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

MYCOBACTERIUM TUBERCULOSIS A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FER...

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MYCOBACTERIUM TUBERCULOSIS 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 2004 by ICON Group International, Inc. Copyright 2004 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., 1960Mycobacterium Tuberculosis: 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: 0-497-00731-2 1. Mycobacterium Tuberculosis-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 Mycobacterium tuberculosis. 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 MYCOBACTERIUM TUBERCULOSIS ........................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Mycobacterium Tuberculosis ........................................................ 5 E-Journals: PubMed Central ....................................................................................................... 60 The National Library of Medicine: PubMed ................................................................................ 89 CHAPTER 2. NUTRITION AND MYCOBACTERIUM TUBERCULOSIS................................................ 139 Overview.................................................................................................................................... 139 Finding Nutrition Studies on Mycobacterium Tuberculosis..................................................... 139 Federal Resources on Nutrition ................................................................................................. 143 Additional Web Resources ......................................................................................................... 143 CHAPTER 3. ALTERNATIVE MEDICINE AND MYCOBACTERIUM TUBERCULOSIS ......................... 145 Overview.................................................................................................................................... 145 National Center for Complementary and Alternative Medicine................................................ 145 Additional Web Resources ......................................................................................................... 152 General References ..................................................................................................................... 153 CHAPTER 4. DISSERTATIONS ON MYCOBACTERIUM TUBERCULOSIS ........................................... 155 Overview.................................................................................................................................... 155 Dissertations on Mycobacterium Tuberculosis.......................................................................... 155 Keeping Current ........................................................................................................................ 156 CHAPTER 5. PATENTS ON MYCOBACTERIUM TUBERCULOSIS ...................................................... 157 Overview.................................................................................................................................... 157 Patents on Mycobacterium Tuberculosis................................................................................... 157 Patent Applications on Mycobacterium Tuberculosis ............................................................... 171 Keeping Current ........................................................................................................................ 200 CHAPTER 6. BOOKS ON MYCOBACTERIUM TUBERCULOSIS .......................................................... 201 Overview.................................................................................................................................... 201 Book Summaries: Federal Agencies............................................................................................ 201 Book Summaries: Online Booksellers......................................................................................... 202 Chapters on Mycobacterium Tuberculosis................................................................................. 202 CHAPTER 7. PERIODICALS AND NEWS ON MYCOBACTERIUM TUBERCULOSIS ............................ 205 Overview.................................................................................................................................... 205 News Services and Press Releases.............................................................................................. 205 Academic Periodicals covering Mycobacterium Tuberculosis ................................................... 207 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 209 Overview.................................................................................................................................... 209 U.S. Pharmacopeia..................................................................................................................... 209 Commercial Databases ............................................................................................................... 210 Researching Orphan Drugs ....................................................................................................... 210 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 215 Overview.................................................................................................................................... 215 NIH Guidelines.......................................................................................................................... 215 NIH Databases........................................................................................................................... 217 Other Commercial Databases..................................................................................................... 219 APPENDIX B. PATIENT RESOURCES ............................................................................................... 221 Overview.................................................................................................................................... 221 Patient Guideline Sources.......................................................................................................... 221 Finding Associations.................................................................................................................. 223 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 225 Overview.................................................................................................................................... 225

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Preparation................................................................................................................................. 225 Finding a Local Medical Library................................................................................................ 225 Medical Libraries in the U.S. and Canada ................................................................................. 225 ONLINE GLOSSARIES................................................................................................................ 231 Online Dictionary Directories ................................................................................................... 231 MYCOBACTERIUM TUBERCULOSIS DICTIONARY......................................................... 233 INDEX .............................................................................................................................................. 297

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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 Mycobacterium tuberculosis 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 Mycobacterium tuberculosis, 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 Mycobacterium tuberculosis, 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 Mycobacterium tuberculosis. Abundant guidance is given on how to obtain free-ofcharge 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 Mycobacterium tuberculosis, 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 Mycobacterium tuberculosis. 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 MYCOBACTERIUM TUBERCULOSIS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on Mycobacterium tuberculosis.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and Mycobacterium tuberculosis, 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 “Mycobacterium tuberculosis” (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: •

Risk and Prevention of Transmission of Infectious Diseases in Dentistry Source: Quintessence International. 33(5): 376-382. May 2002. 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. Summary: Health care providers are at risk for infection with bloodborne pathogens, including hepatitis B virus, human immunodeficiency virus (HIV), and hepatitis C virus. This article reviews the risk and prevention of transmission of infectious diseases in dentistry. Recommended infection control practices are applicable to all settings in

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Mycobacterium Tuberculosis

which dental treatment is provided. Dentists remain at low risk for occupationally acquired HIV. Dental health care workers, through occupational exposure, may have a 10 times greater risk of becoming a chronic hepatitis B carrier than the average citizen. Tuberculosis is caused by Mycobacterium tuberculosis. In general, persons suspected of having pulmonary or laryngeal tuberculosis should be considered infectious if they are coughing, are undergoing cough-inducing or aerosol-generating procedures, or have sputum smears positive for acid-fast bacilli. Although the possibility of transmission of bloodborne infections from dental health care workers to patients is considered to be small, precise risks have not been quantified by carefully designed epidemiologic studies. Emphasis should be placed on consistent adherence to recommended infection control strategies, including the use of protective barriers and appropriate methods of sterilization or disinfection. Each dental facility should develop a written protocol for instrument reprocessing, operatory cleanup, and management of injuries. Such efforts may lead to the development of safer and more effective medical devices, work practices, and personal protective equipment. 14 references. •

Human Immunodeficiency Virus Infection Among Homeless Men in a New York City Shelter Source: Archives of Internal Medicine; Vol. 150, no. 10. Contact: Saint Vincents Catholic Medical Centers of New York, Saint Vincents Hospital Manhattan, Comprehensive HIV Center, 153 W 11th St, New York, NY, 10011, (212) 6048321, http://www.svcmc.org/hiv/manhattan/staff.asp. Summary: This reprint of a journal article outlines the result of a study of Human immunodeficiency virus (HIV) infection among homeless men in a congregate shelter in New York, NY, associated with Mycobacterium tuberculosis infection, where seroprevalence is relatively high. It concludes that seropositivity for HIV correlated significantly with intravenous drug use and active tuberculosis. Most cases of active tuberculosis were among homeless men with Acquired immunodeficiency syndrome (AIDS) or AIDS-related complex; and significant CD4 lymphocyte depletion was associated with active tuberculosis. Compliance rates with return for HIV antibody test results, medications, and follow-up visits were 70 percent, suggesting a significant degree of knowledge, awareness, and personal concern regarding HIV infection among homeless men; yet 28 percent of homeless injecting drug users (IDU's) continue active drug injection, despite HIV infection. Cohabitation in overcrowded congregate dormitories creates a risk of airborne transmission of tuberculosis, which is a common reactivation infection in HIV-seropositive homeless men. Medically appropriate housing should be provided to such homeless persons, and expanded HIV antibody testing, counseling, and medical services on-site should be offered to residents of shelters.

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Renal Tuberculosis Presenting as a Large Perinephric Mass Source: Infections in Urology. 10(6): 171-172, 175. November-December 1997. Contact: Available from SCP Communications, Inc. 134 West 29th Street, New York, NY 10001-5399. (212) 631-1600. Fax (212) 629-3760. Website: http://www.scp.com. Summary: Tuberculosis (TB) infections most commonly affect the respiratory and genitourinary systems. In industrialized countries, between 8 and 10 percent of patients with pulmonary TB develop renal (kidney) TB, and 15 to 20 percent of the population in developing countries have Mycobacterium tuberculosis cultured from the urine. This article reports a case of a patient who exhibited an unusual case of renal TB presenting as a perinephric mass. A 56 year old man with a 3 year history of untreated

Studies

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hypertension presented with a 2 week history of low grade fever, 10 pound weight loss, and acute onset of right hemiparesis (muscular weakness on one side of the body). The patient had no history of TB or urinary symptoms. Muscle strength in the right arm and right leg were diminished. A 15 by 20 cm, well defined, round, nontender, mobile mass was found in the left upper quadrant and flank. Other findings on abdominal and chest exam were normal. Urinalysis revealed many white blood cells per high power field, but no bacteria. Intravenous pyelogram was performed: the upper and mid poles of the left kidney were absent on nephrogram, and delayed excretion of contrast from the lower pole was observed. The right kidney was normal. The patient underwent an uncomplicated left radical nephrectomy for suspected liposarcoma. The gross pathology revealed a hard, fibrotic mass measuring 24 by 18 by 12 cm, filled with yellow purulent material surrounding a dilated collecting system and a 2 cm calculus. The renal tissue culture grew M. tuberculosis. The patient did well postoperatively and was discharged on the fourth day after the operation. In this patient, computed tomography (CT scan) provided the first clue to the diagnosis by suggesting the inflammatory nature of the renal mass; the diagnosis was confirmed by culture. 2 figures. 12 references. •

Tuberculosis and the Kidney Source: JASN. Journal of the American Society of Nephrology. 12(6): 1307-1314. June 2001. Contact: Available from Lippincott Williams and Wilkins. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-6423. Website: www.jasn.org. Summary: Tuberculosis of the kidney and urinary tract is, like other forms of the disease, caused by members of the Mycobacterium tuberculosis complex. This article reviews the clinical features of classical renal (kidney) tuberculosis, tuberculous interstitial nephritis, tuberculosis and glomerular disease, end stage renal disease (ESRD) caused by tuberculosis, tuberculosis developing in patients on hemodialysis and peritoneal dialysis, tuberculosis in transplant patients, genital tuberculosis, and hypercalcemia in dialysis patients. The authors also discuss laboratory diagnosis, pathology, the role of immunodeficiency in genitourinary tuberculosis, and treatment options. In developed nations, tuberculosis is relatively uncommon, but the risk of acquiring the disease is increased in immunosuppressed individuals, including patients on dialysis and recipients of kidney transplants. The signs and symptoms of renal tuberculosis mimic those of other infections of the kidney, so diagnostic awareness may prevent unnecessary morbidity (illness or complications). Tuberculosis may involve the kidney as part of generalized infection throughout the body or as localized genitourinary disease. The morphology (shape and appearance) of the lesions depends on the site of infection, the virulence of the organism, and the immune status of the patient. Modern short course antituberculosis drug regimens are effective in all forms of tuberculosis. However, special considerations apply to the treatment of tuberculosis in patients with impaired renal (kidney) function, as some drugs may not be metabolized properly. Surgical intervention is indicated in cases of advanced unilateral (involving one kidney) disease complicated by pain or hemorrhage and for bladder augmentation. 5 figures. 49 references.

Federally Funded Research on Mycobacterium Tuberculosis The U.S. Government supports a variety of research studies relating to Mycobacterium tuberculosis. These studies are tracked by the Office of Extramural Research at the National

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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 Mycobacterium tuberculosis. 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 Mycobacterium tuberculosis. The following is typical of the type of information found when searching the CRISP database for Mycobacterium tuberculosis: •

Project Title: A NOVEL MECHANISM OF INNATE IMMUNITY AGAINST TB Principal Investigator & Institution: Remold, Heinz G.; Associate Professor; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: Tuberculosis (TB) persists as a global health concern due to high prevalence of infection and drug resistance. More detailed knowledge of TB pathogenesis is needed to unravel novel approaches for prevention and treatment. Early antimicrobial mechanisms which are part of the innate immune response system are crucial for the outcome of the infection with Mycobacterium tuberculosis (Mtb). In this application we investigate a novel mechanism, how human macrophages (Mphi), the primary host cell of Mtb, inhibit growth of Mtb when they undergo apoptosis. Our preliminary data show that apoptosis of the Mphi infected with Mtb is associated with their capacity to exhibit strong antimycobacterial activity, whereas necrosis promotes extracellular bacterial growth. We further showed that virulent Mtb are able to avoid host Mphi apoptosis, whereas the attenuated Mtb strain H37Ra strongly induces apoptosis. We postulate that Mphi- apoptosis 1) restricts Mtb growth by sequestering the bacilli within apoptotic bodies and 2) packages Mtb for rapid and efficient elimination by freshly recruited phagocytes. Uptake of free Mtb is also associated with arrested phagosome maturation and unrestricted intracellular growth. We think that Mtb packaged in apoptotic bodies are eliminated more effectively by the defense systems of the Mphi. We will examine possible cooperative effector systems when uninfected Mphi are presented with Mtb contained in apoptotic bodies. We have also found that Mtb-induced Mphi apoptosis and associated anti-mycobacterial activity are dependent on the concerted action of tumor necrosis factor alpha, cytosolic phospholipase A2, and on intra-cellular Ca++ levels, but the specific role and function of these mechanisms is not understood. We will investigate the role of these mechanisms in induction of apoptosis and antimycobacterial activity and how attenuated and virulent Mtb differ in the activation of these processes. The goals, thus, are to 1) determine how a virulent Mtb induce apoptosis and antimycobacterial mechanisms and how virulent Mtb avoid it, 2) to find out how apoptotic Mphi block growth of Mtb and 3) to define the anti-mycobacterial mechanisms of naive Mphi after uptake of apoptotic infected Mphi. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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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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Project Title: ALTERED M. TUBERCULOSIS MANNOSYLATION AND THE MACROPHAGE Principal Investigator & Institution: Schlesinger, Larry S.; Professor of Medicine; Internal Medicine; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-OCT-2002 Summary: (provided by applicant): Tuberculosis continues to cause tremendous morbidity and mortality throughout the world's population. Critical in establishment of a M. tuberculosis (M.tb) infection within its human host are entry and survival in the macrophage. The macrophage mannose receptor (MR) participates in the phagocytosis of virulent strains of M.tb. Components of the M.tb cell wall serve as ligands for host cell receptors and can modulate host microbicidal and inflammatory responses. The M.tb cell envelope is heavily mannosylated containing lipoglycans such as lipoarabinomannan (LAM) which serves as a ligand for the MR. We hypothesize that the nature of surface mannosylation of M.tb has a major impact on the ability of M.tb to interact with the MR as well as to modulate macrophage function and consequently host responses, enabling the establishment of infection. PimB was recently described as M.tb phosphatidyl myo-inositol monomannoside transferase (pimB). We have used allelicexchange to inactivate pimB in M.tb strain Erdman. Macrophages display marked cellular adhesion following infection with wild-type M.tb. In contrast, macrophages infected with the pimB mutant display minimal cellular adhesion and a significant increase in the rate of macrophage death. We have developed an assay in which Salmonella mannose-specific binding pili agglutinate M.tb LAM coated microspheres that we will develop as a screen for alterations in M.tb surface mannosylation. We propose to further characterize the role of pimB and other selected enzymes potentially involved in mannosylation of M.tb surface molecules in the biology of the M.tb-host interaction, to develop a novel screening strategy for M.tb clones altered in surface mannosylation, and to evaluate these bacterial clones for anomalous host cell interaction. Our specific aims are to: 1A. Determine the mechanism for reduced homotypic adhesion and increased rate of macrophage death following infection with the pimB mutant of M.tb: 1 B. Determine the biochemical nature of the pimB mutation. Analyze the structure of LAM and other mannosylated cell wall glycoconjugates from wild type, the pimB mutant, and pimB overproducing M.tb strains. 2. Perform transcription and genetic studies of genes encoding the biosynthetic enzymes of LAM and mannose glycoconjugates: 2A. Quantify the level of transcription of pimB and its homologues in M.tb grown in broth, solid medium and within human macrophages using the AbI 7700 (TaqMan) "real-time" quantitative PCR system; 2B. Construct and analyze genetically defined M.tb strains with alterations in the mannose biosynthetic genes. 3). Utilize Salmonella mannose-binding (type 1) pili to screen for M.tb mutants and clones respectively altered in surface mannosylation from an M.tb transposon library and M. smegmatis library complemented with M.tb genes to characterize the effect of alterations in bacterial mannosylation on macrophage interaction. The assembled investigators will combine techniques in genetics, biochemistry, and cell biology to accomplish the goals of this proposal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ALTERNATIVE RESPIRATORY CHAINS OF M. TUBERCULOSIS Principal Investigator & Institution: Schnappinger, Dirk; Microbiology Immunology; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2008

and

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Summary: (provided by applicant): About a third of the world's population is infected with Mycobacterium tuberculosis (MTB). In a stand off that may last decades during the period of clinical latency, a population of MTB persists in a state of apparent bacteriostasis until the host's ability to restrict growth of the pathogen is reduced by declining cell-mediated immunity. Then bacterial replication can resume and reactivation of latent foci leads to clinical disease in about 10% of the immunecompetent individuals infected with MTB. Drug therapy of active TB takes 6 to 9 months. Premature termination of therapy decreases its success rate and leads to the development and spread of drug resistant and multi-drug resistant MTB. Drugs for treating active TB are relatively ineffective against MTB in the latent phase of the infection and against non-replicating MTB. New drugs that are active against nonreplicating MTB might shorten drug therapy of active TB and also allow the treatment of latently infected individuals that are at high risk to develop active TB. Respiration is fundamental for growth of most bacterial species and also for survival during bacteriostasis. Respiratory chains that occur in MTB but not in humans might be suitable targets for the development of novel anti-mycobacterial drugs that are active against persisting as well as growing bacteria. The goal of this project is to determine the importance of these (alternative) respiratory chains for MTB pathogenesis. We will determine how the energy metabolism of MTB adapts to environments encountered within the host with experiments that monitor the expression levels of genes encoding respiratory enzymes. Using transposon mutants we will test whether alternative respiratory chains are important for pathogenesis of MTB in mice. We will also investigate whether respiratory chains with a low bioenergetic efficiency are important for the pathogen's ability to metabolize highly reduced carbon sources like fatty acids and whether anaerobic respiration is essential for MTB to survive hypoxia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ARYL MYCOBACTERIU

