, 513 Hydrogen Peroxide, 123, 142, 486, 492, 501 Hydrogenation, 492, 528 Hydrolysis, 456, 492, 512, 518, 520, 526 Hydrophobic, 487, 492, 502 Hydroxylysine, 466, 492 Hydroxyproline, 449, 466, 492 Hyperglycemia, 383, 492 Hyperoxia, 128, 493 Hyperreflexia, 493, 542 Hypersecretion, 83, 96, 493 Hypersensitivity, 39, 69, 71, 97, 103, 239, 240, 448, 473, 478, 493, 535 Hypertension, 399, 460, 489, 493, 543 Hypertrophy, 196, 493 Hypogammaglobulinemia, 171, 291, 466, 493 Hypoglycaemia, 472, 493 Hypotension, 452, 493, 522 Hypothalamus, 493, 521, 538 Hypothermia, 136, 331, 493 Hypotrophy, 316, 493 Hypoxanthine, 13, 493 Hypoxemia, 42, 140, 493 Hypoxia, 47, 104, 112, 400, 472, 493, 542 Hypoxic, 140, 493 I Id, 317, 330, 424, 428, 429, 430, 436, 438, 493 Idiopathic, 36, 82, 87, 88, 89, 108, 115, 119, 133, 177, 206, 207, 222, 225, 227, 228, 239, 240, 241, 247, 260, 264, 284, 301, 308, 338, 493, 528, 534 Imidazole, 491, 493, 529 Imipenem, 158, 170, 174, 183, 254, 289, 314, 464, 493 Immune adjuvant, 66, 448, 493 Immune function, 69, 99, 105, 121, 385, 493

Index 561

Immune Sera, 493, 494 Immunization, 21, 28, 59, 69, 86, 101, 121, 129, 161, 164, 168, 170, 207, 243, 447, 494, 524, 535, 536 Immunocompromised Host, 21, 69, 129, 136, 144, 439, 494 Immunodeficiency syndrome, 99, 113, 280, 363, 365, 388, 389, 390, 417, 418, 427, 466, 491, 494 Immunofluorescence, 142, 494 Immunogenic, 21, 94, 121, 140, 161, 361, 494 Immunohistochemistry, 135, 494 Immunologic, 7, 8, 9, 12, 16, 51, 64, 65, 69, 74, 89, 93, 120, 159, 341, 384, 447, 463, 491, 494, 504, 529, 550 Immunosuppressant, 494, 507 Immunosuppressive, 14, 20, 279, 470, 486, 494 Immunosuppressive therapy, 494 Immunotherapy, 80, 100, 110, 447, 456, 473, 494 Impairment, 58, 114, 399, 453, 472, 481, 494, 506 Implant radiation, 494, 497, 498, 528, 550 Implantation, 111, 494 In vitro, 11, 17, 28, 31, 39, 40, 44, 45, 48, 51, 63, 65, 66, 68, 69, 71, 74, 78, 80, 82, 86, 87, 98, 99, 100, 101, 102, 105, 113, 121, 122, 123, 130, 132, 133, 136, 138, 140, 142, 145, 149, 150, 169, 485, 494, 523, 533, 536, 540 Incision, 119, 384, 494, 498, 499, 541 Incompetence, 485, 494 Incubated, 95, 495 Incubation, 386, 495, 500 Incubation period, 386, 495, 500 Indicative, 65, 376, 495, 517, 547 Indigestion, 495, 499 Induction, 19, 40, 46, 62, 75, 98, 99, 112, 115, 125, 163, 282, 306, 401, 450, 452, 495, 497 Induction therapy, 282, 495 Infancy, 279, 495 Infant Mortality, 78, 495 Infant, Newborn, 447, 495 Infarction, 73, 495, 531, 543 Infection Control, 275, 310, 376, 382, 391, 495 Infectious Bovine Rhinotracheitis, 362, 495 Infectious Diarrhea, 373, 495 Infectious Mononucleosis, 495, 509

Infertility, 45, 495 Infiltration, 19, 29, 88, 116, 486, 491, 495, 550 Inflammatory bowel disease, 45, 496 Informed Consent, 37, 355, 417, 496 Infusion, 115, 133, 279, 339, 373, 496, 545 Ingestion, 20, 135, 225, 275, 496, 523 Inhalation, 6, 46, 58, 258, 348, 406, 408, 447, 458, 496, 498, 523 Initiation, 9, 27, 29, 46, 63, 64, 71, 108, 171, 191, 212, 354, 362, 417, 496, 525, 544 Inlay, 496, 532 Inner ear, 461, 496, 547 Innervation, 360, 368, 496 Inoperable, 40, 496 Inorganic, 127, 496, 509 Insertional, 56, 111, 496 Insight, 59, 66, 76, 81, 96, 133, 138, 496 Insulin, 82, 473, 496, 499, 546 Insulin-dependent diabetes mellitus, 496 Integrins, 51, 115, 129, 496 Intensive Care Units, 5, 43, 103, 183, 213, 249, 286, 372, 497 Interferon-alpha, 497 Interleukin-1, 11, 44, 68, 77, 153, 163, 193, 299, 497 Interleukin-18, 153, 299, 497 Interleukin-2, 253, 497 Interleukin-4, 253, 497 Interleukin-5, 244, 497 Interleukin-6, 44, 301, 497 Intermittent, 497, 502, 519 Internal radiation, 497, 498, 528, 550 Intervention Studies, 72, 145, 497 Intestinal, 37, 50, 62, 215, 454, 470, 497, 498, 499, 504 Intestinal Mucosa, 455, 498 Intestine, 458, 466, 498, 499, 539 Intoxication, 15, 472, 498, 549 Intracellular Membranes, 498, 506 Intramuscular, 33, 362, 367, 498, 517 Intramuscular injection, 362, 367, 498 Intraocular, 477, 498 Intraperitoneal, 71, 498 Intravascular, 130, 498 Intrinsic, 49, 447, 455, 498 Intubation, 104, 119, 273, 372, 460, 498 Invalidate, 106, 498 Invasive, 21, 44, 56, 60, 68, 76, 77, 80, 86, 94, 157, 242, 266, 325, 385, 494, 498, 504, 516