BRANCHED

CHAIN

ACYL

COA

ESTERS

INHIBIT

Principal Investigator & Institution: Silverstein, Samuel C.; John C Dalton Professor and Chairman; Physiology/Cellualr Biophysics; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: All current antibiotics, with the exception of isoniazid (INH) and ethionamide, inhibit bacterial growth by inhibiting bacterial RNA, DNA, protein or cell wall synthesis. While bacteria and mammalian cells synthesize lipids via pathways that are similar in principle, the enzymes that catalyze bacterial lipid synthesis differ in fundamental respects from their mammalian counterparts. Bacteria, especially M. tuberculosis (M.tb.), contain unique lipids not found in mammalian cells. We have discovered that the lypolipidemic drug gemfibrozil (GFZ), which has been used safely in humans for >20 years, blocks growth of 27 different pan-drug sensitive and multidrug resistant strains of M tb. as well as 10 other species of bacteria. GFZ exerts a bactericidal effect on L. pneumophila, both in bacterial growth medium and in macrophages. Thus metabolites found in mammalian cells do not block GFZ's inhibitory effect on L. pneumophila. We have screened >10(12) L. pneumophila colonies but have found no GFZ-resistant mutants. This suggests that GFZ acts on highly conserved, hard to mutate enzyme(s). The 3- and 6-propylene analog of GFZ are 5- fold more potent than GFZ in blocking 14C-acetate incorporation into L. pneumophila lipids. Other fibric acids such as clofibrate and bezafibrate, are ineffective. We have identified an L. pneumophila enoyl reductase (Lpn FabX) that is GFZ's presumptive target, purified the enzyme and

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showed it is competitively inhibited by GFZ's CoA adduct (GFZ-CoA), but not by GFZ. GFZ-CoA also competitively inhibits InhA, the M.tb. enoyl reductase that is a target of INH. L. pneumophila converts 3H-GFZ to 3H- GFZ-CoA in vivo. GFZ-CoA is the first competitive inhibitor of a bacterial enoyl reductase to be identified. Funds are requested to explore the mechanisms by which GFZ inhibits M.tb growth, and to test the effects of GFZ and of its 3- and 6-propylene analogs, alone and in combination with other antituberculosis drugs, on M.tb growth in macrophages and in mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOSYNTHESIS OF THE MYCOBACTERIAL PEPTIDOGLYCAN Principal Investigator & Institution: Pavelka, Martin S.; Assistant Professor; Microbiology and Immunology; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-MAY-2005 Summary: (Adapted from the Applicant's Abstract): Tuberculosis is the leading cause of death in adults due to an infectious organism. By the end of this century there may be as many as 90 million new cases of tuberculosis resulting in up to 30 million deaths. The failure of antimicrobial therapy and the dangerous association between tuberculosis and AIDS have brought renewed interest in studying M. tuberculosis, the organism responsible for this disease. A better understanding of the basic biology of the organism and the development of new anti-mycobacterial drugs are important goals of mycobacterial research. The cell envelope is an outstanding characteristic if the mycobacteria, consisting of a variety of polysaccharides such as arabinogalactan, lipoarabinomannan, and peptidoglycan, along with several different types of lipids including various glycolipids and the mycolic acids. The peptidoglycan layer of the cell envelope serves as the anchor for the principal components of the cell envelope and provides shape and structural integrity to the cell. The long-term goal of this proposal is a deeper understanding of the biosynthesis and assembly of the mycobacterial cell envelope. The specific goal of this proposal is to understand more about the genetics and biosynthesis of the peptidoglycan layer of the envelope. The specific aims of this proposal are: 1) Determining the significance of N-glycolylation of the mycobacterial peptidoglycan. 2) Investigating the architecture of the peptidoglycan and the role it plays in the organization of the cell envelope. 3) Using beta-lactam antibiotics as tools to probe mycobacterial peptidoglycan biosynthesis. For the aims of this proposal, the Pi will study M. tuberculosis and M. smegmatis as a model organism using the techniques of classical bacterial genetics, molecular biology and biochemistry. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: ACTIVATION

CATALASE-PEROXIDASE

CATALYSIS

IN

ANTIBIOTIC

Principal Investigator & Institution: Magliozzo, Richard S.; Chemistry; Brooklyn College 2900 Bedford Ave New York, Ny 11210 Timing: Fiscal Year 2002; Project Start 15-JUN-1998; Project End 31-MAY-2004 Summary: (adapted from applicant's abstract) The major role of the propose research is to explain the catalytic function of Mycobacterium Tuberculosis catalase-peroxidase, a heme-enzyme, in the activation of the antimycobacterial antibiotic, isoniazid (isonicotinic acid hydrazide). The specific aims include identification of the proximal ligand to heme iron in catalase-peroxidase, characterization of the spin state and coordination number of the heme iron in the resting enzyme, identification of

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hypervalent enzyme intermediates, and kinetic analysis of the reaction of these intermediates with isoniazid. Of special interest is the potential catalytic competence of oxy-ferrous catalase- peroxidase, and the potential for peroxynitrite to activate the enzyme. The role of selected amino acid residues in the catalytic mechanism an in isoniazid binding will be evaluated through examination of the properties of two mutant catalase-peroxidase enzymes identified from clinically isolated, isoniazid resistant M. tuberculosis strains. Inhibition of another M. tuberculosis enzyme, a fatty acyl enoyl reductase (the inhA protein) thought to be a target of drug action, by isoniazid activated catalase-peroxidase, will also be investigated. Other aims address the Mn(II)-peroxidase activity of catalase-peroxidase considered important because Mn(III) is an efficient single electron oxidant of isoniazid. The techniques of optical stoppedflow spectroscopy, resonance Raman, and electron paramagnetic resonance spectroscopies will be applied in the experimental protocols. The results of the proposed studies will advance a detailed understanding of the action of a first line antibiotic in current use to treat tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNITY

CATHEPSINS

IN

ANTIGEN

PRESENTATION

AND

LUNG

Principal Investigator & Institution: Riese, Richard J.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): The immune response within the lung is critically dependent on antigen presentation by the major histocompatibility complex (MHC) class II and CD1 molecules. These antigen presentation pathways are critical effector mechanisms in asthma and host defense against infection. Endosomal cysteine proteases, including cathepsin S, play important roles in trafficking of both MHC class II and CD1d. Antigen presenting cells (APC) devoid of cathepsin activity do not degrade class II-associated invariant chain (Ii) resulting in accumulation of endosomal class II-Ii complexes. Interestingly, APC from cathepsin S-deficient mice also exhibit abnormal endosomal trafficking of CD1ld molecules, resulting in defective selection of NK1.1+T cells. These data implicate an interaction between the MHC class II and CD1d antigen presentation pathways, and suggest that cysteine proteases regulate components of both innate and adaptive immunity. The central hypothesis of the proposed studies is that regulation of cathepsin activity, particularly cathepsins S, L, and F, will control MHC class II- and CD1-restricted antigen presentation, T cell activation, and lung inflammation. To study this hypothesis three specific aims are advanced. The first aim addresses the hypothesis that different cysteine proteases control Ii proteolysis and MHC class II function in different APC. This hypothesis will be tested by analyzing Ii processing and class II-dependent antigen presentation in cathepsin-deficient APC, derived from a variety of tissues including the lung. The second aim will focus on examining the molecular basis for class II-CD1d interactions in cathepsin-deficient APC. We will address whether there is a direct class II-CD1d molecular association, or whether these interactions are solely the result of a generalized endosomal trafficking defect. The third aim is based on the premise that alteration of cathepsin activity can modulate lung immunity via effects on class II and CD1d function. These studies will use a mouse model of asthma, based on ovalbumin-induced pulmonary inflammation (Th2-type), and a mouse model of Mycobacterium tuberculosis pulmonary infection (Th1-type). Together, these studies will probe the basic mechanisms by which cysteine

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proteases regulate immunity, and will determine whether inhibition of these enzymes can affect MHC class II- and CD1-dependent inflammatory responses within the lung. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CD1-TARGETED VACCINATION AGAINST TUBERCULOSIS Principal Investigator & Institution: Modlin, Robert L.; Professor; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JAN-2008 Summary: (provided by applicant): The long-range goal of this project is to develop and validate the CD1-based vaccine technology platform to immunize humans against microbial pathogens. This approach is based on the knowledge that several of the CD1 proteins have specific targeting sequences that direct their traffic into endosomal compartments, structures also critical for antigen presentation by MHC class II molecules to CD4+ T cells. We will determine whether this novel vaccine strategy can induce protective immunity against Mycobacterium tuberculosis, a worldwide killer, and now because of multi-drug resistant tuberculosis, a potential agent of a bioterrorist attack. We propose to determine the trafficking pattern of CD1 chimers in antigen presenting cells including monocytes and dendritic cells. The ability of CD1 targeting to be used in immunization in humans will be assessed by studying the immune response to an M. tuberculosis antigen ESAT-6. In addition, the ability of ESAT-6/CD1 fusion constructs to immunize human T cell responses in vitro will be investigated. To determine whether ESAT-6/CD1 chimers can induce protective immunity, ESAT6/CD1 fusion constructs will be used to immunize mice, which will be subsequently challenged with virulent M. tuberculosis. The studies proposed will help develop and test the efficacy of CD1-based DNA vaccines for the prevention of infectious disease, including those from natural pathogens and bioterrorist attacks. Specifically, it should be possible to develop a new approach to the prevention of tuberculosis, including multidrug resistant tuberculosis, in humans. Finally, the CD1-based vaccine technology should prove useful in the vaccination against microbial pathogens in which MHC class II-restricted presentation of antigen to CD4+ T cells is required for host defense. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CELL DIVISION IN MYCOBACTERIUM TUBERCULOSIS/FTSZ PROTEIN Principal Investigator & Institution: Rajagopalan, Malini; Associate Professor; Biochemistry; University of Texas Hlth Ctr at Tyler 11937 Us Highway 271 Tyler, Tx 75708 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-MAY-2005 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHEMOKINES IN HOST RESPONSE TO MYCOBACTERIAL INFECTION Principal Investigator & Institution: Saukkonen, Jussi J.; Medicine; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-JUL-2004 Summary: (Adapted from the Applicant's Abstract): The recruitment of circulating mononuclear cells is crucial to the immune response to Mycobacterium tuberculosis

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(MTB) infection in vivo. It has been shown that both alpha and beta chemokines (CK) are induced by the infection of alveolar macrophages (AM). The predominant beta-CK induced by MTB infection of AM are MIP-1alpha, MIP-1alpha beta and RANTES. Virulent MTB induces significantly less MIP-1alpha than does avirulent MTB, while induction of MIP-1beta and RANTES are comparable for both virulent and avirulent MTB. The hypothesis is therefore that beta CK's produced by AM in response to infection play a significant role in the host response by activating macrophages and recruiting T cells. The mechanism of induction and regulation of beta-CK by MTB will be examined specifically by identifying the receptors involved, the importance of phagocytosis and the presence of preformed CK. Preliminary data suggests that MTB membrane induces the release of preformed beta-CK and that secretion is dependent on TNF. The functional impact of the released beta-CK on macrophages and T cells will be assessed, in particular the effect on MTB binding and uptake of MTB, and the effect on the nature of the T cell response. Further preliminary data show that MTB infection does not alter CK receptor expression on AM but reduces expression on monocytes. In addition beta-CK enhance phagocytosis of MTB and inhibit growth of MTB in macrophages. Mechanisms for these phenomenons will be determined. The role of these multi-functional molecules in protective immunity to TB will be identified. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONTROL OF BACTERIAL TOXINS BY VIRUSES AND PLASMIDS Principal Investigator & Institution: Holmes, Randall K.; Professor and Chair; Microbiology; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 30-SEP-1976; Project End 31-MAR-2005 Summary: (Adapted from the Applicant's Abstract): The long term goals of this project are to determine molecular mechanisms for virulence regulation in pathogenic bacteria and to develop new methods to treat bacterial infections. The investigators will study Corynebacterium diphtheriae, a paradigm for toxin-mediated bacterial infections, and Mycobacterium tuberculosis, a prototype for intracellular bacterial infections. These very different bacterial pathogens produce closely related, iron-activated, global regulatory proteins that govern virulence: the diphtheria toxin repressor (DtxR) and the iron-dependent regulator (IdeR), respectively. The investigators will determine the molecular basis for function of DtxR, IdeR and the homologous regulator SirR from Staphylococcus epidermidis. The investigators will use structure-based design to develop new antimicrobial drugs called "super-activators" that will target DtxR, IdeR or their homologs; activate them by iron-independent mechanisms; and inhibit production of virulence factors that are negatively regulated by iron- and DtxR-related repressors. The development of IdeR as a novel target for antimicrobial therapy could address the urgent global need for improved treatment of tuberculosis. The investigators will characterize the genes and gene products that are iron-regulated and under control of DtxR and IdeR, both to provide new insights into the pathogenesis of diphtheria and tuberculosis and for development of additional classes of antimicrobial agents. Specific Aim I will analyze structure and function of DtxR, IdeR and SirR. The investigators will investigate the molecular basis for repressor-operator interactions, for iron-independent super-repressor activity, and for domain function in biological activity of these regulatory proteins. Specific Aim 2 will characterize the DtxR and IdeR regulons in C. diphtheriae and M. tuberculosis. The investigators will develop an allelic exchange system for C. diphtheriae, characterize the DtxR and IdeR regulons by proteomic and molecular genetic methods, assess physiological functions of DtxR and IdeR domain 3,

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and investigate atypical phenotypes among clinical isolates of C. diphtheriae. Specific Aim 3 will develop super-activators of DtxR and IdeR by structure-based design. The investigators will design combinatorial peptide libraries, test them for super-activator function, identify individual peptides with activity, determine the structural basis for that activity, and develop better super-activators by iterative application of these methods. The investigators will also use molecular genetic methods to identify novel mechanisms for super-repressor activity and new lead compounds for development as tools against these bacterial infections. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COVALENT FLAVIN COENZYME IN FLAVOENZYME CATALYSIS Principal Investigator & Institution: Edmondson, Dale E.; Professor; Biochemistry; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-JUL-1982; Project End 31-MAR-2006 Summary: Monoamine oxidases A and B (MAO A and B) are outer mitochondrial membrane-bound enzymes that function in the degradation of neurotransmitters such as serotonin, dopamine, and norepinephrine and have been pharmacologically important in the treatment of various pathological disorders such as depression, addition, and Parkinson's Disease. Each enzyme contains a covalent 8alpha-ScysteinylFAD as a functional coenzyme. This project seeks continued support to determine the structure of each enzyme by x-ray crystallography to investigate the detailed mechanisms of H+ abstraction in catalysis. To facilitate these studies, we have developed methods for high level expression of each enzyme in Pichia pastrois. The role of the covalent FAD in MAO B will be investigated by disrupting the site for covalent FAD attachment by mutagenesis, followed by expression and purification of the mutant enzyme and comparison of its kinetic properties with WT enzyme The role of the Cterminal hydrophobic domain in enzyme structure and function for MAO A and B will be investigated in preparing the truncated forms and comparison of the purified mutants with WT enzyme properties. Initial studies are proposed to investigat3e the substrate specificity, inhibitor sensitivity, and structural properties of an expressed amine oxidase from Mycobacterium tuberculosis. Results from these studies should provide insights into the structures and mechanisms of these flavoprotein amine oxidases and lead to the development of new, specific drugs for the treatment of neurodisorders and possibly tuberculosis infections. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DEFINED TUBERCULOSIS

NATIVE

ANTIGENS

AND

IMMUNITY

TO

Principal Investigator & Institution: Orme, Ian M.; Professor; Microbiol, Immunology & Path (Mip); Colorado State University-Fort Collins Fort Collins, Co 80523 Timing: Fiscal Year 2002; Project Start 01-MAR-1996; Project End 31-MAY-2007 Summary: (provided by applicant): The purpose of this request for competing continuation funding is to continue our work on dissecting and defining the fundamental nature of the host immune response in the lung after exposure of mice to a realistic low dose aerosol infection with Mycobacterium tuberculosis. While our past work has contributed significantly to the definition of the acquired response, it is now clear that early resistance in the lung to infection is regulated by potentially redundant layers of very poorly understood innate immune mechanisms in addition to the bettercharacterized TH1 protective response. In the next funding period we propose a series

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of experiments to define these early mechanisms more clearly using a variety of approaches including flow cytometry, high speed fluorescence-activated cell sorting, histology, and immunohistochemistry. In our first Aim we will continue to try to identify sources of IFN-gamma that appear very early during the course of the infection, concentrating on the role of NK/NKT cell subsets and their potential restriction by Class-Ib MHC encoded molecules. In a second Aim, we propose to continue studies that are constructed to define the basic requirements needed to adequately and efficiently focus lymphocytes into the infected lungs, using a combination of flow cytometric analysis and sorting followed by adoptive transfer of tagged specific T cell subsets and subsequent tracking. Finally, we propose a fresh look at the memory T cell response in tuberculosis, specifically concentrating on parameters such as longevity, turnover, and potential cell surface marker reversion, primarily defined by flow cytometry. The proposed work will draw upon the broad expertise of various members of the Mycobacteria Research Laboratories at Colorado State University, as well as several eminent consultants and advisers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEFINING MOXIFLOXACIN AS A FIRST-LINE TB DRUG Principal Investigator & Institution: Nuermberger, Eric L.; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2004; Project Start 01-JUN-2004; Project End 31-MAY-2009 Summary: (provided by applicant): Background: Tuberculosis (TB) is a leading cause of mortality worldwide. Efforts to control TB are hampered by the lengthy, cumbersome treatment regimens for active TB, latent TB infection (LTBI), and infection with multidrug-resistant TB (MDR-TB). The new antibiotic moxifloxacin (MXF) has potent activity against Mycobacterium tuberculosis (including MDR-TB) in vitro and in experimental murine models of TB, suggesting great potential to improve current therapy of TB. Objectives and Methods: The objectives of this K08 proposal are fourfold. Objective I is to use a murine model simulating active TB in humans to define the potential of MXF-containing regimens to shorten the duration of therapy needed to cure TB or to permit more intermittent drug administration. Mice will be treated for varying durations and dosing frequencies with combinations of first-line agents and MXF. Outcomes will include CFU counts and relapse rates after therapy. Regimens that effectively sterilize mouse lungs in < 4 months or are effective with once-weekly or more intermittent administration will be sought. Objective 2 is to improve upon a murine model of LTBI using strategies to increase TB-specific immunity and to employ it to develop new MXF-containing regimens for the treatment of LTBI, including LTBI with MDR-TB. Mice vaccinated with M. bovis BCG or another vaccine will be infected with a low dose of M. tuberculosis. After immune control of infection, treatment with daily and intermittent regimens containing MXF and other first-line or experimental agents will be given. Test regimens will be compared to standard regimens for LTBI for their ability to sterilize mouse lungs. Objective 3 is to utilize an in vitro pharmacodynamic (PD) system to determine basic PD parameters for first-line anti-TB agents and MXF that correlate with bactericidal activity, post-antibiotic effects and selection of drug-resistant mutants. Actively growing M. tuberculosis will be exposed to MXF and first-line anti-TB drugs using a flow-controlled methodology that can simulate human pharmacokinetics or give fractionated doses. Outcomes will include change in CFU counts, delay in re-growth after drug exposure and prevention of resistant mutant selection. Relevance: Results of these studies will help to define optimal treatment regimens for TB that can be used to design new clinical trials or, in some cases, directly applied to clinical practice.

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

Project Title: AGENTS

DESIGN/SYNTHESES/STUDIES/NOVEL

ANTITUBERCULOSIS

Principal Investigator & Institution: Miller, Marvin J.; George & Winifred Clark Chair Professor; Chemistry and Biochemistry; University of Notre Dame 511 Main Bldg Notre Dame, in 46556 Timing: Fiscal Year 2004; Project Start 15-FEB-2004; Project End 31-JAN-2008 Summary: (provided by applicant): Design, syntheses and studies of novel antituberculosis agents based on biologically essential mycobacterial iron sequestration processes are proposed. Assimilation of iron is essential for most living organisms. Thus, microbes, including Mycobacterium tuberculosis, have evolved very selective and specific methods to sequester physiologically essential iron. The general hypothesis of this proposal is that the iron sequestration process utilized by Mycobacterium tuberculosis can be exploited as an "Achilles' heel" for the development of novel antituberculosis agents. Though this concept has been considered, no laboratory has previously been able to synthetically access the relevant compounds for related studies. The specific aims are the following. 1. Design, syntheses and studies of focused sets of analogs of natural iron chelators (mycobactins) used by M. tuberculosis to determine if analogs can inhibit iron acquisition, thus, inducing microbe selective iron starvation and microbe death (confirmation of "Snow's Hypothesis"). The analog design will build on our preliminary findings that selective structural variation of mycobactins does produce novel antiTB agents. Thus, practical scale syntheses of lead compounds will be followed by focused structural modification. The synthetic work will be complemented by full chemical and physical characterization of samples, including determination of the iron binding affinity of the mycobactin analogs and conjugates as well as their ability to bind iron from media. 2. Syntheses and studies of a focused and limited set of mycobactin (siderophore)- antibiotic conjugates capable of selective microbe cell transport and drug delivery. All conjugates can be prepared in straightforward fashion (one to three steps) from our already synthesized lead compounds. 3. In Vitro and in vivo biological evaluation of samples for antituberculosis activity, growth inhibition or promotion of other selected mycobacteria and related studies, including gross toxicity, will be performed to determine the mode of action of new compounds with anti-TB activity. Taken together, these studies will determine the feasibility of developing new antituberculosis agents with a novel mode of action related to the required iron uptake processes needed by mycobacteria, including M. tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEVELOPMENT AND TESTING OF NEW TUBERCULOSIS VACCINES Principal Investigator & Institution: Horwitz, Marcus A.; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-APR-1991; Project End 31-MAY-2005 Summary: (Adapted from Applicant's Abstract) Mycobacterium tuberculosis, the primary agent of tuberculosis, infects one-third of the world's population and kills 3 million people annually, making it the world's leading cause of death from a single infectious agent. It is a leading cause of disease and death in AIDS patients, particularly in the developing nations of the world. The rapid global emergence of strains resistant to the major antibiotics used to treat tuberculosis poses a serious threat to public health.

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The highest priority in the fight against tuberculosis is the development of a vaccine that is more efficacious than the current vaccine - BCG. A vaccine more potent than BCG would have an impact on human health greater than virtually any other conceivable development in the fight against infectious diseases. Studies from this laboratory completed under the current grant established the importance of major extracellular proteins of M. tuberculosis in inducing both cell-mediated and protective immunity in the guinea pig model of pulmonary tuberculosis, a highly susceptible species that develops disease remarkably similar to human tuberculosis. Studies under the current grant also succeeded in developing technology for high level expression and secretion in native form of major M. tuberculosis extracellular proteins in a nonpathogenic rapidly growing heterologous host, allowing isolation and purification of 100 mg quantities of recombinant M. tuberculosis extracellular proteins for vaccine studies. In this grant application, we seek to build on the knowledge and experience gained in previous studies to develop a vaccine more potent than BCG in the highly relevant guinea pig model. We seek to develop and test live recombinant vaccines including recombinant BCG expressing major M. tuberculosis extracellular and cell-associated proteins and new non-live particulate vaccines formulated as liposomes and microspheres. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DISSEMINATED TUBERCULOSIS IN HIV INFECTION Principal Investigator & Institution: Von Reyn, C Fordham.; Medicine; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2005 Summary: Disseminated infection (mycobacteremia) with Mycobacterium tuberculosis (dMTB) has been documented by our group in 10-25 percent of patients with HIV infection in Africa using lysis- centrifugation blood cultures. Unlike pulmonary tuberculosis (pMTB), most cases of dMTB are not recognized and death ensues rapidly. Thus, in developing countries dMTB may be a more important cause of HIV-associated mortality than pMTB. Risk factors for dMTB have not been identified and it is not known if most cases are due to primary infection, reactivation or reinfection. We hypothesize that most cases of dMTB are due to primary MTB infection in patients without prior infection with MTB or non-tuberculous mycobacteria (NTM). Mycobacterial immunization in early HIV infection is a potential strategy to prevent dMTB. Mycobacterium vaccae (MV) is an investigational vaccine prepared by heat inactivation of an NTM, and has been shown to be protective against MTB in several animal models. Studies conducted by our group indicate that a 5-dose series of MV is safe in patients with HIV infection and induces a durable cellular immune response to MTB antigens in persons with prior BCG immunization. Our hypothesis is that MV immunization will reduce the risk of HIV-associated dMTB by 50 percent. Our specific aims are: (1) to define risk factors for HIV-associated disseminated tuberculosis and to assess the relative contributions of primary infection, reactivation and re-infection in the pathogenesis of disseminated tuberculosis, and (2) to assess the safety and efficacy of a 5-dose schedule of inactivated MV vaccine for the prevention of HIV-associated pulmonary and disseminated tuberculosis in persons with prior BCG immunization. 2274 HIV-positive patients with prior BCG immunization and 100 HIV-negative controls will be entered in a 5-year study in Zambia. Baseline evaluation will include history, chest x-ray, dual skin tests with purified protein derivative (PPD) and Mycobacterium avium sensitin (MAS), and whole blood assay for interferon-gamma production in response to MV sonicate, PPD, ESAT-6 (a protein antigen unique to MTB) and MTB antigen 85. Subjects with PPD reactions greater than or equal to 5 mm will receive 6

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months of prophylaxis with isoniazid. All subjects will be randomized 1:1 to receive a 5dose series of MV or placebo over 12 months with repeat skin test and in vitro studies at 14 months. Subjects will be followed every 3 months for 3-5 years to assess new pMTB (microbiologic or clinical diagnosis) or dMTB (microbiologic diagnosis). All isolates will have susceptibility tests and IS6110 DNA fingerprinting performed. Potential risk factors for dMTB, including baseline PPD test results, will be assessed in placebo and vaccine groups. Vaccine efficacy against dMTB and pMTB in HIV-positive subjects will be determined, and post immunization interferon gamma responses used to identify a surrogate marker of efficacy. The proposed study has important implications for the reduction in mortality from HIV-associated tuberculosis and for design of future trials of new vaccines against tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ETHANOL-FED, CPG-TREATED MICE: LISTERIA SUSCEPTIBILITY Principal Investigator & Institution: Ray, Nancy B.; Biochemistry; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2006 Summary: (provided by applicant): Chronic ethanol consumption causes immunosuppression, particularly related to Th1 cytokine expression, and causes increased susceptibility to infection including infection with the intracellular bacterial human pathogen, Listeria monocytogenes. CpG DNA induces innate Thl-like responses and reduced susceptibility to Listeria monocytogenes detected by decreased replication of L. monocytogenes in murine spleens and livers. CpG immunostimulatory DNA will be used to stimulate innate systemic and mucosal immune responses in ethanol- fed and water-fed control mice. Induction of cytokine expression in vitro and in vivo in spleen and Peyer's patch cells from CpG-treated, ethanol-fed and water-fed control mice will be detected by enzyme-linked immunosorbant assay (ELISA), and specific Thl cytokine expressing cells will be identified by magnetic cell sorting (MACS) and intracellular cytokine staining. CpG DNA treatment and immunostimulation will be used to overcome ethanol-induced immunosuppression, which will be detected by reduced replication of L. monocytogenes in spleens and livers by a colony forming (CFU) assay. Various routes and doses of CpG treatment and challenge with L. monocytogenes including intraperitoneal (IP), intravenous (IV), and oral will be used to elicit both systemic and mucosal immunity and to determine the limits of protection induced by CpG DNA. Reduced replication of L. monocytogenes will be correlated with cytokine expression detected by ELISA and the mechanism of CpG-induced reduction in replication will be determined by identifying by flow cytometry and intracellular cytokine staining whether specific cells may be suppressed or depleted by chronic ethanol consumption and stimulated by CpG treatment. Because defects in killing Mycobacterium avium, an intracellular bacteria similar to L. monocytogenes and to the organism that causes tuberculosis, have been demonstrated for macrophages following exposure to alcohol, intracellular killing of L. monocytogenes by peritoneal macrophages will be examined to determine whether ethanol-fed mice are deficient in killing L. monocytogenes and whether CpG DNA stimulation may enhance killing. These studies could lead to treatments for protecting alcoholic patients from intracellular bacterial infections such as those caused by L. monocytogenes or Mycobacterium tuberculosis (TB). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ETIOLOGIC ANTIGENS IN SARCOIDOSIS Principal Investigator & Institution: Moller, David R.; Associate Professor of Medicine; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that involves the lungs in over 90 percent of affected individuals and may cause endstage fibrosis, cor pulmonale, and death. The pathologic hallmark of sarcoidosis is noncaseating granulomatous inflammation. Since extracts of diseased tissue injected intradermally elicit a nidus of granulomatous inflammation in patients with sarcoidosis that is indistinguishable from spontaneously arising granulomas (the Kveim reaction), we postulate that sarcoid tissue extracts contain disease-relevant antigens. Biophysical properties of the active component in Kveim extracts include relative heat stability, resistance to neutral detergents and proteases, and a dependence on tertiary structure. The overall goal of this application is to identify these pathogenic tissue antigens in sarcoidosis. Our central hypothesis is that sarcoidosis is caused by linked T and B cell immune responses to aggregates of altered proteins of microbial origin. Consistent with this hypothesis, our preliminary studies demonstrate the presence of a small number of protease-resistant, neutral-detergent insoluble proteins that by immunoblot analysis are targets of T cell dependent IgG from patients with sarcoidosis but not healthy controls. MALDI-TOF mass spectrometry and immunoblot analysis has identified the mycobacterial catalase-peroxidase protein from Mycobacterium tuberculosis (mKatG) or M. smegmatis in these protein fractions from sarcoidosis but not control tissues. Preliminary studies demonstrate both T and B cell responses to mKatG proteins in sarcoidosis, suggesting the mKatG proteins are relevant, pathogenic antigens in sarcoidosis. To test the hypothesis that mycobacterial KatG proteins are pathogenic antigens in sarcoidosis, we propose studies to determine the presence of mycobacterial KatG proteins in sarcoidosis and control tissues using MALDI-TOF mass spectrometry and protein immunoblot analyses. To determine whether these microbial proteins induce disease-specific immune responses, we will determine the molecular basis of the B and T cell immune responses to both M. tuberculosis and M. smegmatis KatG proteins and selected peptides, and determine whether mKatG proteins preferentially expand specific Valpha/Vbeta expressing T cells in patients with sarcoidosis and control subjects. Together, these studies offer the potential of identifying a specific group of microbial antigens involved in the pathogenesis of granulomatous inflammation in sarcoidosis, thus providing a novel target for therapy of this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EXPRESSION OF TUBERCULOSIS IN THE LUNG Principal Investigator & Institution: Ellner, Jerrold J.; Professor and Chair, Umdnj-New Jersey Me; Medicine; Univ of Med/Dent Nj Newark Newark, Nj 07107 Timing: Fiscal Year 2002; Project Start 30-SEP-1993; Project End 31-JUL-2005 Summary: (Adapted from the Applicant's Abstract): Mycobacterium tuberculosis infects a third of the worlds' population and TB is the leading cause of morbidity and mortality due a single infectious agent. However, only 5-10% of M. tuberculosis-infected subjects without an underlying immunodeficiency develop disease during their lifetimes. Therefore protective immunity is induced in the majority of subjects. Understanding correlates of protection against M. tuberculosis in humans is needed to better direct efforts in the development of antituberculosis vaccines. The PI suggests that increased susceptibility to M. tuberculosis infection by patients with IFNgamma

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receptor I deficiency and successful therapeutic use of IFNgamma in refractory mycobacterial infections indicates the importance of IFNgamma in immunity against mycobacteria. However, during the previous funding period the PI found increased levels of IFNgamma in the lungs of patients with TB. Thus, the question is raised as to the effectiveness of IFNgamma and/or involvement of other factors in protective immunity. In the present competitive renewal application, the PI proposes to define pulmonary correlates of protective immunity by comparing several immunological parameters in TB patients, healthy household contacts of TB patients (tuberculin skin test positive), and community control subjects. Bronchoalveolar and blood mononuclear cells obtained from each study subject will be utilized to characterize antigen-specific cytokine induction, killing of M. tuberculosis, CTL activity against M. tuberculosisinfected targets and mediators involved in these effector functions (iNOS, granzyme, perforin, granulysin, FasL) (specific aim 1). According to the PI, this first part of the work should identify correlates of protective immunity as differences between protective immune responses (in skin-test-positive, healthy household contacts) and failed immune responses (patients with TB). Correlates of protection identified in aim #1 should then be used to assess induction of protective immunity and chemokine expression by vaccination of humans with BCG. Two strains of BCG having different efficacy and reactogenicity, and two routes of vaccine administration (oral and intracutaneous) will be compared (specific aim 2). The PI states that this proposal attempts to define new parameters of immunological protection in humans and to rationally assess the impact of BCG strain variation and the route of BCG administration on the induction of protective immunity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FOLK, A MYCOBACTERIUM TUBERCULOSIS DRUG TARGET Principal Investigator & Institution: Suling, William J.; Southern Research Institute Birmingham, Al 35205 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): The purpose of this pilot project is to investigate the enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (FolK, HPPK, EC 2.7.6.3) as a target for intervention in disease caused by Mycobacterium tuberculosis (MTB). Unlike vertebrate cells, which acquire folates exogenously through active transport, MTB and many other bacteria must synthesize folate de novo. HPPK is an enzyme present early in the metabolic pathway for the synthesis of reduced folates from GTP. The absence of HPPK in the host makes this enzyme an attractive target for chemotherapy. Depletion of reduced folates through inhibition of this pathway leads to inhibition of DNA, RNA and protein synthesis. Comprehensive studies of the folate pathway in mycobacteria are lacking but genes coding for enzymes in the pathway have been identified through the Sanger Centre MTB genome sequencing project. A DNA sequence in the MTB genome database has been annotated as a probable folK coding for HPPK. For this pilot study, we propose to establish that the gene listed as Rv3606c codes for HPPK. Our objectives are to clone and express Rv3606c in Escherichia coil, and prove that the protein is functionally HPPK. We will also assess the essentiality of the gene by construction of HPPK-deficient MTB strains. This will be done in MTB by allelic exchange mutagenesis and a counterselection method based upon a mycobacterial thermosensitive origin of replication and toxicity of the sacB gene to MTB in the presence of sucrose. The results of this pilot study will enable us to better understand the biochemistry of folate metabolism in MTB. It will also provide purified HPPK for