562 Pneumonia

Involuntary, 360, 368, 455, 464, 480, 498, 510, 530, 537 Iodine, 144, 498 Ionization, 498 Ionizing, 40, 448, 478, 498, 529, 548 Ions, 455, 474, 476, 492, 498 Irradiation, 41, 115, 191, 498, 550 Ischemia, 48, 454, 484, 498, 531 Isoflurane, 100, 498 J Jejunostomy, 478, 499 Joint, 49, 84, 85, 97, 441, 453, 465, 499, 541 K Kava, 321, 499 Kb, 414, 499 Keratinocyte growth factor, 133, 499 Keratolytic, 472, 499, 522 Keto, 499, 544 Ketone Bodies, 473, 499 Ketosis, 473, 499 Kidney Disease, 239, 258, 358, 384, 414, 421, 499 Kidney Pelvis, 499, 546 Kinetic, 14, 112, 132, 164, 498, 499 L Labile, 466, 499 Laceration, 499, 542 Lactose Intolerance, 382, 499 Laminin, 455, 481, 499 Laparotomy, 66, 499 Large Intestine, 466, 473, 498, 499, 530, 537 Laryngitis, 401, 500 Larynx, 360, 368, 500, 539, 544, 549 Latency, 144, 500 Latent, 51, 78, 95, 197, 500, 524, 536, 548 Lavage, 121, 135, 193, 208, 260, 309, 428, 500 Least-Squares Analysis, 500, 531 Lectin, 125, 127, 134, 500, 506 Legionellaceae, 208, 500 Leishmaniasis, 281, 500, 517 Length of Stay, 25, 118, 500 Lens, 459, 500, 532, 549 Lentivirus, 491, 500 Lethal, 55, 76, 79, 84, 91, 101, 135, 164, 186, 320, 373, 455, 474, 500 Leucocyte, 253, 448, 478, 500, 503 Leucovorin, 226, 339, 340, 341, 345, 347, 351, 352, 353, 355, 357, 500 Leukaemia, 227, 326, 500 Leukemia, 228, 282, 287, 292, 420, 441, 464, 485, 489, 501

Leukocyte Count, 97, 501 Leukocytes, 88, 112, 132, 455, 457, 458, 463, 497, 501, 508, 546 Leukocytosis, 304, 501 Leukoencephalopathy, 12, 501 Leukopenia, 168, 391, 501, 550 Leukoplakia, 353, 382, 389, 390, 501 Levofloxacin, 149, 165, 176, 177, 217, 220, 254, 293, 338, 355, 501 Library Services, 436, 501 Life cycle, 111, 144, 457, 484, 501 Life Expectancy, 12, 54, 385, 501 Ligament, 501, 525 Ligands, 24, 51, 54, 88, 112, 461, 496, 501 Ligation, 116, 501 Likelihood Functions, 501, 531 Lincomycin, 465, 501 Linear Models, 501, 531 Linkage, 35, 38, 80, 85, 97, 146, 501, 518 Lipid, 76, 108, 140, 323, 341, 452, 453, 461, 477, 483, 487, 496, 499, 501, 502, 516 Lipid Peroxidation, 501, 516 Lipophilic, 82, 501 Lipopolysaccharide, 48, 60, 122, 141, 143, 164, 165, 260, 487, 501 Lipoprotein, 13, 34, 195, 487, 502, 548 Liposomal, 292, 502 Liposomes, 6, 161, 502 Liquor, 502, 528 Liver Cirrhosis, 230, 502 Liver Transplantation, 306, 502 Lobe, 19, 121, 194, 502, 517 Localization, 494, 502 Localized, 87, 136, 386, 472, 474, 477, 482, 495, 499, 502, 510, 521, 542, 546 Logistic Models, 502, 531 Longitudinal study, 64, 502 Long-Term Care, 169, 372, 380, 502 Loop, 111, 502 Low-density lipoprotein, 502 Lower Esophageal Sphincter, 485, 502 Lumen, 141, 478, 503 Lung Ta, 290, 503 Lung Transplantation, 119, 192, 284, 503 Lung volume, 41, 503 Lupus, 58, 399, 400, 503, 541 Lymph, 19, 176, 244, 258, 382, 454, 469, 478, 491, 492, 495, 503, 522, 531, 534, 540 Lymph node, 19, 176, 382, 454, 503, 531, 534 Lymphadenopathy, 244, 258, 491, 495, 503

Index 563

Lymphatic, 478, 495, 503, 506, 537, 538, 543 Lymphatic system, 503, 537, 538, 543 Lymphoblastic, 503 Lymphoblasts, 446, 503 Lymphocyte Count, 64, 100, 121, 445, 503 Lymphocytic, 31, 64, 108, 227, 251, 256, 294, 315, 503 Lymphocytosis, 64, 503 Lymphoid, 8, 51, 64, 243, 256, 272, 420, 451, 488, 500, 503 Lymphokines, 503, 504 Lymphoma, 221, 280, 282, 382, 420, 489, 503 Lymphoproliferative, 272, 503 Lymphoproliferative Disorders, 272, 503 Lysosome, 35, 503 Lytic, 503, 536, 548 M Macrolides, 187, 199, 247, 503 Macrophage Activation, 100, 504 Magnetic Resonance Imaging, 80, 135, 504, 513 Magnetic Resonance Spectroscopy, 8, 504 Maintenance therapy, 401, 504 Major Histocompatibility Complex, 66, 497, 504 Malabsorption, 420, 504 Malaria, 116, 363, 504 Malaria, Falciparum, 504 Malaria, Vivax, 504 Malignancy, 114, 232, 279, 504 Malignant, 280, 384, 420, 445, 451, 504, 509, 511, 529, 534 Malignant tumor, 384, 504, 509 Malnutrition, 147, 402, 454, 459, 504, 510 Mammary, 469, 504, 505 Mandible, 463, 504 Mania, 185, 505 Manifest, 381, 505 Mannans, 484, 505 Mastitis, 505, 536 Matrix metalloproteinase, 84, 287, 505 Measles Virus, 69, 406, 505 Mechanical ventilation, 104, 119, 197, 208, 244, 369, 372, 505 Mediate, 73, 74, 87, 100, 107, 130, 138, 141, 461, 474, 505, 529, 530 Mediator, 28, 40, 83, 91, 116, 127, 130, 133, 497, 505, 536 Medical Errors, 53, 505 Medical Staff, 475, 505