20


future drug discovery studies based upon structure-activity relationships, molecular modeling and crystallographic structure-based drug design. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTION OF CD8 T CELLS IN TUBERCULOSIS Principal Investigator & Institution: Flynn, Joanne L.; Associate Professor; Molecular Genetics & Biochem; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 30-SEP-1997; Project End 31-MAR-2007 Summary: (provided by the applicant): The immune response against Mycobacterium tuberculosis results in control, but not elimination, of infection. T cells are a crucial component of this response. This proposal extends our current work on examining the CD8 T cell subset and the effect of these cells in tuberculosis. It is clear that the naturally induced immune response is insufficient to resolve a M. tuberculosis infection. Understanding how the CD8 T cell response develops and is modulated over the course of infection may provide clues to augmenting this response to provide better control of infection. In this proposal, we will focus on following CD8 T cell responses to specific antigens, focusing on the function of the CD8 T cells at various times post-infection. Specifically, cytokine production and cytotoxic ability will be tested during acute, chronic, memory and reactivation states. Our hypothesis is that the CD8 T cell response and function wane during a chronic infection, and boosting this response would result in improved control of the infection. In addition, preliminary data indicates a role for CD4 T cells in maintaining CD8 CTL function, and the mechanisms responsible for this will be investigated. Our long term goal is to have a clear picture of the CD8 T cell response in tuberculosis, including antigen specificity, function, evolution, and maintenance. This information will impact directly on vaccine development, since it appears that stimulation of both CD4 and CD8 T cells will be necessary to provide adequate protection against tuberculosis. To this end, our specific aims are: Aim 1. To examine evolution in the antigen specific CD8 T cell responses during M. tuberculosis infection. Aim 2: To investigate the function of CD8 T cells in M. tuberculosis infection. Aim 3: To assess the development, maintenance and function of memory and recall CD8 T cell responses in tuberculosis. Aim 4: To determine the effects of CD4 T cells on CD8 T cell maintenance and function in tuberculosis. Animal models will be used in these studies, and we have adapted a variety of functional assays for CD8 T cells for use with lung cells. These complementary aims will provide a definitive picture of the CD8 T cell response in tuberculosis, and contribute to a greater understanding of the challenges facing vaccine development and design against this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FUNCTIONAL GENOMICS STUDY AND DATABASE FOR TUBERCULOSIS Principal Investigator & Institution: Fu, Li M.; Pacific Tuberculosis/Cancer Res Org Anaheim, Ca 92812 Timing: Fiscal Year 2004; Project Start 12-AUG-2004; Project End 31-JUL-2007 Summary: (provided by applicant): The functional genomics of Mycobacterium tuberculosis will be studied and a database will be constructed for both scientific and clinical applications. Representing a new endeavor in microbiology and genomics, this project is important at this time when multidrug-resistant tuberculosis is increasingly a public-health threat and scientists are seeking new drugs with novel mechanisms of

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action. In light of the tremendous impact of the microarray technology on genomics, the database will store the microarray gene expression data engendered under various designed experimental conditions as well as provides functional annotations of genes based on expression and regulation profiling. M. tuberculosis clinical isolates both drugsensitive and - resistant that meet experimental criteria will be obtained. A web-based SQL Server relational database will be developed to implement the functional genomics database, providing query and analysis capabilities via a web-based graphical interface. Each gene in the database will be annotated by its expression characteristics, coregulated genes and associated regulated pathways or networks, and its clinical significance, if appropriate. Furthermore, the database links each gene to major bioinformatics and genomics databases to produce an integrated retrieved report. All functional genomics data and analyses will be placed in the public domain. Working synergistically with other federally funded resource centers, the database is designed to allow other researchers to deposit microarray data, conduct data analysis, and obtain program code for making in-house systems. In this project, a set of differential and coordinated genome-wide gene expression studies will be performed to explore drug targets, drug resistance, and biology. Important anti-tubercular drugs and promising new drug candidates will be assessed using drug-challenged gene expression studies to induce drug-specific gene-expression patterns resulting from drug action. Cell biology will be investigated using synchronized M. tuberculosis culture based on in vitro induced non-replicating persistence so that cycle-dependent genes and pertinent regulatory mechanisms will be identified and gene expression accompanying metabolic reprogramming that occurs during shift from non-replicating to replicating states will be studied. These studies will uncover many co-regulated families of genes and allow the functions of uncharacterized genes to be deduced based on co-expression with genes of known function. Combining cluster analysis, search of cis-regulatory elements upstream of regulons, and use of transcription factor databases will unravel gene regulatory networks and enable inferences about biological pathways and discovery of novel drug targets. Important regulatory genes identified will be subjected to further analysis for confirming their regulatory roles using knockout strains. Partial drug resistance and bacterial persistence, which are two important clinical circumstances often encountered in tuberculosis, will be analyzed using functional-genomics studies. The potential value of the proposed methods has been demonstrated and advantages over previous technology been recognized. Research results will advance molecular biological knowledge and benefit public health management in tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE MACROPHAGES

EXPRESSION

OF

M.TUBERCULOSIS

WITHIN

Principal Investigator & Institution: Mcdonough, Kathleen A.; Research Scientist; Wadsworth Center Empire State Plaza Albany, Ny 12237 Timing: Fiscal Year 2002; Project Start 01-JUL-2000; Project End 31-MAY-2005 Summary: (Adapted from the Applicant's Abstract): The long term objective of this proposal is to gain a better understanding of how Mycobacterium tuberculosis establishes infection so that effective strategies can be developed to prevent it. A multidisciplinary approach will focus on the interaction of tubercle bacilli with macrophages at the molecular, genetic and cellular levels, with an emphasis on M. tuberculosis gene expression within macrophages. The specific aims are: 1) Identifying M. tuberculosis genes that are induced when bacteria are within macrophages by 2D gel electrophoresis coupled with mass spectrometry. 2) Identifying class-specific regulatory

22


motifs among intracellular induced promoters using a combination of molecular and computational techniques. 3) Characterizing the roles in the M. tuberculosismacrophage interaction of selected intracellular induced M. tuberculosis genes. Assays will include bacterial survival, replication and trafficking in macrophages. 4) Assessing the role of cAMP signaling in M. tuberculosis within macrophages by defining the distribution and expression among mycobacteria of genes encoding novel cyclase and cyclic NMP binding proteins; estimating the minimum number of cAMP-responsive proteins using 2D gels; and determining the effects of a novel adenylate cyclase gene knock-out on M. tuberculosis interaction with macrophages using tissue culture, microscopy, and 2D gel analyses. This work will contribute to our understanding of the factors needed for the establishment of tuberculosis infection and disease and will identify potential targets for tuberculosis vaccines, therapeutics, and diagnostic purposes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC DISSECTION OF MYCOBACTERIAL INFECTION Principal Investigator & Institution: Schurr, Erwin; Associate Professor; Mc Gill University James Admin. Bldg., Room 429 Montreal, Pq H3a 2T5 Timing: Fiscal Year 2002; Project Start 14-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) The objective of the studies proposed in this application is to identify genotypic combinations of mice and mycobacteria that result in significant alterations of host responses to experimental mycobacterial infection. Susceptibility or resistance to experimental infection will be defined by determination of median survival time, weight loss, mycobacterial load in the lung and spleen, and in addition various immunological parameters in lung and other tissues. In these experiments, the host genome will be varied by use of 37 recombinant congenic strains (RCS), which are derived from inbred progenitors that are either susceptible to tuberculosis (A/J, abbreviated A) or resistant to tuberculosis (C57BL/6J, abbreviated B). The AcB/BcA RCS are now fully inbred and genotyped with a dense set of genomewide microsatellite markers. These strains will be infected with a panel of Mycobacterium tuberculosis and M. bovis strains that have been deleted for genome regions associated with attenuation of BCG vaccines. The infection protocol in the RCS will reveal informative, significant deviations from the "expected" or "parental" disease phenotypes which signify the presence of quantitative trait loci (QTL) with strong effect on phenotype expression and possibly specific gene(s) interaction between the host and pathogen. In RCS carrying QTL with strong effect on phenotype expression, changes in gene expression level in both lung macrophages and intracellular mycobacteria will be revealed by microarray analysis. The knowledge to what extent host responses in mycobacterial infections are a reflection of specific host pathogen combinations will be crucial for our understanding of the epidemiological flow of M. tuberculosis through an exposed population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC MYCOBACTERIA

SCREENS

FOR

VIRULENCE

FACTORS

OF

Principal Investigator & Institution: Briken, Volker; Microbiology and Immunology; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2004

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Summary: (provided by applicant): Mycobacterium tuberculosis (M.tb) infects onethird of the world's population and claims the lives of two to three million people each year. Its success is achieved by its ability to persist in the hostile intracellular environment of infected macrophages. After invasion, M.tb manipulates the phagocytic pathway of the host cell to inhibit the maturation of the phagosome into a phagolysosome. In addition, M.tb inhibits the apoptotic response of infected macrophages. These effects are likely to represent a highly evolved strategy that is used by M.tb to evade the host immune response. Although some cellular proteins have been characterized as targets of M.tb, it is currently unclear which bacterial proteins or lipids mediate the interactions. The proposed research project aims at filling this gap in our knowledge by focusing on the identification of proteins or lipids of M.tb that are implicated in either inhibition of maturation of the bacterial phagosome or inhibition of the apoptotic response of the host cell. The recent advances in the genetic manipulations of mycobacteria will be used to randomly mutagenize green fluorescence protein (GFP)labeled M.tb and screen for mutants deficient in inhibiting phagosome maturation using a newly developed FACS-based, high- throughput assay. In a second approach, Mycobacterium smegmatis, a nonpathogenic mycobacterium deficient in inhibiting phagosome maturation and apoptosis of the host cell, will be complemented with M.tb genes and clones that have gained this capacity will be selected. Identification of M.tb genes essential for persistence of the pathogen will provide important targets for the development of new drugs for the treatment of tuberculosis and the development of new attenuated strains of M.tb that may be used as vaccines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC TUBERCULOSIS

STUDIES

OF

HUMAN

SUSCEPTIBILITY

TO

Principal Investigator & Institution: Scott, William K.; Associate Research Professor; Medicine; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 10-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) Tuberculosis (TB) is currently and historically an enormous public health problem. Approximately one-third of the world's population are currently infected with Mycobacterium tuberculosis (M. tuberculosis) and TB accounts for over 25% of preventable adult deaths world-wide. Despite the high infection rate, only about 10% of people infected with M.tb ever become sick with active TB. Evidence suggests that progression to active TB is influenced by host genetic factors. For example, the epidemiology of TB suggests that genetic selection takes place after introduction of M. tuberculosis to the population; genetically susceptible individuals succumb to the infection and relatively resistant individuals survive to reproduce. As well, twin studies demonstrate higher concordance rates for TB among identical twins, compared to fraternal twins. Mouse models of mycobacterial infection have identified several potential susceptibility loci, such as the gene named Nramp1, as well as several cytokine and cytokine receptor genes. Family-based linkage studies and case-control studies of candidate genes in humans suggest roles for these and other genes associated with development of TB in humans. In light of these observations, we propose a familybased association study of candidate genes for TB susceptibility. To accomplish the goal of identifying genes influencing susceptibility to TB we specifically propose to: 1) Ascertain 1,000 parent- child triads (500 Caucasian, 500 African-American) from North and South Carolina for genetic studies of TB susceptibility genes. 2) Test candidate genes in the first 500 parent-child triads. Multiple single nucleotide polymorphisms (SNPs) will be genotyped in each gene and analyzed using familybased tests of

24


association; significant results will be followed-up in the remaining 500 triads. 3) Examine the relationship between candidate genes and other clinical variables such as PPD skin test results, disease severity, treatment relapse and failure, and presence of extrapulmonary disease. 4) Evaluate gene-gene and gene-environment interactions using multivariable models and data reduction techniques such as the multifactor dimensionality reduction (MDR) method. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEAT SHOCK PROTEIN BASED VACCINE FOR TUBERCULOSIS Principal Investigator & Institution: Mo, Annie Xy.; Antigenics, Inc. 3 Forbes Rd Lexington, Ma 02421 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2005 Summary: (provided by applicant): Mycobacterium tuberculosis is a continuing health threat both in the United States and the rest of the world with an estimated two billion people currently infected worldwide. Antibiotic regimens requiring lengthy direct observation of patients and the emergence of drug resistant strains create a pressing need for novel therapies. One such novel therapy is the use of heat shock protein to adjuvant a tuberculosis peptide vaccine for optimal generation of cell-mediated immune response. Heat shock protein-peptide complexes are recognized by HSP receptors on antigen presenting cells. Peptides chaperoned by HSP are then re-presented by MHC Class I and II molecules leading to cell mediated immunity including stimulation of antigen-specific CD4+ and CD8+ T cells. Cell mediated immunity is an important major protective mechanism in tuberculosis. The ability of heat shock protein-peptide complexes to elicit T cell responses may address a shortcoming of traditional tuberculosis vaccines that primarily elicit antibody responses. The proposed product will consist of Mycobacterium tuberculosis antigens complexed in vitro to mammalian heat shock protein 70. Total cytosolic and culture filtrate fractions from M tuberculosis will be obtained and subjected to proteolysis with highly selective proteases to generate a large array of peptides containing T cell epitopes. Murine heat shock protein 70 will be complexed to the TB peptide extract and utilized as a vaccine. The product will be evaluated in mice for induction of cellular immune responses, assessed by antigenspecific cytotoxicity, cytokine response, and proliferation. The ultimate purpose of the research funded by this grant is to ascertain whether it will be possible to utilize the heat shock protein technology to generate a novel and efficacious therapeutic vaccine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HOST DEFENSE FUNCTIONS OF M. TUBERCULOSIS LIPOGLYCAN Principal Investigator & Institution: Chan, Edward D.; Associate Professor; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2002; Project Start 15-JUL-2001; Project End 31-MAY-2006 Summary: (Adapted from the Applicant's Abstract): Tuberculosis (TB) is the leading cause of death by an infectious agent. Macrophages play a pivotal role in the control of Mycobacterium tuberculosis through the expression of nitric oxide (NO.) and TNFalpha. NO plays an important mycobactericidal role in murine TB and is increasingly recognized to be important in humans. The overall hypothesis of this proposal is that macrophages, by specific surface receptor(s), recognize mycobacterial cell wall products to initiate iNOS- and TNFa-induction. Hence, the focus of this proposal is to: i) determine the receptor and signaling mechanisms which regulate iNOS and TNFa following exposure to the mycobacterial cell wall component

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lipoarabinomannan (ManLAM) and ii) to determine the significance of each of these components in an in vitro model of infection. Based on experiments showing that macrophages from the Toll-like receptor 4 (TLR4)-mutant C3H/HeJ mice produced significantly lower levels of NO than TLR4-intact C3H/HeN macrophages in response to IFNg + ManLAM, we hypothesize that ManLAM engages a TLR to induce iNOSNO*/ TNFa expression. Since non-mannose capped LAM (AraLAM) from M. smegmatis induced greater NO about expression than ManLAM, we hypothesize that ii) the exposed arabinose residues on ManLAM or AraLAM are the components of ManLAM that bind to its putative TLR. Since initial studies show that the mitogenactivated protein kinases (MAPKs) and NFkB signaling pathways regulate iNOS and TNFa expression, we hypothesize that the proximal kinase MAP/ERK kinase kinase (MEKK) is a pivotal regulator for ManLAM-induction of iNOS and TNFa. Lastly, because TLRs recognize pathogen-derived molecules and enhance host-defenses, we hypothesize that blocking one or more of the TLRs will enhance the growth of M. tuberculosis and inhibit NO* and TNFa expression. These hypotheses will be addressed by three specific aims: 1. To determine the ManLAM structures that mediate the induction of iNOS-NO*/TNFa and the receptor that mediates these ManLAM effects. 2. To investigate the role of the MAPK and NFkB signaling pathways in ManLAM- and other lipoglycan-induced iNOS-NO* and TNFa. 3. To elucidate the role of the TLRs, MAPK and NFkB signaling pathways, and ManLAM in controlling the growth of M. tuberculosis in mouse and human macrophages and to correlate effects on growth with NO* and TNFa expression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HOST DETERMINANTS OF INFECTIOUSNESS IN TUBERCULOSIS Principal Investigator & Institution: Fennelly, Kevin P.; Assistant Professor; Medicine; Univ of Med/Dent Nj Newark Newark, Nj 07107 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-MAY-2004 Summary: Both experimental and epidemiological data suggest that there is a wide range of infectiousness among patients with tuberculosis. Although much research has focused on the virulence of the organism, little is known of the host determinants of infectiousness. A novel Cough Aerosol Sampling System (CASS) can isolate and quantify (viable airborne Mycobacterium tuberculosis from individual patients with pulmonary tuberculosis. We hypothesize that the production of viable aerosols of M. tuberculosis determined by this method is correlated with infectiousness. Our central hypothesis is that most of the variability of infectiousness in tuberculosis is explained by non-immunological host factors including the duration of antimycobacterial therapy with drugs to which the organism is susceptible, the strength and frequency of coughing, and the physicochemical properties of the sputum. The first specific aim is to correlate viability assessed by the air sampling method used in the CASS and infectiousness using the mouse and guinea pig models. The second aim is to determine if the infectiousness of tuberculosis decreases rapidly with appropriate antimycobacterial therapy. The third aim is to assess whether cough strength and frequency are associated with the quantity of viable aerosol. The fourth aim is to determine if infectiousness is associated with physicochemical properties of sputum. These data may alter clinical practice and public health control measures. Changes in tuberculous aerosol viability associated with drug therapy may provide insight into the basic biology of the mycobacterial cell wall. Similarly, the rapid changes in cough strength and frequency may suggest mechanisms in the pathophysiology of cough. Verifying the correlation between quantitative aerosol cultures and infectiousness using animal

26


models may validate the use of the cough aerosol sampling system at the bedside. Data obtained from patients with tuberculosis may in turn validate the use of animal models of infection. This approach may open a new field of investigation of the host determinants of infectiousness, which could be extended to other respiratory infectious agents in the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HOST RESPONSES TO MYCOBACTERIUM INFECTION IN ZEBRAFISH Principal Investigator & Institution: Ramakrishnan, Lalita; Assistant Professor; Microbiology; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Tuberculosis is the leading cause of death from infectious diseases worldwide, with increasing consequences due to the HIV epidemic. The existing vaccine, BCG, has marginal efficacy. Infection and disease are caused by the intracellular bacterial pathogen Mycobacterium tuberculosis. In the face of a complex immune response, the bacteria can persist indefinitely in granulomas, tight aggregates of highly differentiated macrophages and other immune cells. As with most infectious diseases, the impact of the different aspects of host immunity on tuberculous infection and disease are not well understood. To better understand the host responses to tuberculous infections, we will exploit the fact that Mycobacterium marinum, a close relative of M. tuberculosis is a natural pathogen of zebrafish, causing a tuberculosis-like disease. Zebrafish are genetically tractable vertebrates that are used as models of disease and development. We have exploited the optical transparency of the zebrafish embryo to visualize M. marinum infection of embryonic macrophages in real time. The infection parallels adult tuberculosis in many ways. We will use the zebrafish-M, marinum infection model to study the role of host immune genes in infection. We will use whole mount in situ hybridizations to determine which host immune markers thought to be important in tuberculosis, are expressed in the developing embryo. We will determine if their expression is changed during infection. We will inactivate these genes using morpholino technology and determine by real time visualization when and how they act in infection. We will determine their role for the different facets of infection, from early macrophage migration in response to M. marinum to granuloma formation. The ability to visualize infection in real time in zebrafish embryos with functional inactivation of individual host genes will allow us to study the role of the host immune system in unprecedented detail. The proposed experiments will inherently yield new information about the role of various immune genes in zebrafish development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IDENTIFICATION OF GENES CONTROLLING TB IN MURINE LUNGS Principal Investigator & Institution: Apt, Alexander S.; Central Institute for Tuberculosis Yauza Alley 2 Moscow, Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) Elucidation of the mechanisms of host resistance against Mycobacterium tuberculosis infection and of TB pathogenesis is a high objective. Identification of genes and their alleles that confer resistance versus susceptibility to TB provides deep insight into basic mechanisms of immunity and pathology. Limitations to identifying human TB susceptibility genes are the polygenic

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27

control of susceptibility and the absence of clearly delineated phenotypes required for genetic analysis. Animal models of TB proved to be extremely valuable in elucidating immunity to mycobacteria and genetic control of susceptibility/resistance. Recently we and others accomplished a provisional genome-wide linkage analysis of TB susceptibility in mice, and mapped several quantitative trait loci (QTLs) in the genome control the course of the disease. Despite the fact that chromosome regions surrounding all QTLs contain genes that regulate the function of cells of the immune system (candidate genes), the physiologic basis for the difference in susceptibility to TB remains unknown and is a subject of this research project. To determine the genes that are differentially expressed in lung macrophages of susceptible and resistant mice following mycobacterial infection we have established a culture model of lung macrophages infected with mycobacteria that exactly follows genetic pattern of TB susceptibility control. We propose to compare gene expression in normal and M. tuberculosis-infected macrophages from susceptible and resistant mice using a DNA chip technology that allows the monitoring of more than 11,000 mouse genes simultaneously. To genetically dissect susceptibility to TB at the organism level, we will establish two independent pairs of congenic mouse strains. In each pair, genetic difference will be restricted to a small chromosome segment surrounding a particular QTL, one on distal chromosome 3 and the other on proximal chromosome 9. We will study gene expression in macrophages in these novel mouse strains and thus link shifts in gene expression with the alleles of particular QTLs. We will perform a new genome screening experiments, employing combination of strain in which an unusual inheritance of resistance with the strong heterosis effect was observed, in order to identify the novel chromosomal regions participating in TB control. We will define the chromosome 3 and 9 QTLs map location to approximately 1 cM intervals by a sequential 2-stage interval-specific congenic strains approach, and we will clone corresponding QTLs relying on testing of candidate genes available from complete gene map of the mouse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNOEPIDEMIOLOGY OF CONCOMITTANT INFECTION Principal Investigator & Institution: Perry, Sharon; Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 31-MAR-2009 Summary: (provided by applicant): The candidate is a mid-career Ph.D. epidemiologist interested in an academic research career. She seeks training and research experience in collaborative immunoepidemiologic methods. Helicobacter pylori, intestinal helminths and Mycobacterium tuberculosis are three of the most common chronic infections of the developing world. We hypothesize that combined infection with two or more of these agents alters host responses to individual infections resulting in different clinical outcomes. The objectives of this study are to (1) identify asymptomatic adults in San Francisco South Bay communities who have combinations of infections with Helicobacter pylori, intestinal helminths and/or Mycobacterium tuberculosis; (2) to conduct immunologic studies evaluating differential patterns of host immune response to chronic co-infection in untreated subjects; and (3) to evaluate immune and clinical responses post-treatment in a pilot sample of subjects with known sequence of eradication therapy. As part of an ongoing prospective study of H. pylori transmission in the South Bay Area, approximately 1000 adults (ages 18-45) will be screened for latent TB infection [LTBI], Helicobacter pylori (CagA+) and intestinal helminth infection using established screening tests. Based on these results, approximately 200 subjects with combinations of single and multiple infection, including a sample without target

28


infections, will be selected for specialized immunologic studies. In this group, additional assessments will include medical history, testing for other major infections, and in a subset, gastric cytokine expression. We will compare baseline measures of cellular and humoral immunity, including Th-1 and Th-2 associated cytokine production, delayedtype hypersensitivity, species-specific antibody subclass responses and measures of gastric inflammation pre- and post-treatment of these agents, and assess intra- and intersubject variabilities in time. Secondary aims of the study include characterization of regulatory T-cell activity associated with co-infection. We will also store specimens with linked epidemiologic data for possible use in future studies to assess variations in PBMC gene expression patterns. Studies characterizing the immuno-modulatory effects of coinfection with these organisms have implications for treatment intervention and vaccine development of great relevance to the health needs of U.S. foreign born and the developing world. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INHIBITION TUBERCULOSIS

OF

MACROPHAGE

INNATE

IMMUNITY

IN

Principal Investigator & Institution: Kusner, David J.; Associate Professor; Internal Medicine; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Tuberculosis (TB) is one of the world's greatest health problems, causing approximately 3 million deaths per year. Despite continuing increases in global morbidity and mortality, therapeutic and preventative options for TB remain severely limited. The central feature of TB pathogenesis is infection and intracellular survival of Mycobacterium tuberculosis (Mtb) within human macrophages. Following phagocytosis, Mtb evades the normally potent antimicrobial defenses of innate immunity by inhibiting the maturation of its phagosome to a microbicidal phagolysosome. The molecular mechanisms by which Mtb blocks phagosomal maturation and survives intracellularly are incompletely understood. The long-term goal of this project is to define the molecular mechanisms of tuberculous pathogenesis, to provide a foundation for improved therapies and vaccines. Recently, we demonstrated that live, virulent Mtb, but not killed Mtb, inhibit macrophage Ca2+signaling, and that this defect in host activation directly contributes to inhibition of phagosomal maturation and promotion of the bacilli's intracellular survival. Important gaps in our knowledge include: (1) the mycobacterial determinants responsible for inhibition of macrophage Ca2+-signaling, and (2) the macrophage targets of Mtbinduced inhibition during this critical phase of the host-pathogen interaction. The hypotheses are: (a) sphingosine kinase (SK) is a critical target of macrophage deactivation by live Mtb, and (b) inhibition of SK is causally related to defective Ca2+signaling, inhibition of phagosome maturation, and the survival of Mtb within human macrophages. We will investigate these hypotheses by pursuing the following Specific Aims: (1) Characterize the activation of macrophage SK during phagocytosis of killed Mtb and its role in Ca2+-signal transduction and phagosome maturation. (2) Determine whether inhibition of SK-mediatedCa2+-signaling by live Mtb is causally related to defective phagosome maturation and intracellular viability. In Aims 1 and 2, pharmacological, biochemical, and genetic approaches will be used to modulate specific signaling pathways. (3) Determine the component(s) of Mtb responsible for inhibition of macrophage SK- and Ca2+-mediated activation. A genetic approach of screening a transposon mutant library of Mtb and a biochemical approach of direct assessment of

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subcellular fractions of Mtb for effects on macrophage SK-andCa2+-mediated signal transduction will be undertaken. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INHIBITION OF TUBERCULAR MYCOTHIOL PATHWAYS Principal Investigator & Institution: Knapp, Spencer A.; Chemistry and Chemical Biology; Rutgers the St Univ of Nj New Brunswick Asb Iii New Brunswick, Nj 08901 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): Drug-resistant tuberculosis now threatens a large portion of the earth's population, and the development of new treatments for tuberculosis infection has become a national and international priority. Mycobacterium tuberculosis depends on a low molecular weight thiol, "mycothiol," to maintain a reducing intracellular environment and to remove exogenous electrophilic agents. Disruption of the enzymatic pathways of mycothiol biosynthesis and/or mycothiolbased detoxification could leave M. tuberculosis vulnerable to drugs, oxygen, and other stress factors, and constitutes a new tactic for the control of tuberculosis. The objective of this project is to develop inhibitors of the mycothiol-related enzymes of M. tuberculosis, and eventually to design new and successful treatments for tuberculosis. Three enzymes will be targeted initially: mycothione reductase, mycothiol S-conjugate amidase, and inosityl GIcNAc deacetylase, although others, including a cysteine ligase and a cysteine transacetylase, could be added. This work will be guided by enzymatic assays conducted by collaborators using existing screens, and by preliminary results that already indicate that substantial structural simplification in designing mycothiol analogues is possible. First, the minimum substrate requirements for the M. tuberculosis enzymes will be defined. Then, inhibitors based on these minimum structures will be synthesized and evaluated. New methods for the synthesis of mycothiol-analogous compounds will be developed, and new ideas for enzyme inhibitor design will be explored. The most active compounds will be taken as leads for further analogue development and for increasing the potency, specificity, bioavailability, and metabolic stability in M. tuberculosis itself. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RESEARCH

INTERNATIONAL

TRAINING

IN

AIDS/TB

PREVENTION

Principal Investigator & Institution: Prasad, Vinayaka R.; Professor & Director; Microbiology and Immunology; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-MAY-2005 Summary: This international training program in AIDS/TB prevention research at the Albert Einstein College of medicine (AECOM) focuses mainly on India and includes a small program for Eritrea. Towards our goal of capacity building in these countries, we aim to train Indian and Eritrean scientists in critical biomedical research, behavioral/epidemiological studies, as well as clinical research. Short-term training will involved specialized workshops in New York City was well as in-country sites that are going to be coordinated with sites in India where vaccine trials are going to conducted by international agencies such as IAVI. Medium-term training will include both graduate students of their Research Mentors who will perform collaborative research for acquiring training in the areas including but not limited to: characterization of the Indian clade of HIV-1; measurement of drug-resistance in HIV; use of small animal

30


models to study the effect of malnutrition on HIV infection; administration of V3-loop peptide vaccine to prevent materno-fetal transmission, the use of a rapid, inexpensive detection system for drug- resistant strains of Mycobacterium tuberculosis, and the development of diagnostic antibodies and other serodiagnostic and molecular tools specific to the Indian subtype of Cryptococcus neoformans. Furthermore, a Master's degree in Clinical Research Training Program and a Post- doctoral Research Training Program are offered in AIDS/TB research. Furthermore, the program will help develop low-cost HIV/AIDS technologies, mediate the creation of an Indian reposition of essential, HIV clade C-specific reagents and plans to help former trainees independent establish independent AIDS research programs upon their return to their home countries and to interact with them in this capacity- building effort. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: M DESIGN/EVALUATION

TUBERCULOSIS

CTL

EPITOPES:

VACCINE

Principal Investigator & Institution: Clayberger, Carol A.; Associate Professor; Cardiothoracic Surgery; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2003; Project Start 15-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Tuberculosis (TB) is the leading cause of death from a single infectious agent (Mycobacterium tuberculosis (Mtb)), causing approximately 3,000,000 deaths each year. Although TB can be effectively treated with a combination of antibiotics, drug resistant Mtb strains have recently emerged which are classified as Category C biological agents. Thus, it is widely felt that the long term control of TB will require the development of a more effective vaccine. Mycobacterium bovis Bacille Calmette-Guerin (BCG), the current anti-TB vaccine, is quite variable in its ability to protect against TB but is effective against tuberculosis meningitis, suggesting that for the foreseeable future, new TB vaccines will be given as an adjuvant or boost to BCG. Thus, understanding the immune response to both Mtb and BCG is critical for the development of an improved vaccine for TB. An increasing body of evidence indicates that both CD4+ and CD8+ T lymphocytes are critical to a protective immune response against Mtb. However, little is known about the antigens targeted by protective immune responses against Mtb in humans. Such information is required for the rational development and clinical evaluation of new, more effective TB vaccines. We propose here to characterize the human CD4+ and CD8+ T cell response to a panel of Mtb antigens in order to identify correlates with protective immunity. Antigens to be tested include proteins as well as peptide epitopes restricted by HLA-A2, an allele expressed by approximately 50% of the population. Some of these proteins and epitopes were selected from a subset of Mtb genes that are highly expressed under specified conditions and whose products are predicted to localize to the extracellular milieu, while the remainder represent previously identified HLA-A2 restricted epitopes. The T cell response to these antigens will be evaluated in peripheral blood leukocytes from three different groups of BCG immune and/or Mtb infected individuals: i. Neonates immunized a birth with one of 4 strains of BCG; ii. Individuals infected with Mtb but who do not progress to disease (latent TB infected individuals); and iii. PPD+ TB patients and PPD- "anergic" TB patients. Some of these peptide epitopes will be used to develop epitope oligomers which will be used to analyze anti-Mtb responses In vitro and in vivo. Lastly, the localization and function of Mtb peptide specific memory T cells will be studied in vivo. Correlates of protective immunity can be used to identify or prioritize protective antigens and vaccine candidates, to optimize vaccine dosing, schedules, adjuvants, etc., and to provide early evidence of efficacy. For TB, which takes

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31

years to decades to develop after infection with Mtb, immune correlates with protection are an attractive, and perhaps essential, supplement to efficacy trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: M TUBERCULOSIS EVASION OF THE INNATE IMMUNE RESPONSE Principal Investigator & Institution: Fortune, Sarah M.; Immunology/Infections Diseases; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-MAY-2006 Summary: (provided by applicant): This proposal describes a five year, twopart career development program in the study of Mycobacterium tuberculosis. This program will be carried out in the laboratory of Dr. Barry Bloom with the additional guidance of Dr. Eric Rubin, both in the Division of Immunology and Infectious Diseases at the Harvard School of Public Health. The candidate is trained in Infectious Diseases and has the long term goal of establishing an independent laboratory studying M. tuberculosis pathogenesis with a particular focus on mycobacterial interaction with the host immune response and vaccine development. The didactic component of this program involves courses in molecular biology and immunology through Harvard University. The research component of this program involves exploration of two putative mechanisms of immune evasion by M. tuberculosis, inhibition of IFN-gamma signaling and inhibition of inducible IL-12 production in infected macrophages. The specific aims of the research proposed will be: 1) to determine whether Toll-like receptor 2 (TLR-2) activation inhibits IFN-gamma signaling or inducible IL-12 production; 2) to identify the M. tuberculosis genes required for inhibition of IFN-gamma and IL-12 signaling by screening a transposon mutagenized library of M. tuberculosis; and 3) to characterize the genes identified in these screens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PERSISTENCE

M

TUBERCULOSIS

TRUNCATED

HEMOGLOBINS

IN

Principal Investigator & Institution: Chan, John R.; Associate Professor; Medicine; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2004 Summary: (provided by applicant): Recrudescence of latent tuberculous infection contributes significantly to the pathogenesis of disease caused by Mycobacterium tuberculosis (Mtb). The mechanisms by which the tubercle bacillus establishes latency and later reactivates are, however, poorly understood. Two truncated hemoglobins (trHb?s), HbN and HbO, encoded by the gene glbN and glbO, respectively, exist in Mtb. Initial characterization of HbN and HbO in M. bovis BCG has shown that: i) glbN and glbO are differentially expressed --the expression of HbN in vitro is most prominent in the stationary phase of growth, while HbO is invariably detected throughout the various growth phases; ii) both trHb?s have high affinity for oxygen, albeit via different mechanisms; iii) HbN and HbO can detoxify nitric oxide (NO) by conversion of the nitrogen oxide to nitrate; significantly, a BCG deletion mutant of glbN is markedly attenuated for its ability to consume NO; iv) the function of HbO may be essential. Based on these findings, we propose to test the hypothesis that HbN and HbO are required for the survival and/or persistence of Mtb within the host. This survival/persistence-promoting attribute can be due to the ability of HbN and HbO to