Medication Errors, 505 MEDLINE, 415, 420, 421, 505 Megakaryocytes, 458, 505 Meiosis, 111, 505, 510, 541 Melanin, 505, 520, 546 Melanocytes, 505 Melanoma, 420, 505 Membrane Fusion, 96, 506 Membrane Lipids, 506, 520 Membrane Proteins, 461, 502, 506, 526 Memory, 54, 121, 381, 450, 472, 506 Meninges, 3, 461, 462, 470, 475, 506 Meningitis, 3, 24, 56, 60, 71, 78, 138, 139, 141, 143, 144, 155, 196, 277, 289, 330, 331, 388, 399, 424, 506 Menopause, 354, 506, 523 Menstruation, 506 Mental Disorders, 358, 506, 524, 527 Mental Health, iv, 5, 358, 414, 418, 506, 524, 527 Mental Processes, 474, 506, 527 Mentors, 94, 124, 506 Mercury, 483, 506 Mesenchymal, 479, 506 Mesenteric, 48, 258, 454, 506 Mesentery, 506, 519 Mesothelial, 11, 506 Meta-Analysis, 38, 152, 214, 215, 323, 507 Metabolite, 500, 507, 524 Metaplasia, 83, 96, 507 Metastasis, 71, 461, 505, 507 Metastasize, 385, 507, 534 Metastatic, 385, 507, 534 Methionine, 99, 507, 540 Methotrexate, 309, 401, 507 Methylprednisolone, 137, 292, 352, 356, 507 MI, 20, 32, 36, 39, 50, 60, 87, 88, 93, 116, 119, 128, 194, 205, 303, 305, 311, 444, 507 Microbe, 97, 507, 544 Microbiological, 103, 142, 165, 175, 222, 237, 254, 259, 266, 269, 379, 507 Microcirculation, 502, 507, 521 Microorganism, 20, 97, 427, 465, 507, 517, 549 Micro-organism, 472, 507, 535 Microscopy, 19, 32, 58, 94, 97, 126, 138, 142, 455, 507 Microtubules, 507, 516 Migration, 88, 91, 99, 132, 504, 507, 530 Milliliter, 457, 508 Mineralization, 19, 508

564 Pneumonia

Mineralocorticoids, 447, 469, 508 Minority Groups, 109, 508 Mitosis, 112, 452, 508 Mitosporic Fungi, 453, 508 Mitotic, 111, 480, 508 Mobility, 119, 508 Mobilization, 48, 508 Mode of Transmission, 51, 252, 508 Modeling, 39, 57, 92, 99, 138, 165, 286, 475, 508 Modification, 34, 41, 60, 65, 88, 100, 449, 508, 528, 550 Molecule, 99, 111, 112, 164, 247, 248, 299, 451, 455, 456, 467, 474, 476, 478, 479, 480, 487, 490, 492, 496, 500, 508, 513, 515, 521, 529, 530, 536, 540, 544, 547 Monitor, 8, 93, 323, 349, 352, 508, 513 Monoclonal, 20, 51, 86, 94, 100, 129, 151, 168, 172, 203, 498, 508, 528, 550 Monoclonal antibodies, 86, 94, 508 Monocyte, 16, 34, 89, 115, 116, 143, 221, 508 Monocyte Chemoattractant Protein-1, 221, 508 Mononuclear, 34, 52, 73, 100, 488, 495, 509, 546 Mononucleosis, 385, 509 Monotherapy, 153, 158, 187, 261, 278, 509 Morbillivirus, 505, 509 Morphological, 275, 476, 484, 505, 509 Morphology, 34, 113, 142, 453, 488, 504, 509 Motility, 43, 87, 509, 536 Motion Sickness, 509, 511 Mucins, 235, 472, 487, 509, 533 Mucociliary, 372, 509, 537 Mucociliary Clearance, 372, 509 Mucocutaneous, 500, 509 Mucolytic, 445, 458, 509 Mucosa, 60, 103, 485, 503, 509, 539, 540 Mucositis, 509, 543 Mucus, 83, 96, 122, 372, 509, 546 Multicenter study, 176, 177, 204, 242, 254, 273, 274, 289, 509 Multidrug resistance, 509, 519 Multiple Myeloma, 325, 509 Multiple Organ Failure, 48, 509 Multiple Trauma, 245, 509 Multivalent, 454, 509 Multivariate Analysis, 127, 510 Mupirocin, 292, 315, 510 Muscle Fibers, 510

Muscular Atrophy, 420, 510 Muscular Dystrophies, 476, 510 Musculoskeletal System, 430, 510 Myalgia, 496, 510 Mycobacterium, 6, 10, 98, 126, 164, 263, 388, 391, 454, 510 Mycobacterium avium, 10, 98, 391, 454, 510 Mycoplasma Infections, 98, 462, 510 Mycosis, 70, 510 Myelogenous, 510 Myeloma, 492, 510 Myocardial infarction, 22, 53, 73, 85, 469, 507, 510 Myocarditis, 141, 474, 510 Myocardium, 507, 510 Myopathy, 163, 510 Myositis, 304, 510 Myotonic Dystrophy, 420, 510 N Nadir, 121, 511 Naive, 9, 13, 51, 63, 75, 511 Naloxone, 221, 511 Narcotic, 511, 513 Nasal Mucosa, 496, 511 Nasogastric, 119, 478, 511 Nasopharynx, 146, 162, 511 Natural selection, 456, 511 Nausea, 383, 441, 452, 485, 495, 499, 511, 546 NCI, 1, 358, 413, 465, 511 Nebulizer, 346, 350, 417, 511 Needle biopsy, 443, 482, 511 Neonatal, 44, 56, 60, 78, 108, 122, 143, 144, 154, 185, 264, 283, 495, 511 Neonatology, 108, 511 Neoplasia, 420, 511 Neoplasm, 470, 511, 534 Neoplastic, 503, 511, 534 Nephropathy, 499, 511 Nervous System, 139, 420, 430, 447, 462, 505, 511, 512, 519 Networks, 7, 41, 52, 57, 285, 511 Neural, 285, 447, 449, 492, 511 Neuraminidase, 160, 509, 512 Neuroendocrine, 260, 512 Neuroleptic, 452, 465, 512 Neurologic, 10, 12, 18, 54, 90, 104, 137, 391, 491, 512 Neurologic Manifestations, 391, 512 Neurology, 10, 18, 78, 108, 194, 202, 315, 512