32


detoxify the antimycobacterial NO. In addition, by virtue of their ability to bind oxygen with high affinity, HbN and HbO can function as an oxygen reservoir in the relatively anaerobic environment of the tuberculous granuloma, thereby optimizing the functions of critical intracellular oxygen-dependent enzymes. Finally, the ability of these trHb?s to avidly bind oxygen may protect Mtb against oxidative damage. To begin testing these hypotheses, we will take a genetic approach, by generating glbN and glbO mutants, to rigorously test the in vivo significance of Mtb trHb?s in survival and/or persistence using murine experimental TB models. We will also evaluate the roles of HbN and HbO in Mtb respiration and in protection against the adverse effects of NO on the respiratory process. Establishment of the significance of HbN and HbO in persistence and unraveling the biochemical and physiochemical properties of these hemeproteins will set the stage for developing novels anti-tuberculous agents effective against Mtb, particularly those in the dormant state. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: M. BOVIS AS A POTENTIALLY MORE VIRULENT MDR PATHOGEN Principal Investigator & Institution: North, Robert J.; Member; Trudeau Institute, Inc. Saranac Lake, Ny 12983 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (PROVIDED BY APPLICANT): Virulence may be defined as the ability of a microorganism to survive host defenses and cause disease. There is no reason to believe that multi-drug resistant (MDR) strains of Mycobacterium tuberculosis are more virulent than drug sensitive (DS) strains There is evidence, on the other hand, that M. bovis is much more virulent than M. tuberculosis as a species. Therefore, if M. bovis were engineered to be MDR, it could pose a more serious threat to public health than MDRM. tuberculosis. The proposed research will use the superior virulence for mice of the Ravenel strain of M. bovis over M tuberculosis H37Rv to determine whether superior virulence, as manifest by ability to induce faster development of lung pathology and cause earlier death, is associated with the ability to induce a higher level of expression of Th1 immunity in the lung. This will be investigated by measuring levels of expression of genes for Th1 cytokines, proinflammatory cytokines and chemokines in the lungs. Elispot and flow cytometry will be used to enumerate total numbers of IFN-?, producing, pathogen-specific CD4 and CD8 T cells in the lungs. The possibility that superior virulence of M. bovis is also associated with higher levels of bacterial gene expression will be investigated, keeping in mind that M. bovis Ravenel and M. tuberculosis cause the same level of stationary lung infection. Real-time RT-PCR will be used to measure levels of pathogen gene expression in terms of mRNA copy number per lung and per CFU. Genes within the RD1 region of the M. tuberculosis and M. bovis chromosome, including esat6 and cfp-10, will receive attention. The virulence of a number of M. bovis and M. tuberculosis strains will be compared. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: M. TUBERCULOSIS INFECTION IN THE LUNG Principal Investigator & Institution: Boom, W Henry.; Professor of Medicine; Medicine; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 30-SEP-1995; Project End 31-MAY-2006 Summary: (Adapted from the Applicant's Abstract): The lung is the major portal of entry for Mycobacterium tuberculosis, the cause of human tuberculosis. The lung is the site where immune responses to this bacterium are initiated, and where growth of the

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33

organism is controlled without complete eradication. Acquire immunity of T cells and macrophages controls infection in the majority of healthy individuals. The lung is not only the first site of infection, but also uniquely susceptible to M. tuberculosis. Mechanisms responsible for susceptibility of the lung to M. tuberculosis and the inability of acquired immunity to eradicate the bacteria are poorly understood. The murine model of aerogenic mycobacterial infection provides an excellent means to analyze the initiation and effector phases of acquired immunity to mycobacterial infection in the lung. This competitive renewal application for HL-55967 builds on the collaborative infrastructure developed during the last 4 years between Case Western Reserve University (CWRU) and Colorado State University (CSU) aimed at addressing immune mechanisms responsible for control of mycobacterial infection in the lung. The PI hypothesizes that mechanism(s) for the pulmonary susceptibility to M. Tuberculosis differ(s) according to stage and site of infection. Initially, M. Tuberculosis resists innate immune mechanisms in lung and uses alveolar and interstitial spaces as privileged sites. As acquired immunity develops, the ability of M. Tuberculosis to inhibit the function of antigen-processing cells becomes a dominant means to assure its survival within the lung. This hypothesis leads to the following specific aims: Aim1: To determine the mechanism(s) responsible for permissive mycobacterial growth in alveolar and interstitial lung macrophages and the role of chemokines and NK cells in control of mycobacterial growth during the innate phase of pulmonary M. Tuberculosis and M. bovis BCG infection. Aim2: To determine the ability of lung antigen presenting cells (alveolar macrophages, lung parenchymal macrophages and lung dendritic cells) to activate naive and memory T cells, and the mechanism(s) used by M. Tuberculosis to interfere with class II MHC antigen presenting cell function. Aim 3: To determine the ability of chemokines, CpG and cholera toxin to enhance innate and acquired immune defenses to M. bovis-BCG and M. Tuberculosis within lung. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: M. TUBERCULOSIS SURVIVAL IN MACROPHAGES Principal Investigator & Institution: Friedman, Richard L.; Associate Research Scientist & Lecturer; Microbiology and Immunology; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2004 Summary: (provided by the applicant): Central to the disease process in tuberculosis are the interactions of the bacilli with host macrophages. The infection of macrophages by Mycobacterium tuberculosis can be divided into four steps: adherence, entry, intracellular survival, and multiplication. This proposal will concentrate on one of these steps, survival. The role virulence factors of M. tuberculosis play in these complex interactions is virtually unknown. The aim of the proposed research is to identify, clone, and characterize genes and their protein products of M. tuberculosis which are required for intracellular survival within macrophages. Potential virulence factor genes of M. tuberculosis will be cloned by first constructing a recombinant library and incorporating it into the non-pathogenic Mycobacterium smegmatis. This rapidly growing mycobacterium is internalized and killed by macrophages. Clones with enhanced survival in macrophages will be identified and examined for the presence of M tuberculosis genes involved in survival. Using this system we have already isolated a M. tuberculosis gene, named eis (enhanced intracellular survival gene), which does enhance intracellular survival of M. smegmatis within macrophages. The primary focus of this grant application is the further characterization of the eis gene and its protein product Eis. The specific aims are: 1.Effect of eis Gene Inactivation on Survival and

34


Multiplication of M tuberculosis in Macrophages and Mice. Mutations will be constructed in eis and introduced into the chromosome of both avirulent and virulent M tuberculosis (H37Ra and H37Rv) by allelic exchange. The ability of the eis knockout mutants to survive and replicate in the U-937 macrophage survival assay and in human mononuclear phagocytes will be tested and compared to the parental strain. Additionally, the ability of the eis mutants to persist and replicate in vivo in a mouse intravenous infection model will also be evaluated. 2.Mechanism(s) Whereby eis Enhances Survival and Multiplication of M tuberculosis in Unactivated and Interferongamma-Activated Macrophages. To learn how eis may enhance intracellular survival of mycobacteria in macrophages, survival in interferon-gamma-activated U-937 cells and human monocytes will be evaluated. The ability of M. smegmatis with and without eis, as well as wild-type M. tuberculosis and eis knock-out mutants, constructed in Specific Aim No.1, to survive/multiply in both unactivated and interferon-gamma-activated U937 cells and human monocytes will be determined. Studies will also be done to determine what role Eis may play in the ability of M. tuberculosis to resist known killing mechanisms operating in macrophages. 3.Properties of the Eis Protein and their Relationship to its Survival-Increasing Action. These studies will include: (I) intracellular localization of Eis in M. tuberculosis and M. smegmatis, (2) purification of the Eis protein, (3) screening of sera from tuberculosis patients for presence of antibody to Eis, and (4) measurement of eis gene expression in vitro and within macrophages using integrative reporter gene vectors. 4.Identification of Non-eis Survival Genes in a New M. tuberculosis DNA Library. In initial studies, eis-containing clones were the predominate clones isolated after the sixth passage in the U-937 macrophage survival assay. Such eis-containing clones are preferentially selected and appear to outcompete/dominate other M. tuberculosis genes which may also play a role in intracellular survival. Thus, in order to identify these other potential genes, a new M. tuberculosis plasmid library will be constructed with larger (10-12 kb) DNA inserts of genomic DNA from an H37Rv eis knockout mutant. This eis knockout library will then be screened for survival in the U-937 macrophage survival assay. Clones with enhanced survival will be isolated and further characterized. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: M.TUBERCULOSIS GENES REGULATING PERSISTENT INFECTION Principal Investigator & Institution: Zahrt, Thomas C.; Assistant Professor; Microbiol & Molecular Genetics; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 15-AUG-2001; Project End 31-MAY-2006 Summary: (provided by applicant) Tuberculosis is the leading cause of death in the world from a single infectious agent, and is responsible for more than 3 million deaths annually. The high mortality rate in individuals infected with Mycobacterium tuberculosis is due in part to its ability to parasitize macrophages and establish longterm, persistent infection in the host despite cell-mediated immunity. Although the current anti-tubercular drug arsenal is effective in treating individuals suffering from active disease, these drugs are ineffective in treating the 2 billion people that currently suffer from latent tuberculosis, or that are infected with multi-drug resistant strains of M. tuberculosis. One group of transcriptional regulatory determinants that may play a critical role in processes associated with M. tuberculosis latency is the two-component signal transduction systems. These systems mediate adaptation processes and have been shown to contribute to virulence and disease elicitation in other organisms. The goals of this study are to characterize further a two-component system of M. tuberculosis

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35

(MprA-MprB) that is required for the establishment and maintenance of persistent infection. In this proposal, we plan to: (i) Identify and characterize the genes regulated by the MprA transcription factor. The genes regulated by MprA will be identified from the M. tuberculosis chromosome using biochemical enrichment and genetic selection techniques, and will be characterized by gene inactivation, promoter expression analysis, and evaluation in model systems for infection. (ii) Analyze the in vivo expression profile of the MprA response regulator, and the genes regulated by MprA. This will be accomplished by expression analysis of these genes using GFP reporter technology, primer extension analysis, molecular beacon technology, and DNA microarray based analysis under physiologically relevant conditions. (iii) Delineate the effects of MprA de-regulation on host-pathogen interactions. This will be accomplished by examining effects of MprA loss or overexpression on M. tuberculosis virulence. Virulence studies will include bacterial survival and cytokine expression analysis as assayed in in vitro tissue culture systems and animal model systems of infection. These studies will also address the effects of MprA de-regulation on Mycobacterium bovis BCG attenuation. The proposal outlined here is expected to improve our understanding of genes required by M. tuberculosis for pathogenesis, and help better define the conditions encountered and responses utilized by M. tuberculosis during the latent stage of infection. We hope that the analysis of two-component systems will aid in the identification of genetic determinants for which novel anti-tubercular drugs can be developed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISM AND INHIBITION OF PYRUVATE PHOSPHATE DIKINASE Principal Investigator & Institution: Dunaway-Mariano, Debra; Associate Professor; Chemistry; University of New Mexico Albuquerque Controller's Office Albuquerque, Nm 87131 Timing: Fiscal Year 2002; Project Start 01-JAN-1986; Project End 31-MAR-2006 Summary: (provided by applicant): This revised application requests funds to continue studies of separate site catalysis by the enzyme pyruvate phosphate dikinase (PPDK). PPDK catalyzes the interconversion of ATP, Pi, and pyruvate with AMP, PPi and PEP by using two separate active sites linked by a carrier histidine residue. The overall goal of the proposed studies is to determine the mechanism by which the carrier histidine is transferred between active sites through precisely oriented and timed domain-domain docking steps. These studies will provide a deeper understanding of the forces controlling transient protein-protein complex formation in signal transduction pathways and template directed biosynthetic pathways. Five specific aims are listed. These are (1) determine the X-ray crystal structure of PPDK conformer 2, (2) determine the role of domain linkers in facilitating successful domain-domain docking, (3) determine the role of interactions between domain-domain interface residues in facilitating correct docking orientation and in optimizing residence time, (4) distinguish between a through-solventdomain-diffusion model and a sliding-domain model and (5) identify the role of the PPDK homologue in Mycobacterium tuberculosis. This last aim will be carried out for the purpose of discovering a novel metabolic pathway operating with in this pathogen, as well as a novel target for drug design. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF CELL GROWTH ARREST IN LATENT TUBERCULOSIS. Principal Investigator & Institution: Fontan, Patricia A.; Public Health Research Institute 225 Warren St Newark, Nj 071033535 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): During the latent phase of tuberculosis the tubercle bacillus is believed to be metabolically active but in a slow or non-growing state which can resume bacterial replication at an opportune time later in life. However the mechanisms involved in the cessation of Mycobacterium tuberculosis (Mtb) division are unknown. There have been recent descriptions of bacterial possessing systems, resembling plasmid encoded toxin-antitoxin proteins that induce cell growth arrest when the microorganism is exposed to an environmental stress. We and other investigators have identified proteins resembling these putative toxin-antitoxin modules in Mtb. To provide evidence that these systems are cell growth arrest modules involved in the persistent phase of Mtb infection, we propose: 1-To demonstrate the inhibitory effect of the putative Mtb "toxin-antitoxin modules" on bacterial growth in vitro. 2-To determine the patterns of expression of the putative Mtb "toxin-antitoxin modules" during the persistent phase of bacterial infection in mice lung and guinea pig granulomas. 3-To analyze the regulatory mechanisms for the expression of the putative Mtb "toxin-antitoxin modules". 4-To determine the mechanism of action of the putative Mtb '_toxin-antitoxin modules". 5-To evaluate the role of the Mtb "toxin-antitoxin modules" in bacterial virulence, using a model of mouse lung infection. These studies will provide insight into the latent phase of tuberculosis and they will allow us to identify possible targets form the design of antimycobacterial drugs. During the research supported by this proposal the candidate will gain knowledge in the study of transcriptional regulation of Mtb under the mentorship of Dr. Issar Smith, who is an expert in the field. The candidate will obtain expertise in the management of State-ofthe-Art techniques at the Public Health Research Institute, an Institution with a high level of scientific achievement in the area of infectious diseases like TB. The completion of this proposal in this framework of scientific and institutional support will be fundamental for the candidate to establish herself as an independent investigator in the field of Mtb pathogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: METALLOPROTEINASE GRANULOMAS

FUNCTON

IN

TUBERCULOSIS

Principal Investigator & Institution: Izzo, Angelo A.; Microbiol, Immunology & Path (Mip); Colorado State University-Fort Collins Fort Collins, Co 80523 Timing: Fiscal Year 2004; Project Start 01-JUN-2004; Project End 31-MAY-2005 Summary: (provided by applicant): Mycobacterium tuberculosis (Mtb) infects approximately one third of the world's population. In the US, there are an estimated 10 to 15 million people infected with Mtb who have the potential to develop active disease. Among otherwise healthy persons, infection with Mtb is likely to be asymptomatic. In recent years it has become clear that if these individuals become immunosuppressed, as in cases of HIV infection, Mtb infection is reactivated. The purpose of this proposal is to use a murine model of pulmonary Mtb infection to dissect the host's immune response to identify factors that promote the formation and maintenance of granulomas during chronic Mtb infection and possible mechanisms that may also cause reactivation. Expression of anti-mycobacterial immunity depends on type 1 immune cytokines such

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37

as interferon-gamma that enable the host to mount a granulomatous inflammatory response to the infection. The lung provides an excellent environment for the organism to persist, despite the presence of a continuous immune response. Matrix metalloproteinases (MMPs) are endopeptidases that degrade the extracellular matrix and have been associated with various pathogenic states. Tissue inhibitors of MMPs regulate the activity of MMPs and provide a mechanism for controlling their activity. We propose that during pulmonary Mtb infection, MMPs are a dual-edged sword, being induced by Mtb, but required by the host to form the granuloma and then down regulated to maintain the structure. Specifically, increased MMP activity causes extracellular matrix degradation/tissue remodeling, which enables Mtb to disseminate and facilitates leukocyte trafficking into infected lungs, providing the foundation for granuloma formation. Finally, MMP down regulation is critical for fibrosis formation that is essential for granuloma stability. The MMPs that function during this process are macrophage-derived MMP-2, MMP-9 and MMP-12, which play significant roles in the disease process, being regulated directly by the virulent organism. Understanding how the immune response modulates MMP activity and produces tight, well-formed granulomas will provide insight into mechanisms that could accelerate and stabilize the natural healing process. It is intended that the information obtained from these investigations will provide a better understanding of the immunopathogenesis of tuberculosis and therefore allow for the development of better treatment regimens particularly during reactivation of infection that can be used in association with conventional anti-tuberculosis therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOGENS

MICROMACHINED

BIOSENSOR

FOR

MYCOBACTERIAL

Principal Investigator & Institution: Wavering, Tom A.; Luna Innovations, Inc. 2851 Commerce St Blacksburg, Va 24060 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-JUL-2003 Summary: (Provided by applicant): Mycobacteria are slender, nonmotile, gram-positive rods and do not produce spores or capsules. Nineteen Mycobacterium species are associated with disease in humans. The most dangerous of these diseases is tuberculosis, caused by infection with M. tuberculosis. Tuberculosis kills about 2 million people annually and infects another 8 million people each year. Treatment and diagnosis of the disease is complicated by current laboratory methods that can take from four to six weeks to establish a definitive identification of infection. New diagnostic systems are needed for earlier detection of tuberculosis, to better monitor the treatment of tuberculosis, and to study the epidemiology of the disease. Luna Innovations has assembled a team of researchers to develop a micromachined biosensor array that combines technology from silicon micromachining, optical fiber sensors, and biochemistry for measurement of mycobacterial pathogens. The sensing element of the biosensor array will be a microcantilever beam coated on one side with receptors. As pathogens bind to the coated beam, a biochemical induced surface stress causes the beam to deflect proportionally to concentration. The Phase I program will focus on developing the microcantilever biosensor array, demonstrating detection of mycobacterial pathogens in neat solutions, and comparing performance to known standards. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MINORITY PREDOCTORAL FELLOWSHIP PROGRAM Principal Investigator & Institution: Onwueme, Kenolisa C.; Administration; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2003; Project Start 01-NOV-2003; Project End 31-OCT-2006 Summary: (provided by applicant): Mycobacterium tuberculosis, MTb, accounts for the largest infectious cause of human mortality worldwide, a title that is reinforced by its synergy and co-morbidity with AIDS and the emergence of multi-drug resistant MTb strains. The complete MTb genome contains at least 10 predicted loci dedicated to the synthesis of polyketides and related compounds. Polyketide-like compounds are well known and appreciated for their pharmacological utilities, including antitumor, antibiotic, immunosuppressive and anti-hypercholesterolimic effects to name but a few. The current proposal seeks to evaluate the relevance of polyketides in MTb pathogenesis. Specifically, we aim to characterize the structure of MTb polyketides and to analyze their timctional roles in mediating microbial virulence and persistence via functions they confer on the bacilli or by alterations m normal processes of host immunity. Our ultimate aim is to clarify roles of microbial metabolites in pathogenesis and virulence with a view to discover novel targets for therapeutic intervention in infectious disease processes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MULTI-DRUG RESISTANCE TUBERCULOSIS AS BIOTERRORISM AGENT Principal Investigator & Institution: Cantarero, Luis A.; Mycos Research, Llc 217 Racquette Dr, #6 Ft. Collins, Co 805244729 Timing: Fiscal Year 2004; Project Start 15-APR-2004; Project End 31-MAR-2005 Summary: (provided by applicant): In recent years, there has been a resurgence of drugresistant strains of Mycobacterium tuberculosis, MDR-TB. This coupled with the fact that enclosed spaces, such as commercial aircraft among others, are effective locations to spread this serious respiratory disease, either purposely or accidentally, has influenced current CDC guidelines classifying MDR-TB as a Class C bioterrorism agent. The current vaccine for tuberculosis, BCG, while safe and effective at protecting young children, has been found only variably efficacious at protecting adults from this serious pulmonary disease. It is the purpose of this application to address the feasibility and provide proof of principle that a post-exposure (immunotherapeutic) vaccine can be developed that could inhibit the growth and associated pathogenesis of virulent forms of drug resistant M. tuberculosis, at least to an extent that the exposed individual is no longer infectious. This work will test vaccine candidates 72f, a recombinant polyprotein, and a mixture of low oxygen proteins both in MPL-SE adjuvant that have shown extremely promising early results by our consultants in mouse, guinea pig and monkey model systems. Mice will be exposed via aerosol to disease producing doses of M. tuberculosis H37Rv, then treated with various vaccine protocols at early disease phase, 30 days post exposure, and late disease phase 90 days post exposure, and monitored for approximately 120 days at 15 day intervals for disease. A guinea pig model, which resembles the disease seen in humans will also be utilized. Guinea pigs will be infected via aerosol with M. tuberculosis H37Rv and then vaccinated at 30 and 45 days and monitored for 15 weeks until signs of distress and weight loss occur during the remaining 10 months. The results of this study will be the basis for replicate studies using selected MDR-TB strains in a follow up phase to this work. Choice of one of the two post exposure therapeutic vaccine candidates, expansion of material production,