Index 565

Neuromuscular, 400, 445, 512 Neuronal, 8, 96, 512 Neurons, 472, 484, 512, 541 Neuropathy, 141, 384, 512, 519 Neuropeptide, 51, 512 Neuroretinitis, 512, 532 Neurosyphilis, 390, 512 Neurotoxic, 512 Neurotoxins, 8, 512 Neurotransmitter, 445, 446, 449, 457, 458, 464, 474, 486, 487, 491, 512, 513, 536, 538, 540 Neutralization, 26, 66, 130, 512 Neutrons, 448, 498, 512, 528 Neutrophil, 11, 14, 23, 24, 29, 50, 68, 99, 101, 114, 132, 150, 152, 158, 164, 214, 299, 322, 512, 513 Neutrophil Infiltration, 101, 513 Nitric Oxide, 48, 74, 98, 141, 168, 244, 258, 513 Nitrogen, 74, 99, 133, 449, 450, 470, 481, 483, 486, 513, 546 Nitrous Oxide, 99, 513 Norepinephrine, 447, 449, 474, 512, 513 Nuclear, 15, 30, 80, 116, 160, 231, 455, 468, 480, 484, 513 Nuclear magnetic resonance imaging, 80, 513 Nuclei, 448, 468, 485, 504, 508, 512, 513, 514, 526 Nucleic acid, 34, 271, 321, 459, 471, 485, 492, 493, 513, 528, 533, 548, 550 Nucleic Acid Hybridization, 492, 513 Nucleus, 452, 455, 464, 470, 471, 473, 476, 480, 484, 505, 509, 512, 513, 526, 539, 542 Nutritional Status, 102, 513 Nutritional Support, 485, 513 O Observational study, 197, 514 Occult, 272, 402, 514 Occult Blood, 402, 514 Ocular, 361, 514 Odds Ratio, 514, 531 Ointments, 514, 516 Oligosaccharides, 145, 512, 514 Omeprazole, 272, 514 Oncogene, 420, 490, 514 Oncogenic, 497, 500, 514, 526 Oncology, 40, 108, 146, 221, 248, 278, 279, 280, 309, 315, 328, 514, 531 Opacity, 472, 514 Operon, 143, 160, 174, 231, 514, 525, 532

Ophthalmology, 10, 78, 483, 514 Opiate, 511, 514 Optic Nerve, 512, 514, 516, 532 Oral Health, 4, 385, 515 Oral Hygiene, 4, 515 Oral Manifestations, 64, 386, 515 Organ Transplantation, 114, 190, 306, 383, 515 Orofacial, 386, 515 Oropharynx, 103, 515 Osteoporosis, 386, 515 Otitis, 21, 24, 55, 60, 69, 85, 93, 138, 139, 331, 382, 384, 515 Otitis Media, 21, 24, 60, 69, 85, 93, 138, 139, 331, 382, 515 Otolaryngology, 390, 515 Otorhinolaryngology, 382, 515 Outpatient, 38, 131, 216, 229, 230, 273, 339, 340, 350, 479, 515 Overexpress, 62, 89, 133, 141, 515 Ovum, 486, 501, 515, 524, 550 Oxidants, 74, 123, 515 Oxidation, 34, 139, 445, 452, 470, 473, 486, 501, 515, 516 Oxidation-Reduction, 515 Oxidative Phosphorylation, 123, 515 Oxidative Stress, 15, 89, 142, 181, 516 Oximetry, 43, 516 Oxygen Consumption, 480, 516, 532 Oxygenation, 160, 309, 493, 516 Oxygenator, 481, 516 P Pachymeningitis, 506, 516 Paclitaxel, 328, 516 Paediatric, 181, 197, 270, 276, 301, 316, 516 Palate, 511, 516 Palliative, 117, 380, 516, 542 Pancreas, 445, 456, 473, 496, 516, 538, 546 Pancreatic, 382, 420, 485, 516 Pancreatic cancer, 420, 516 Pancreatic Juice, 485, 516 Panic, 281, 397, 516 Paraffin, 225, 516 Paranasal Sinuses, 516, 537 Parasite, 59, 71, 113, 350, 516, 517 Parasitic, 13, 98, 102, 470, 516, 544 Parasitic Diseases, 102, 516 Parasitism, 59, 517 Parietal, 514, 517, 519, 522 Parotid, 517, 534 Paroxysmal, 420, 489, 517 Partial remission, 517, 531

566 Pneumonia

Pastoral Care, 117, 517 Patch, 469, 501, 517 Pathologic, 44, 45, 112, 229, 268, 274, 445, 452, 456, 459, 469, 493, 517, 523, 527 Pathologic Processes, 452, 517 Pathologies, 97, 517 Pathologist, 381, 517 Pathophysiology, 11, 57, 74, 87, 89, 91, 113, 116, 123, 143, 375, 392, 517 Patient Education, 72, 383, 387, 426, 434, 436, 444, 517 Patient Selection, 417, 517 Pelvic, 384, 517, 525 Pelvis, 445, 517, 528, 547 Penicillin, 86, 130, 150, 152, 156, 158, 159, 162, 165, 166, 167, 171, 172, 173, 217, 236, 277, 364, 449, 450, 517 Penicillin Resistance, 130, 156, 517 Pepsin, 42, 518 Pepsin A, 518 Peptic, 382, 399, 518, 540 Peptic Ulcer, 382, 399, 518 Peptide, 6, 24, 39, 48, 54, 80, 101, 162, 164, 372, 449, 465, 477, 482, 518, 526 Peptide Chain Elongation, 465, 518 Peptide Fragments, 80, 518 Peptide T, 372, 518 Perceived risk, 391, 518 Perception, 85, 257, 518, 534 Percutaneous, 110, 518 Perfusion, 294, 443, 493, 518, 543 Pericarditis, 196, 518 Pericardium, 518, 541 Perinatal, 11, 81, 109, 110, 146, 283, 391, 495, 518 Periodontal disease, 4, 45, 385, 518 Periodontics, 385, 518 Periodontitis, 4, 386, 486, 518 Perioperative, 26, 100, 383, 518 Peripheral blood, 8, 65, 73, 114, 121, 135, 167, 188, 322, 489, 497, 519 Peripheral Nervous System, 512, 519, 538, 540 Peripheral Neuropathy, 90, 141, 519 Peripheral stem cell transplantation, 228, 519 Peripheral stem cells, 487, 519 Peritoneal, 21, 84, 107, 385, 498, 519 Peritoneal Cavity, 107, 498, 519 Peritoneal Dialysis, 385, 519 Peritoneum, 506, 519 Peritonitis, 27, 97, 107, 112, 170, 239, 519

Permissiveness, 96, 519 Peroxide, 123, 519 Petroleum, 110, 516, 519 P-Glycoprotein, 137, 519 PH, 149, 157, 161, 162, 185, 209, 254, 259, 280, 304, 457, 519 Phagocyte, 29, 34, 515, 520 Phagocytosis, 15, 18, 21, 45, 54, 63, 76, 86, 95, 97, 126, 164, 520 Pharmacists, 38, 146, 184, 256, 262, 520 Pharmacodynamics, 151, 169, 188, 217, 520 Pharmacokinetic, 6, 8, 110, 157, 169, 355, 520 Pharmacologic, 7, 12, 104, 450, 488, 520, 543, 544 Pharynx, 79, 485, 496, 511, 515, 520 Phenotype, 21, 24, 46, 56, 67, 71, 100, 122, 135, 520 Phenyl, 362, 520 Phenylalanine, 518, 520, 546 Phenytoin, 459, 520 Pheromone, 111, 520 Phorbol, 520, 526 Phorbol Esters, 520, 526 Phospholipases, 520, 536 Phospholipids, 141, 481, 502, 506, 520, 526 Phosphorus, 459, 520 Phosphorylates, 520, 526 Phosphorylation, 67, 520 Phosphorylcholine, 23, 60, 520 Photocoagulation, 465, 521 Physical Examination, 121, 428, 521 Physiologic, 37, 55, 82, 84, 105, 107, 112, 120, 176, 447, 488, 506, 521, 525, 530 Physiology, 45, 75, 135, 177, 180, 195, 200, 201, 204, 206, 209, 216, 217, 221, 226, 234, 235, 237, 241, 244, 245, 246, 249, 255, 258, 259, 263, 269, 274, 289, 290, 302, 307, 308, 310, 321, 477, 488, 518, 521, 532, 540, 547 Picornavirus, 142, 521 Pilot study, 40, 53, 98, 121, 314, 320, 322, 354, 521 Pituitary Gland, 469, 482, 521 Plants, 456, 457, 458, 459, 486, 500, 509, 512, 513, 521, 527, 534, 544, 545 Plaque, 22, 44, 103, 104, 463, 521 Plasma cells, 451, 488, 509, 510, 521 Plasma protein, 470, 478, 521 Plasmid, 56, 521, 547 Plasmin, 361, 521

Index 567

Plasminogen, 73, 84, 177, 278, 521 Plasminogen Activators, 521 Plasticity, 142, 521 Platelet Activating Factor, 24, 522 Platelet Activation, 112, 522, 537 Platelet Aggregation, 450, 513, 522, 543 Platelets, 112, 351, 513, 522, 542, 543 Platinum, 502, 522 Pleura, 522 Pleural, 11, 176, 276, 443, 506, 522 Pleural cavity, 522 Pleural Effusion, 176, 522 Pleurisy, 281, 382, 522 Pneumonitis, 39, 40, 42, 65, 87, 89, 112, 115, 157, 158, 171, 191, 240, 241, 400, 522 Pneumothorax, 189, 277, 385, 522 Podophyllotoxin, 480, 522 Poisoning, 185, 472, 485, 498, 506, 511, 523, 533, 535 Polycystic, 421, 523 Polymerase, 32, 36, 67, 121, 197, 284, 523, 525, 531 Polymerase Chain Reaction, 32, 36, 121, 197, 523 Polymers, 138, 523, 526 Polymorphic, 91, 464, 523 Polymorphism, 91, 150, 177, 186, 248, 301, 364, 369, 370, 371, 523 Polyneuritis, 474, 523 Polysaccharide, 21, 49, 51, 56, 70, 85, 143, 165, 206, 260, 265, 451, 462, 523, 526 Positron emission tomography scan, 225, 523 Posterior, 449, 453, 464, 516, 523 Postherpetic Neuralgia, 448, 523 Postmenopausal, 354, 515, 523 Postoperative, 53, 99, 118, 207, 225, 276, 298, 327, 383, 509, 523 Postoperative Complications, 53, 523 Postsynaptic, 523, 536 Post-traumatic, 240, 489, 523 Potassium, 316, 508, 523 Potentiates, 497, 523 Potentiating, 362, 449, 524 Potentiation, 167, 464, 524, 536 Practice Guidelines, 61, 72, 184, 223, 418, 428, 524 Preclinical, 40, 102, 116, 130, 524 Precursor, 453, 470, 474, 476, 478, 513, 520, 521, 524, 546 Predisposition, 57, 91, 369, 371, 524 Prednisolone, 507, 524

Prednisone, 37, 121, 524 Preoperative, 118, 383, 524 Prevalence, 4, 22, 37, 64, 98, 102, 109, 169, 214, 215, 285, 306, 314, 384, 390, 400, 514, 524 Primary endpoint, 46, 524 Primary Prevention, 73, 524 Primary tumor, 40, 524 Private Sector, 127, 524 Probe, 20, 396, 524 Prodrug, 102, 524 Progeny, 468, 524 Progesterone, 524, 539 Prognostic factor, 73, 119, 197, 206, 305, 525, 541 Progression, 8, 34, 64, 84, 129, 144, 162, 199, 388, 450, 525 Projection, 307, 472, 513, 514, 525, 530 Proline, 466, 492, 525 Promoter, 96, 143, 177, 371, 525 Promotor, 525, 532 Prospective Payment System, 25, 525 Prospective study, 54, 180, 199, 224, 237, 399, 502, 525 Prostaglandin, 48, 525 Prostaglandins A, 525 Prostate, 420, 456, 525, 546 Protease, 8, 17, 28, 39, 58, 90, 141, 147, 466, 526 Protease Inhibitors, 8, 28, 39, 147, 526 Protein Binding, 526, 543 Protein C, 85, 171, 449, 452, 455, 502, 526, 546, 548 Protein Conformation, 449, 526 Protein Kinase C, 77, 526 Protein S, 48, 378, 421, 457, 465, 474, 479, 485, 526, 533, 542 Proteinuria, 282, 509, 526 Proteoglycans, 455, 481, 526 Proteolytic, 39, 84, 448, 467, 482, 521, 526 Protocol, 9, 10, 11, 81, 89, 100, 137, 178, 292, 315, 335, 339, 341, 526 Proton Pump, 514, 526 Protons, 448, 492, 498, 504, 526, 528 Proto-Oncogene Proteins, 516, 526 Proto-Oncogene Proteins c-mos, 516, 526 Protozoa, 59, 125, 468, 500, 507, 527, 544, 546 Protozoal, 137, 333, 427, 470, 527 Protozoan, 13, 125, 462, 470, 504, 527 Proximal, 77, 474, 527 Proxy, 42, 527