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testing expanded dose levels of the therapeutic aqent as well as, expanded safety and effectiveness studies are contemplated for a Phase II studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MYCOBACTERIAL ANTIGEN COMPARTMENTALIZATION & IMMUNITY Principal Investigator & Institution: Sandor, Matyas; Pathology and Lab Medicine; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: Tuberculosis remains one of the most significant public health challenges the modern world faces. Improved vaccines are needed for prevention of infection and improved immunotherapies are needed to combat existing or recurring disease. An better vaccine would induce a concerted protective response by CD4+ and CD8+ T cells together. Our hypothesis is that CD4+ and CD8+ T cells sample different bacterial compartments differently. Information about which compartment is optimal for effective presentation of ClassII and Class I epitopes and generation of protective responses will help create better vaccines. To do this we will use a novel approach while building on the strengths of previous experimental systems. TCR transgenic mice will be infected with recombinant Mycobacterium bovis strain bacille Calmette Guerin (BCG), the current vaccine strain. These rBCG will express T cell epitopes in the context of the same fusion proteins located in different subcellular compartments of the bacteria. A parallel series of rBCG strains will be constructed for both class I or class II presentation using either Lymphochoriomeningitis Virus (LCMV) gp33 peptide or pigeon cytochrome C peptide (PCC) respectively. We will study how access of each epitope to its respective presentation pathway is influenced by its location in different bacterial compartments. Subsequently, we will study the activation and recruitment of antigen specific cells both systemically and in the BCG induced liver granulomas in response to various rBCG using adoptively transferred antigen specific T cells. Our final analysis will be to study how bacteremia is effected when antigen is presented in different bacterial compartments with or without prior peptide specific immunization. In this manner we hope to define how the different epitopes in different bacterial compartments effect T cell responses and protection. We chose PCC (CD4+ specific) and gp33 (CD8+ specific) for this work because they are both widely studied model antigens and a multitude of reagents are available, including T cell clones, hybridomas, TCR transgenic mice, and MHC tetramer reagents. The mouse model of BCG infection was chosen because we wish to improve the vaccine capacity of this attenuated strain and also because infection of mice with BCG has been widely employed and many of the characteristics of this model are well understood. The experimental results from this proposal should have direct relevance to improving vaccine design for protection against tuberculosis, and will also provide knowledge about how bacterial antigen access different antigen presenting pathways. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MYCOBACTERIAL MACROPHAGES

CELL

WALL

RECOGNITION

BY

Principal Investigator & Institution: Smith, Kelly D.; Assistant Professor; Pathology; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2004

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Summary: Mycobacterium tuberculosis is a leading cause of death by infectious disease in the world. Mycobacterial cell wall components are potent stimulators of the immune system, and have long been as adjuvants. The host systems that recognize these components are poorly defined, but several studies implicate CD14, a component of LPS recognition pathway that utilizes Toll- like receptor-4 (TLR4). TLRs appear to be early and important inducers of tumor necrosis factor-alpha (TNFalpha). TNFalpha is a critical factor for protective immunity to tuberculosis. We hypothesize that innate recognition of mycobacterial cell wall components by TLRs is important for host defense. TLRs have a signaling pathway that has similarities to the IL-1 receptor pathway, and include MyD88 as a proximal component. Using murine macrophage cell line RAW 264.7, we have identified three cell wall fractions that stimulate MyD88dependent TNFalpha production. This implies TLR-dependent recognition of mycobacterial cell wall components. The mechanism of stimulatory ligand recognition by TLRs is unknown and may require direct or indirect involvement of CD14. Phagocytosis of mycobacterium involves another set of receptors including the complement and mannose receptors. Complement opsonization increases the infectivity of mycobacteria in vitro. In addition, phagocytic receptors recognize mycobacterium and potentially activate an overlapping set of signaling pathways. This suggests that cross- talk may exist between phagocytic and inflammatory signaling pathways. The aims of this proposal are to 1) identify the specific mycobacterial cell wall components recognized by TLRs, 2) identify the corresponding receptors that are responsible for MyD88-dependent recognition of mycobacteria, 3) characterize mycobacterial cell wall ligand-recognition by TLRs, and 4) characterize the consequences of complement opsonization and TLR- dependent recognition on phagocytosis of mycobacteria. Understanding the innate recognition of mycobacteria will greatly advance our understanding of tuberculosis, point to possible sites of host genetic variation that alter responses to M. tuberculosis, and disclose fundamental principles of innate immunity in infectious and inflammatory diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MYCOBACTERIAL GENES, ANTIGENS, AND VACCINES Principal Investigator & Institution: Bloom, Barry R.; Dean; Immunology/Infections Diseases; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-APR-1986; Project End 31-MAY-2006 Summary: (provided by the applicant): Tuberculosis and HIV/AIDS represent the major infectious causes of death in the world, and tuberculosis (TB) is the attributable cause of death in a third of AIDS patients in Africa. Drug resistance to TB is emerging in Europe and Asia, drug treatment regimens are long and expensive and compliance is limited. For these reasons, we propose to bring a multidisciplinary approach, joining molecular genetics and immunology, to developing safe and effective live attenuated vaccines against TB. Since peak age of disease is 15-25y, we believe a live attenuated vaccine that induces long enduring immunological memory will provide the most useful protection against disease. In previous work we have developed tools to genetically manipulate slow growing mycobacteria, including the capability of creating specific deletion mutants to attenuate virulent M tuberculosis. One aim is to test the hypothesis that M tuberculosis represents a better vaccine candidate than BCG, to create and test auxotrophic mutants, growth mutants and persistence mutants of M. tuberculosis for safety and immunogenicity in mice. A second is to determine the optimal duration of growth of vaccine strains in vivo for the development of immunological memory

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responses, particularly through the use of regulated promoters. This will also allow us to elucidate similar requirements for producing tissue damage. Our final aim remains to understand the immunological mechanisms of protection against experimental tuberculosis, particularly exploring the role of innate responses mediated by the Tolllike receptor family, the minimum epitope and antigen requirements for protection, and the possible role of cytotoxic T-lymphocytes (CTL) in protection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INITIATION

MYCOBACTERIUM

TUBERCULOSIS

AND

REPLICATION

Principal Investigator & Institution: Madiraju, Murty V.; Associate Professor; Biochemistry; University of Texas Hlth Ctr at Tyler 11937 Us Highway 271 Tyler, Tx 75708 Timing: Fiscal Year 2003; Project Start 01-AUG-1997; Project End 31-JAN-2008 Summary: (provided by applicant): Human tuberculosis caused by Mycobacterium tuberculosis is the most prevalent and deadly bacterial infectious disease worldwide. This problem is compounded by the emergence of strains of M. tuberculosis that are resistant to one or more anti-tuberculous drugs. Following initial infections, M. tuberculosis frequently enters a latent or dormant state for extended periods and subsequently, under appropriate conditions or following immune suppression, revives, multiplies and causes a secondary infection. DNA replication constitutes an important step in the exit from latency. The development of novel therapeutic agents to control M. tuberculosis infections in HIV infected patients as well as other individuals is severely hindered by our limited understanding of the initiation and regulation of M. tuberculosis DNA replication and its coordination with other events in cell cycle. Initiation of DNA replication is believed to be triggered when DnaA, the putative initiator protein, interacts with oriC or origin of replication. Although oriC is essential for survival, some clinical strains of M. tuberculosis appear to tolerate major deletions and IS6110 insertions in their oriC, thereby raising questions as to how these clinical strains replicate their genome. Our research proposal focuses on understanding the replication initiation process in M. tuberculosis. Specifically, we propose to inactivate oriC, dnaA individually and together by homologous recombination in an attempt to determine whether replication in M. tuberculosis can proceed from alternate origins, and if so whether dnaA function is required for such replication. The interactions of DnaA with replication origins and consequences of these interactions will be investigated using biochemical and genetic approaches. To begin identifying the factors that could potentially affect DnaA activity, a proteomic approach combining twodimensional gel electrophoretic separations of proteins with subsequent identification of protein spots by matrix-assisted laser ionization desorption/ionization mass spectrometry, will be used. Defining the molecular events involved in the initiation and regulation of replication is an essential prerequisite for developing defined systems for identifying novel antimycobacterial compounds, and thereby preventing the development of potentially lethal infections of M. tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MYCOBACTERIUM TUBERCULOSIS IN VIVO GENE EXPRESSION Principal Investigator & Institution: Graham, James E.; Microbiology and Immunology; University of Louisville Jouett Hall, Belknap Campus Louisville, Ky 40292 Timing: Fiscal Year 2002; Project Start 17-SEP-2001; Project End 31-MAY-2006

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Summary: (provided by applicant) Mycobacterium tuberculosis is a pathogen that is able to adapt to a variety of different environments encountered during the progressive course of human infection. An ability to inhibit maturation of the macrophage phagosome initially created an ideal environment for bacterial growth, allowing colonization of the body. when deprived of this favorable environment by the hosts's own tissue-damaging immune response, infection often fails to progress, and bacilli enter an nonreplicating latent state, having reached a degree of equilibrium with the host. Changes in the host over time may then allow bacteria to resume replication, leading to further tissue destruction and extracellular growth to high titers. This project will identify bacterial genes that are specifically expressed by M. tuberculosis during adaptation to these in vivo environments. A new method developed specifically for examination of mycobacterial mRNAs expressed in infected host cells and tissues (SCOTS) has so far identified 9 M. tuberculosis genes which are expressed in response to growth within cultured human macrophage phagosomes. The first aim of the proposed work is to make bacterial strains specifically inhibited in expression of these genes and evaluate their ability to survive and grow in cultured human macrophages. The second aim is to identify additional M. tuberculosis genes that are differently expressed by tubercle bacilli in another environment that bacilli normally encounter during the natural course of human infection. Bacterial genomic array hybridization with cDNAs obtained by SCOTS will be used to analyze global mRNA expression patterns in bacilli recovered from patient sputum samples, providing insight into the physiology and metabolism of the microbe during active growth in the human lung. Our third aim is to extend analysis of differential bacterial gene expression to a C57BL/6 mouse model of host interaction, facilitating studies of both active and latent types of infection in a genetically defined host. Bacterial cDNA already obtained by SCOTS from tubercle bacilli growing in cultured mouse macrophages and from infected mouse lung tissues will be compared by array hybridization to cDNA from tubercle bacilla growing in human macrophages and lung tissues. A limited number of M. tuberculosis genes commonly expressed in response to these mammalian host interactions will then be evaluated for their contributions to virulence in this animal model. Understanding the roles of such differentially expressed genes will further define host-pathogen interactions in human disease, and allow development of new tools to reduce the enormous global impact of tuberculosis on mankind. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MYCOTHIOL BIOSYNTHESIS AND METABOLISM AS TB DRUG TARGETS Principal Investigator & Institution: Fahey, Robert C.; Chemistry and Biochemistry; University of California San Diego La Jolla, Ca 920930934 Timing: Fiscal Year 2004; Project Start 01-AUG-2000; Project End 31-MAY-2007 Summary: (provided by applicant): Tuberculosis is second behind AIDS, as the World's most deadly microbial infection. However, a major fraction of AIDS patients die of mycobacterial infections, including TB. The TB problem is aggravated by the growing prevalence of drug-resistant TB, and especially multi-drug resistant (MDR) TB, which cannot be treated with the front-line antibiotics for Mycobacterium tuberculosis. It is therefore important that targets be identified for development of new drugs for treatment of MDR TB. Suitable target enzymes should have biochemical functions essential for mycobacteria but have no similar function in mammals, making it likely that drugs can be developed that will not lead to adverse reactions in humans. They must have well-defined assays suitable for screening of potential drugs. The proposed

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research elucidates the biochemistry associated with the production and utilization of the antioxidant thiol known as mycothiol. Mycothiol is produced only by mycobacteria, and other actinomycetes, and is not found in animals. The key genes for mycothiol biosynthesis have recently been identified and provide important potential novel drug targets. Studies of mycothiol-deficient mutants indicate that mycothiol metabolism is involved in protecting against oxidative damage and in the detoxification of antibiotics, including a first-line TB drug. Although not essential for the laboratory culture of the model organism Mycobacterium smegmatis, it has been shown that mycothiol is essential for aerobic growth of M. tuberculosis. The present studies will determine the extent to which mycothiol is essential for survival of dormant M. tuberculosis, will define the biochemistry involved in the first key step of mycothiol biosynthesis, and will identify compounds capable of inhibiting mycothiol biosynthesis in mycobacteria. Methods used include new analytical and enzyme assays developed in these laboratories as well as established protocols in biochemistry and molecular biology. The results obtained will provide a key test of the suitability of mycothiol biosynthesis as a target for new TB drugs and will elaborate the biochemistry of a novel class of thiol important to a broad range of soil microorganisms, including most antibiotic-producing bacteria. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NOVEL TUBERCULOSIS

ANTIFOLATES

AGAINST

AIDS-ASSOCIATED

Principal Investigator & Institution: Li, Rongbao; Southern Research Institute Birmingham, Al 35205 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): The overall goal of this project is to develop both potent and selective antifolates against Mycobacterium tuberculosis (Mtb), an opportunistic pathogen known to cause morbidity and mortality in AIDS patients. Specifically this project will focus on design of novel antifolates, through a structurebased approach in light of the recently solved crystal structure of Mtb dihydrofolate reductase (DHFR), organic synthesis, and evaluation of the synthetic compounds for their biological activity. DHFR is a key enzyme of the folate metabolic pathway and is required for both prokaryotic and eukaryotic cell-growth. Recent clinical studies of agents inhibiting enzymes of the folate pathway, including DHFR, demonstrated therapeutic effect in AIDS-associated TB patients. Highly potent DHFR inhibitors are available but are toxic due to their low selectivity. To increase the selectivity, a new pharmacophore model is needed, which relies critically on structural differences between the host and pathogen enzymes. The comparison between the available structures of the host and the pathogen DHFR enzymes has revealed potential target sites that allow for the design of selective inhibitors. With the common binding motifs of the DHFR family as platforms, such as 2,4-diaminopyrimidine and diaminopteridine heterocyclic systems, we have designed a series of molecules with special features that would bind tightly and specifically to these sites on Mtb DHFR but unlikely to the same sites on the human enzyme. In this proposed research, these designed molecules will be synthesized and evaluated for their inhibition of DHFR and their effect on Mtb cell growth. Lead compounds that actively and selectively inhibit Mtb will be co-crystallized with Mtb DHFR. The crystal structures of these complexes will be determined by X-ray crystallography. The structural analysis of these complexes will reveal the ligand binding mode to the target and the structural changes in the target induced by the binding of these compounds, which is critically useful for the lead-compound