568 Pneumonia

Psoriasis, 97, 527, 533 Psychiatry, 185, 202, 482, 527, 548 Psychic, 506, 527, 535 Psychoactive, 527, 549 Psychology, 108, 474, 527 Psychomotor, 459, 472, 512, 527 Psychotherapy, 527, 530 Public Policy, 127, 415, 527 Pulmonary Artery, 213, 335, 457, 527, 548 Pulmonary Edema, 266, 527 Pulmonary Embolism, 210, 286, 527 Pulmonary Fibrosis, 36, 40, 82, 207, 225, 301, 527 Pulmonary Ventilation, 528, 532 Pulsation, 111, 528 Pulse, 43, 187, 314, 401, 441, 508, 516, 528 Purulent, 445, 477, 528, 547 Putrefaction, 484, 528 Pyelonephritis, 138, 384, 528 Pyoderma, 279, 528 Pyoderma Gangrenosum, 279, 528 Pyogenic, 11, 528, 535 Pyridoxal, 528, 544 Pyrimidines, 528, 536, 548 Q Quality of Life, 13, 78, 102, 380, 385, 528, 540 Quinolones, 172, 288, 528 R Race, 126, 426, 507, 528 Radiation, 40, 146, 191, 240, 445, 474, 476, 478, 481, 483, 484, 494, 497, 498, 528, 529, 534, 548, 550 Radiation therapy, 40, 445, 474, 481, 483, 497, 498, 528, 534, 550 Radioactive, 471, 488, 492, 494, 497, 498, 508, 509, 513, 514, 528, 529, 550 Radiography, 288, 424, 529 Radioimmunotherapy, 466, 529 Radiolabeled, 498, 528, 529, 550 Radiological, 306, 379, 391, 424, 518, 529 Radiology, 194, 205, 225, 234, 241, 256, 264, 267, 268, 269, 275, 283, 288, 296, 307, 315, 424, 529 Radiotherapy, 40, 328, 458, 498, 528, 529, 550 Random Allocation, 529 Randomization, 53, 356, 529 Randomized clinical trial, 53, 104, 128, 529 Randomized Controlled Trials, 327, 529 Ranitidine, 152, 272, 529 Reactivation, 51, 95, 120, 384, 529

Reactive Oxygen Species, 74, 529 Reassurance, 402, 530 Receptors, Chemokine, 65, 530 Recombinant, 28, 29, 45, 121, 130, 133, 134, 141, 149, 160, 163, 166, 218, 530, 547 Recombination, 112, 161, 468, 485, 530 Reconstitution, 7, 18, 20, 40, 67, 80, 100, 105, 120, 138, 241, 530 Rectum, 452, 458, 466, 473, 483, 485, 496, 499, 525, 530 Recurrence, 226, 342, 356, 357, 362, 367, 385, 530 Red blood cells, 479, 490, 530, 534 Red Nucleus, 453, 530 Reductase, 13, 137, 166, 507, 530, 542, 545 Refer, 1, 459, 466, 482, 484, 491, 502, 509, 511, 512, 513, 529, 530, 544 Reference Values, 302, 530 Reflective, 7, 530 Reflex, 242, 319, 360, 368, 372, 530 Reflux, 221, 401, 485, 530, 540 Refraction, 530, 538 Refractory, 292, 341, 345, 347, 351, 352, 476, 530 Regeneration, 482, 530 Regimen, 32, 120, 180, 299, 341, 353, 417, 465, 476, 530 Regional lymph node, 46, 531 Regression Analysis, 119, 531 Regurgitation, 214, 401, 485, 489, 531 Rehabilitative, 25, 381, 531 Reinfection, 34, 69, 130, 384, 531 Relapse, 228, 342, 343, 357, 401, 531 Relative risk, 23, 53, 531 Reliability, 123, 390, 531 Remission, 228, 231, 292, 401, 504, 530, 531 Renal Circulation, 457, 531 Renal failure, 363, 472, 531 Renal pelvis, 384, 531, 545 Reperfusion, 48, 531 Reperfusion Injury, 531 Repressor, 514, 531 Research Design, 5, 532 Research Support, 36, 532 Resection, 100, 182, 532 Residual Volume, 43, 532 Resolving, 20, 265, 532 Respiration, 113, 182, 191, 192, 210, 244, 283, 301, 305, 310, 459, 508, 532 Respirator, 505, 532, 548 Respiratory distress syndrome, 248, 287, 309, 532

Index 569

Respiratory failure, 128, 134, 194, 266, 294, 301, 303, 356, 369, 481, 532, 548 Respiratory syncytial virus, 5, 52, 75, 129, 135, 169, 191, 261, 305, 361, 532 Respiratory System, 97, 447, 509, 532 Response Elements, 23, 532 Response rate, 348, 351, 532 Restoration, 10, 121, 529, 530, 531, 532, 549 Retina, 464, 469, 500, 512, 514, 532, 533, 549 Retinitis, 78, 532 Retinoblastoma, 420, 532 Retinoids, 48, 532, 549 Retrograde, 79, 385, 533 Retrospective, 118, 533 Retroviral vector, 485, 533 Retrovirus, 363, 533 Rhabdomyolysis, 246, 252, 295, 533 Rheumatoid, 515, 533 Rhinitis, 458, 533, 536 Rhinovirus, 135, 295, 533 Ribavirin, 169, 407, 533 Ribosome, 533, 545 Risk patient, 121, 273, 350, 533 Ristocetin, 533, 547 Rod, 454, 455, 478, 488, 527, 533 Rotavirus, 130, 533 Rubber, 533, 539 S Saliva, 360, 368, 533 Salivary, 104, 382, 430, 471, 472, 473, 516, 533, 540 Salivary glands, 430, 471, 472, 473, 533 Salmonella, 26, 269, 281, 385, 485, 533 Salvage Therapy, 466, 534 Saphenous, 469, 534 Saphenous Vein, 469, 534 Saponins, 534, 539 Sarcoid, 430, 534 Sarcoidosis, 34, 191, 193, 235, 300, 430, 534 Sarcoma, 90, 382, 388, 389, 390, 391, 534 Satellite, 10, 534 Schizoid, 534, 549 Schizophrenia, 534, 549 Schizotypal Personality Disorder, 534, 549 Sclerosis, 18, 31, 247, 267, 268, 290, 420, 453, 534 Screening, 31, 56, 81, 300, 360, 364, 369, 370, 371, 372, 385, 425, 465, 534 Secondary tumor, 507, 534 Secretory, 24, 26, 28, 51, 96, 509, 514, 534 Sedative, 449, 499, 534

Sediment, 534 Sedimentation, 204, 462, 534 Segmental, 258, 535 Segmentation, 535 Segregation, 455, 530, 535 Seizures, 459, 472, 517, 520, 535 Selection Bias, 118, 535 Selenium, 141, 535 Semen, 525, 535 Semisynthetic, 449, 461, 462, 465, 480, 493, 535 Senescence, 54, 535 Senile, 515, 535 Sensitization, 51, 535 Septic, 27, 44, 50, 91, 107, 228, 233, 248, 301, 371, 535 Septicaemia, 535, 536 Septicemia, 44, 385, 535 Sequence Analysis, 141, 535 Sequence Homology, 518, 535 Sequencing, 56, 89, 95, 141, 169, 523, 535 Serine, 477, 526, 535 Seroconversion, 382, 536 Seroepidemiologic Studies, 22, 536 Serologic, 22, 73, 106, 310, 536 Serology, 154, 160, 292, 536 Serotonin, 449, 452, 465, 512, 536, 546 Serotypes, 49, 60, 106, 143, 184, 536 Serous, 47, 382, 478, 522, 536 Sex Determination, 421, 536 Shedding, 473, 536 Ships, 76, 536 Shock, 19, 27, 37, 44, 91, 228, 233, 244, 248, 301, 371, 444, 478, 536, 545 Signal Transduction, 21, 77, 91, 96, 111, 112, 461, 536 Signs and Symptoms, 73, 512, 531, 537 Sinusitis, 34, 93, 204, 230, 382, 384, 537 Skeletal, 80, 450, 464, 509, 510, 533, 537 Skeleton, 445, 482, 499, 525, 537 Skin test, 69, 103, 537 Skull, 470, 537, 542 Small cell lung cancer, 40, 537 Small intestine, 51, 464, 475, 491, 498, 511, 537 Smoke Inhalation Injury, 481, 537 Smoking Cessation, 400, 537 Smooth muscle, 448, 450, 457, 468, 483, 491, 537, 540 Sneezing, 22, 536, 537 Social Environment, 528, 537 Social Security, 529, 537

570 Pneumonia

Sodium, 92, 363, 508, 537 Soft tissue, 229, 338, 457, 537 Solid tumor, 450, 537 Solvent, 480, 487, 537 Somatic, 447, 492, 505, 508, 519, 537 Somatic cells, 505, 508, 537 Somatostatin, 48, 538 Sound wave, 530, 538, 546 Specialist, 379, 431, 538 Specificity, 30, 43, 49, 64, 94, 137, 447, 477, 538, 543 Spectroscopic, 504, 514, 538 Spectrum, 20, 37, 38, 63, 84, 101, 106, 133, 145, 275, 299, 306, 388, 493, 538, 540 Sphincter, 500, 538 Spinal cord, 137, 462, 463, 475, 477, 478, 484, 506, 511, 512, 516, 519, 530, 538 Spleen, 306, 382, 430, 454, 471, 492, 503, 534, 538 Splenectomy, 306, 538 Spondylitis, 253, 538 Sporadic, 326, 396, 532, 538 Sputum, 103, 135, 165, 182, 184, 197, 245, 306, 428, 443, 538 Staging, 178, 388, 538 Standard therapy, 168, 352, 357, 538 Statistically significant, 100, 538 Steady state, 124, 340, 538 Stem cell transplantation, 322, 338, 489, 538 Stem Cells, 448, 489, 519, 538, 539 Stenosis, 34, 539 Sterility, 470, 495, 539 Steroid, 187, 308, 314, 315, 323, 352, 470, 534, 539 Steroid therapy, 315, 323, 352, 539 Stethoscope, 123, 539 Stimulants, 6, 486, 539 Stimulus, 14, 29, 83, 476, 480, 496, 500, 530, 539, 542 Stool, 402, 466, 499, 539 Strand, 5, 157, 322, 523, 539 Streptococcal, 56, 197, 299, 384, 501, 539 Streptococci, 60, 78, 144, 212, 510, 539 Stress Ulcer, 152, 272, 316, 539 Striatum, 262, 539 Stricture, 539 Stridor, 470, 539 Stroke, 25, 34, 53, 73, 79, 118, 126, 180, 270, 287, 297, 358, 414, 460, 539 Stromal, 458, 539 Stromal Cells, 458, 539

Subacute, 338, 495, 537, 540 Subarachnoid, 489, 540 Subclinical, 73, 106, 121, 350, 390, 495, 535, 536, 540 Subcutaneous, 82, 289, 381, 484, 517, 540 Submaxillary, 479, 540 Subspecies, 538, 540 Substance P, 479, 507, 530, 533, 534, 540 Substrate, 139, 360, 369, 478, 512, 540 Substrate Specificity, 139, 540 Sucralfate, 152, 272, 540 Suction, 178, 540 Sulbactam, 218, 314, 540 Sulfadoxine, 216, 314, 540 Sulfur, 481, 507, 540 Superinfection, 79, 540 Superoxide, 15, 123, 148, 540 Supplementation, 47, 102, 147, 157, 322, 324, 327, 328, 329, 540 Supportive care, 101, 540 Suppression, 13, 14, 16, 24, 63, 66, 69, 244, 469, 541, 550 Suppressive, 14, 137, 541 Surfactant, 17, 28, 74, 82, 95, 97, 127, 133, 136, 140, 141, 170, 235, 239, 309, 310, 541 Surgical Wound Infection, 100, 384, 541 Survival Analysis, 120, 541 Survival Rate, 40, 320, 385, 541 Symphysis, 463, 525, 541 Symptomatic, 53, 243, 448, 541 Symptomatic treatment, 448, 541 Synaptic, 512, 536, 541 Syncytium, 486, 541 Synergistic, 28, 79, 541 Syphilis, 512, 541 Systemic disease, 4, 372, 385, 386, 535, 541 Systemic lupus erythematosus, 58, 264, 277, 541 Systolic, 493, 541 T Tachycardia, 454, 541 Tachypnea, 186, 454, 541 Teichoic Acids, 487, 541 Telangiectasia, 421, 541 Temporal, 29, 32, 40, 489, 542 Terminal disease, 31, 542 Terminator, 542, 550 Testosterone, 530, 542 Tetani, 542 Tetanic, 542 Tetanus, 70, 244, 406, 542 Tetracycline, 38, 542

Index 571

Thalamic, 453, 542 Thalamic Diseases, 453, 542 Therapeutics, 38, 79, 147, 176, 177, 178, 204, 213, 226, 254, 274, 289, 408, 542 Thermal, 99, 474, 512, 523, 542 Thigh, 482, 542 Thioredoxin, 221, 542 Thorax, 186, 190, 193, 206, 210, 232, 235, 242, 253, 256, 281, 299, 308, 445, 542 Threonine, 518, 526, 535, 542 Threshold, 53, 272, 493, 542 Thrombin, 482, 522, 526, 542, 543 Thrombocytes, 522, 542 Thrombocytopenia, 351, 363, 522, 543 Thromboembolism, 53, 543 Thrombolytic, 521, 543 Thrombomodulin, 526, 543 Thrombosis, 112, 496, 526, 539, 543 Thrombus, 469, 495, 522, 543, 547 Thrush, 353, 391, 427, 428, 459, 543 Thymidine, 131, 543 Thymidine Kinase, 131, 543 Thymidylate Synthase, 13, 543 Thymus, 219, 494, 503, 543 Thyroid, 498, 543, 546 Ticlopidine, 247, 543 Tin, 185, 519, 522, 543 Tinnitus, 515, 543 Tissue, 4, 8, 19, 20, 27, 32, 34, 45, 51, 65, 68, 69, 71, 80, 83, 84, 88, 89, 91, 93, 94, 97, 115, 121, 132, 139, 147, 157, 203, 235, 261, 323, 357, 363, 373, 383, 445, 446, 448, 450, 451, 454, 455, 456, 457, 458, 459, 461, 463, 465, 466, 468, 470, 473, 475, 476, 477, 478, 481, 482, 484, 487, 488, 491, 493, 494, 495, 497, 501, 503, 504, 505, 506, 509, 510, 511, 512, 515, 518, 519, 521, 522, 523, 530, 531, 532, 534, 536, 537, 539, 541, 543, 545, 549 Tissue Distribution, 363, 543 Titre, 304, 543 Tolerance, 6, 101, 150, 284, 346, 348, 349, 446, 544 Tomography, 247, 274, 326, 328, 467, 504, 544 Tone, 515, 544 Tonicity, 490, 544 Tooth Preparation, 446, 544 Topical, 5, 106, 144, 372, 463, 480, 492, 516, 544 Torsion, 495, 544 Toxicology, 5, 416, 544

Toxin, 26, 77, 150, 315, 474, 478, 542, 544 Toxoid, 70, 544 Toxoplasma, 6, 137, 544 Toxoplasmosis, 13, 382, 388, 389, 390, 391, 427, 454, 544 Trachea, 458, 459, 500, 520, 539, 543, 544 Trachoma, 380, 544 Transaminase, 351, 544 Transcriptase, 341, 388, 533, 544 Transcription Factors, 96, 116, 139, 532, 544 Transduction, 91, 96, 111, 536, 544 Transfection, 457, 485, 545 Transfer Factor, 494, 545 Transfusion, 53, 225, 545 Transitional cell carcinoma, 384, 545 Translation, 72, 449, 480, 545 Translational, 9, 16, 60, 545 Translocate, 37, 545 Translocating, 455, 545 Translocation, 15, 26, 30, 37, 114, 454, 465, 480, 545 Transmitter, 445, 474, 505, 513, 545 Transposons, 60, 545 Trauma, 43, 48, 50, 112, 176, 181, 212, 213, 214, 218, 245, 251, 272, 286, 296, 297, 472, 480, 545, 549 Treatment Failure, 7, 187, 242, 254, 288, 545 Triad, 126, 545 Triage, 117, 545 Trimethoprim-sulfamethoxazole, 6, 245, 308, 315, 427, 545 Trimetrexate, 339, 340, 341, 345, 347, 351, 352, 353, 355, 357, 408, 545 Trimetrexate glucuronate, 341, 345, 347, 355, 408, 545 Tropism, 64, 70, 120, 304, 545 Trypanosomiasis, 102, 517, 546 Tryptophan, 466, 536, 546 Tube-feeding, 383, 546 Tuberous Sclerosis, 421, 546 Tumor marker, 456, 546 Tumor Necrosis Factor, 14, 44, 48, 77, 159, 164, 172, 301, 364, 370, 401, 546 Tunica, 509, 546 Type 2 diabetes, 4, 546 Tyrosine, 29, 125, 474, 546 U Ulcer, 488, 518, 539, 540, 546 Ulcerative colitis, 247, 496, 528, 546 Ultrasound test, 73, 546

572 Pneumonia

Unconscious, 444, 471, 493, 546 Urban Health, 42, 546 Urban Population, 546 Urea, 546 Uremia, 385, 531, 546 Ureter, 384, 499, 531, 545, 546 Urethra, 525, 546, 547 Urinary, 224, 229, 245, 289, 380, 383, 384, 385, 399, 455, 461, 464, 465, 470, 527, 540, 546, 547 Urinary tract, 229, 245, 380, 383, 384, 385, 399, 455, 461, 527, 540, 547 Urinary tract infection, 229, 245, 380, 383, 385, 399, 455, 527, 547 Urine, 159, 166, 197, 384, 455, 457, 479, 489, 490, 499, 526, 531, 546, 547 Uterus, 469, 476, 506, 524, 547 Uvea, 477, 547 V Vaccination, 6, 33, 42, 49, 98, 174, 223, 251, 265, 361, 385, 426, 547 Vacuole, 126, 547 Vagina, 459, 506, 547, 549 Vaginal, 144, 547, 549 Vaginitis, 459, 547 Vancomycin, 204, 254, 325, 547 Varicella, 120, 248, 255, 296, 305, 316, 383, 407, 547 Vascular endothelial growth factor, 244, 547 Vasculitis, 302, 400, 547 Vasodilators, 513, 547 VE, 187, 201, 240, 547 Vector, 68, 95, 496, 517, 545, 547 Vein, 110, 450, 453, 498, 513, 517, 534, 547 Vena, 110, 385, 547 Venoms, 512, 547 Venous, 110, 453, 457, 501, 526, 543, 547 Venous blood, 457, 501, 547 Venous Thrombosis, 543, 547 Ventilation, 135, 266, 369, 443, 460, 547, 548 Ventricle, 493, 527, 528, 541, 548 Ventricular, 196, 548 Venules, 457, 459, 478, 507, 548 Vertebrae, 538, 548 Vertigo, 515, 548

Vesicular, 491, 548 Veterinary Medicine, 415, 548 Vinculin, 126, 548 Viral Load, 65, 120, 199, 548 Viremia, 81, 548 Virion, 147, 548 Virulent, 6, 19, 26, 27, 31, 58, 59, 76, 86, 106, 282, 548 Virus Activation, 31, 548 Virus Replication, 30, 548 Visceral, 121, 196, 281, 500, 519, 549 Visceral Larva Migrans, 196, 549 Viscosity, 80, 445, 549 Vital Statistics, 117, 549 Vitamin A, 102, 147, 329, 549 Vitreous, 138, 464, 500, 532, 549 Vitreous Body, 464, 532, 549 Vocal cord, 381, 549 Volition, 498, 549 Vulva, 549 Vulvovaginitis, 384, 549 W Wakefulness, 472, 549 War, 393, 463, 488, 549 Weight Gain, 362, 549 Wheezing, 186, 442, 549 White blood cell, 430, 446, 451, 464, 482, 488, 495, 501, 503, 504, 508, 509, 510, 512, 521, 549 Windpipe, 520, 543, 549 Withdrawal, 417, 472, 549 Wound Healing, 99, 112, 400, 461, 482, 496, 505, 510, 549 Wound Infection, 99, 225, 300, 385, 549 X Xenograft, 450, 549 X-ray, 194, 208, 307, 424, 428, 442, 443, 455, 457, 467, 480, 483, 484, 498, 513, 528, 529, 550 X-ray therapy, 498, 550 Y Yeasts, 459, 484, 520, 550 Z Zidovudine, 342, 345, 550 Zoster, 120, 296, 383, 401, 550 Zygote, 468, 550 Zymogen, 526, 550

Index 573

574 Pneumonia

Index 575

576 Pneumonia

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