44


optimization. This study presents a new direction in the design of antifolates against mycobacterial infection. This study will also provide the molecular basis for further developing compounds that are highly potent and selective against Mtb and are potentially useful for the TB treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NOVEL COMPOUNDS FOR IMPROVED TREATMENT OF TUBERCULOSIS Principal Investigator & Institution: Owens, Albert H.; Member; Fasgen, Inc. 5210 Eastern Ave Baltimore, Md 21224 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2004 Summary: (provided by applicant): In 2000, the U.S. had over 16,000 cases of infectious tuberculosis and an estimated 10-15 million latent cases. Despite prolonged treatment regimens with significant side effects, reports of drug resistant TB in 43 states, and an estimated $345 million market opportunity, few new drugs to treat TB are in development. FASgen's SBIR Phase I goal is to choose a lead anti-tuberculosis candidate from 6 molecules active in vitro against Mycobacterium tuberculosis. Phase I specific aims are: 1) resupply candidate compounds and determine purity and chemical and biological stability; 2) determine minimum inhibitory concentrations (MICs) against a panel of mycobacteria in vitro; 3) determine in vitro cytotoxicities (lC50s) against Vero cells; 4) determine maximum tolerated dose (MTD) and dose limiting toxicity in mice for compounds with selectivity index (MTD/IC50) >10; 5) test the best compound in a murine inhalation model of TB; 6) verify that the MTD is not substantially different in immunocompromised (beige) mice; 7) test whether the best anti-tuberculosis compound is also active against M. avium in an immunocompromised mouse model; 8) repeat/confirm efficacy in animal models. In SBIR phase II, the lead compound will undergo safety/toxicology testing in animals and Phase I/Il safety and Phase II efficacy testing in man, most likely against multidrug resistant TB. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NOVEL CONTROL MECHANISMS IN ENDOSPORE FORMATION Principal Investigator & Institution: Switzer, Robert L.; Professor; Biochemistry; University of Illinois Urbana-Champaign Henry Administration Bldg Champaign, Il 61820 Timing: Fiscal Year 2004; Project Start 01-MAY-1991; Project End 31-MAR-2007 Summary: (provided by applicant): This research will study the regulation of bacterial genes by an important class of mechanisms called attenuation or antitermination. Such mechanisms control gene expression by regulating transcription termination signals that lie between the start of transcription (mRNA synthesis) and the coding regions of the genes being regulated. They are very widespread in bacteria. Two such systems have been discovered in the Switzer laboratory; these will be biochemically characterized in detail. In the first system the attenuation regulatory protein PyrR regulates pyrimidine biosynthetic (pyr) genes by binding to specific sites on pyr mRNA. A detailed study of PyrR-RNA interaction will be undertaken by binding studies using surface plasmon resonance and by high-resolution x-ray crystallography of PyrR-RNA complexes. The role of transcriptional pausing in PyrR action will be studied by genetic methods. The integrated regulation of the B. subtilis pyr operon by PyrR at three termination sites in the operon will be characterized by quantitative measurements of pyr RNA species in vivo. In the second system direct regulation of termination in the 5' leader of B. subtilis

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pyrG RNA (encoding CTP synthetase) by CTP without involvement of a regulatory protein has been demonstrated. The mechanism of this regulation will be studied by biochemical analysis of pyrG transcription in vitro. Comparative genomics demonstrates that the regulation of pyr genes by PyrR-dependent processes and pyrG antitermination similar to B. subtilis are found in many diverse bacterial genera, including many disease-causing bacteria in which antibiotic resistance is a growing clinical problem and others that are important in fermentation and biotechnology. A final objective of this research is to characterize the regulation of pyr genes in Mycobacteria, in which PyrR appears to act as an inhibitor of protein synthesis. It is planned to use nonpathogenic species for these investigations, but Mycobacteria are the agents of tuberculosis and leprosy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NUDIX HYDROLASES AND HAD SUPERFAMILY PHOSPHATASES Principal Investigator & Institution: O'handley, Suzanne F.; Chemistry; Rochester Institute of Technology 1 Lomb Memorial Dr Rochester, Ny 14623 Timing: Fiscal Year 2003; Project Start 15-JUN-2003; Project End 31-MAY-2006 Summary: (provided by applicant): The broad, long-term objectives of this research are three-fold: 1) to discover and characterize new enzyme families to help properly annotate the growing body of data from genome sequencing projects, 2) to discover and characterize new enzymes that could be potential novel antibiotic targets, and 3) to better understand how enzymes recognize their substrates, which could lead to better drug design. Progress toward these objectives will be made by studying enzymes of two different enzyme families, the Nudix hydrolases that hydrolyze substrates composed of nucleoside diphosphate linked to some moiety "x," and a phosphatase family of the HAD (haloacid dehalogenase) superfamily. The Nudix hydrolases contain the signature sequence GX5EX7REUXEEXGU where U=I, L, or V, and appear to perform vital functions in the cell by removing toxic compounds or natural metabolites that would be harmful at elevated levels. The principal investigator will focus on the Nudix hydrolases from Mycobacterium tuberculosis, because they could be potential novel antibiotic targets due to their important cellular roles. As for the phosphatases of the HAD superfamily, the principal investigator will initially focus on the pyridoxal phosphatase YZGD from P. thiaminolyticus and NAGD from E. coli. She will clone the genes, and express, purify, and characterize enzymes of these two families. Characterization will include determining substrate specificity, pH optimum, metal ion requirements, kinetic values, and products released. The principal investigator will also continue structural determination of the enzymes through NMR spectroscopy or x-ray crystallography. Since all of the enzymes will be members of one of two distinct enzyme families, they will be related except for substrate specificity. Therefore, these two protein families make excellent model systems for asking the question, "What determines substrate specificity? Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NUTRIENT TRANSPORT MECHANISMS IN MYCOBACTERIA Principal Investigator & Institution: Connell, Nancy D.; Associate Professor and ViceChair for r; Microbiol & Molecular Genetics; Univ of Med/Dent Nj Newark Newark, Nj 07107 Timing: Fiscal Year 2002; Project Start 01-JUL-1993; Project End 31-MAY-2005

46


Summary: (Adapted from the Applicant's Abstract): Mycobacteria are extremely important human pathogens. Their unusual cell wall structure and slow growth rate make them difficult to study from the standpoint of basic bacterial physiology. Mycobacteria have evolved into facultative intracellular parasites, capable of surviving with the phagocytic vacuole of the macrophage. It is likely that the ability of mycobacteria to acquire nutrients within the macrophage vacuole is tightly linked to intracellular survival and, therefore, to virulence. Knowledge of nutrient transport mechanisms for virulent mycobacteria will contribute directly to the design of novel therapeutic strategies and the development of new vaccines. The PI has isolated several mutants of Mycobacterium bovis BCG and M. tuberculosis which are deficient in transport of amino acids and peptides. In this competing continuation proposal, the PI will use classical and molecular genetic techniques and macrophage infection technology to address four specific aims: (1) to isolate and/or construct mutants of BCG and M. tuberculosis defective in transport and metabolism of arginine and oligopeptides; (2) to characterize transport of substrates by mutant and wild type BCG and M. tuberculosis; (3) to isolate and characterize transport regulatory mutants of BCG and M. tuberculosis; and (4) to examine the survival and growth characteristics, and nutrient transport activities, of mutant mycobacteria within mouse and human macrophages. These experiments will lead to a more complete understanding of the vacuolar environment which is the preferred ecological niche for mycobacteria within a mammalian host, and the nutrient uptake strategies employed by virulent mycobacteria to survive and grow in that intracellular environment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: POPULATION BASED MOLECULAR EPIDEMIOLOGY OF TB Principal Investigator & Institution: Hopewell, Philip C.; Professor of Medicine; Medicine; University of California San Francisco 3333 California Street, Suite 315 San Francisco, Ca 941430962 Timing: Fiscal Year 2002; Project Start 01-APR-1993; Project End 31-MAY-2006 Summary: (provided by applicant): Since January 1991 we have been using genotyping ot Mycobacterium tuberculosis together with conventional epidemiological approaches to elucidate the distribution and dynamics of tuberculosis in San Francisco. During this time we have refined and validated molecular epidemiological methods and applied these methods in a systematic series of studies that have been used to guide interventions tailored to the prevailing epidemiological circumstances. This study will extend our previous population-based, molecular epidemiologic studies of tuberculosis in support of the broad objective of eliminating tuberculosis in San Francisco that is caused by the transmission of Mycobacterium tuberculosis in San Francisco. This objective can be measured only by long-term application of molecular epidemiological methods. In addition, we propose to contribute to this objective by utilizing our detailed understanding of the dynamics of tuberculosis in San Francisco to examine genetic factors in both host and microbe that are associated with transmission of M. tuberculosis and progression of tuberculosis infection to clinical tuberculosis. In the proposed studies we will be combining state-of-the-art molecular epidemiology with recent advances in molecular biology, genomics, and computational biology in the setting of an effective tuberculosis control program to address some of the major current impediments to the elimination of the disease. The specific aims have been divided into four closely related components, intended to examine the interrelationships between clinical and epidemiological features of tuberculosis and human host and microbial genetic events in a setting wherein findings can be translated quickly to tuberculosis control efforts. The

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specific aims are divided as follows: 1) Identification and evaluation of tuberculosis control strategies; 2) Quantification of exposure and transmission; 3) Identification of host gene expression responses that distinguish susceptible and resistant persons; 4) Identification of mycobacterial factors associated with various outcomes following exposure to infectious tuberculosis. The components of these aims are all related to elucidating the factors related to transmission of M. tuberculosis and directed toward providing the scientific basis for measures designed to prevent transmission. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PRACTICAL DIAGNOSTICS FOR AIDS-RELATED PEDIATRIC TB,PERU Principal Investigator & Institution: Oberhelman, Richard A.; Professor; Tropical Med & Parasitology; Tulane University of Louisiana New Orleans, La New Orleans, La 70112 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-MAY-2005 Summary: (provided by applicant)Tuberculosis is the major infectious cause of mortality among AIDS patients in the developing world, and HIV infection has been shown to increase mortality from tuberculosis five-fold in parts of Subsaharan Africa. Increasingly, HI V-infected children in developing countries are becoming infected with Mycobacterium tuberculosis (Mtb) and dying at an early age, presenting new dilemmas that differ from those facing adults with HIV-Mtb coinfection. The diagnosis of pediatric TB is complicated by inefficient and expensive methods to recover Mtb and vague diagnostic criteria. This project will evaluate novel approaches to the diagnosis of AIDSrelated pediatric TB in a hyperendemic setting using 1) rapid, cost-effective Mtb culture and susceptibility methods based on direct microscopic observation techniques and 2) alternative non-invasive specimens such as nasopharyngeal aspirates (NPA) and stool to detect Mtb. An optional component will assess improved rapid detection of Mtb by a semi-nested polymerase chain reaction assay (N2 PCR), a technique appropriate for regional reference laboratories in developing countries. Our preliminary data show a high correlation between culture results and N2 PCR results in adults (sputum PCR) and children (stool and NPA PCR) with tuberculosis, and mean time to detection of Mtb by our microscopic observation method was 9 days (at a fraction of the cost of rapid methods used in the U.S.). This is a collaborative effort between PRISMA, a Peruvian private voluntary organization, two U.S. universities (Tulane and Johns Hopkins), and a Peruvian university (Cayetano Heredia). Two hundred-sixty children with pulmonary disease meeting clinical criteria for TB disease (including at least 100 HIV-infected) from the Hospital del Nino, Lima, Peru, and 260 age-matched controls from both high- and low-risk communities will be enrolled. Mtb will be detected in gastric aspirates (cases only), NPAs, and stool by new and traditional culture methods and by N2 PCR. Children with a positive N2 PCR but without clinical evidence of TB requiring antituberculous therapy will be followed longitudinally. These new diagnostic methods have tremendous potential to improve and simplify the diagnosis of pediatric tuberculosis in low-income countries with limited laboratory resources. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PRO-APOPTOTIC TUBERCULOSIS VACCINE Principal Investigator & Institution: Kernodle, Douglas S.; David E. Rogers Professor; Medicine; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2007

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Summary: (provided by applicant): A major hurdle in the development of effective vaccines against pathogens that reside within macrophages, including Mycobacterium tuberculosis, is how to deliver antigens in a manner that stimulates a protective cellular immune response. Recent investigations involving antisense mutants of M. tuberculosis that have diminished production of iron-cofactored superoxide dismutase (SOD) show that they are attenuated, induce strong CD4+ and CD8+ T-cell responses in mice, and exhibit promising activity as a vaccine prototype. These effects appear to be related to an unmasking of the innate immune responses normally inhibited by SOD, which is a prominent extracellular enzyme of M. tuberculosis and other pathogenic mycobacteria. The enhanced innate host immune responses presumably permit apoptosis-associated cross-presentation of microbial antigens via MHC Class I pathways to induce strong adaptive CD4+ and CD8+ T-cell responses, in contrast to the current vaccine for tuberculosis, BCG, which exhibits a predominant CD4+ T-cell response and minimal CD8+ T-cell responses. The goals of the current proposal are first, to characterize the cellular and cytokine responses in the lung observed early after infection with SODdiminished M. tuberculosis, as rapid pulmonary interstitial infiltration with mononuclear cells undergoing apoptosis appears to be a process unique to the SODdiminished strains that is not observed during infection with either virulent M. tuberculosis or BCG. This should define the conditions under which antigen crosspresentation occurs in vivo, yielding information that may be useful for a variety of vaccines. The second goal is to construct non-reverting SOD-diminished mutants of H37Rv and BCG by replacing the wild-type SOD allele with mutant alleles, some of which encode enzymatically less efficient mutants of SOD. This should yield a SODdiminished vaccine candidate that is stable and safe enough for administration to man. The third goal is to determine the optimal level of SOD production for maximal vaccine efficacy and the immune correlates of protection. Diminishing the production of factors produced by intracellular pathogens that inhibit macrophage apoptosis is a strategy for making new vaccines that achieve MHC Class I antigen presentation. This should have implications not only for tuberculosis but also for other infectious diseases in which CD8+ T-cell responses are a critical component of a protective immune response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RAPID DETECTION OF MYCOBACTERIUM TUBERCULOSIS Principal Investigator & Institution: Dorman, Susan E.; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Background: Tuberculosis (TB) is a leading cause of infectious disease mortality worldwide. The increase in multi-drug resistant (MDR) TB threatens the success of global TB control. There is a need for rapid, inexpensive methods for detection of M. tuberculosis (MTB) in clinical specimens and for drug susceptibility testing. An inexpensive, efficient, liquid culture method ("Microscopic Observation for Detection and Susceptibility", or MODS) that relies on microscopic detection of early bacterial growth has been described recently. Objectives: The overall objectives of this K23 proposal are 1) to optimize the MODS assay for drug susceptibility testing for ethambutol, streptomycin, and pyrazinamide; 2) to determine the performance characteristics of MODS for detection of MTB among pulmonary TB suspects in a TB-endemic setting; 3) to compare the time to detection of MTB growth for MODS versus conventional Loewenstein-Jensen (LJ) culture; 4) to determine the clinical benefit of MODS for detection of MDR TB among high risk persons in a TB-endemic setting; and 5) to gain training in clinical research through mentored experience and

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coursework. Methods: Project 1 will be a laboratory study performed at Johns Hopkins University to optimize MODS performance for drug susceptibility testing for ethambutol, streptomycin, and pyrazinamide. Project 2 will be a prospective study of laboratory performance of two diagnostic tests in which study subjects will be adult pulmonary TB suspects at a university-based hospital in Rio de Janeiro, Brazil. Sensitivity and specificity of MODS will be determined using a clinical TB case definition as the gold standard. Days to positivity will be compared for the two methods. Project 3 will be a prospective, randomized, controlled study of the clinical benefit of MODS for drug susceptibility testing among retreatment pulmonary TB cases at community Health Centers in Rio de Janeiro. The primary objective is to compare the time to initiation of appropriate anti-tuberculosis therapy when MODS versus LJ is used for INH and RIF susceptibility testing. These studies will be nested into ongoing collaborative TB studies in Rio de Janeiro. Relevance: Results of these studies will improve our understanding of the laboratory performance and clinical benefit of this test, and lead to improved detection and treatment of TB. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RECOMBINOGENIC ENGINEERING OF PATHOGENIC BACTERIA Principal Investigator & Institution: Murphy, Kenan C.; Molecular Genetics & Microbiol; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (Provided by applicant): Gene deletion and/or replacement is the single most important tool for definitively identifying critical functions of infectivity and virulence in pathogenic bacteria. Yet the tools available to make such gene replacements in pathogenic bacteria have, for the most part, remained unchanged for the last 10 years. While genome sequencing projects continue to increase the number of open reading frames available for genetic analysis, gene knock-out technology in many bacterial systems remains technically cumbersome, and in some cases, unfeasible. This project is designed to explore a novel methodology for the enhancement of gene replacement in pathogenic bacteria. The Red recombination system from bacteriophage lambda, when expressed in Escherichia coli, generates a hyper-recombinogenic phenotype whereby gene replacement occurs at an extremely high efficiency following transformation with small (2-3 kb) linear DNA substrates. This gene replacement scheme is unique in that plasmid-chromosome co-integrants do not have to be formed (or resolved), and prior cloning of the gene of interest is not required. PCR-generated substrates with as little as 40 bp of flanking homology are substrates for efficient Red-mediated gene replacement. The recombination intermediates generated by lambda Red are channeled into the host recombination pathway. It is this "jump start" in the initiation of recombination that likely plays a key role in the generation of the hyper-rec phenotype of lambda Redcontaining E. coli. Since most bacteria contain homologs of many of the recombination functions described in E. coli (e.g., recA, recBCD, ruvAB), Red will likely serve to generate the same hyper-rec phenotype when expressed in other (pathogenic) strains of bacteria. This proposal is a test of this hypothesis. This project is designed to generate hyper-recombinogenic strains of Pseudomonas aeruginosa and Mycobacterium tuberculosis by expression of red and phage anti-RecBCD functions in vivo from plasmids, or by replacing the chromosomal recBCD genes with a red-expressing operon. The system can be set up so that the hyper-rec phenotype is transient, resulting in pathogens that are altered only within the gene of interest. This project has the potential to revolutionize the methods of genetic manipulation in microorganisms, leading to

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faster identification of virulence genes, greater flexibility in the genetic analysis of these genes, and the speedy generation of bacterial mutants for vaccine development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF HOST RESPONSE GENES IN PATHOGENESIS OF TB Principal Investigator & Institution: Roman, Jesse R.; Division Director; Medicine; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 10-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) Mycobacterium tuberculosis (Mtb) is the leading infectious cause of death worldwide. Our inability to control the spread of this disease and the absence of new effective chemotherapeutic agents are due in part to the limited knowledge about host genes that control granuloma formation and other aspects of the host's response to this pathogen in lung. One host response considered important in tuberculosis is that of tissue remodeling which is characterized by alterations in extracellular matrix expression and degradation. Tissue remodeling is responsible for the development of Mtb- mediated fibrosis, bronchiectasis, and cavitation. Although these processes are often considered late manifestations of pulmonary tuberculosis, mounting evidence suggests that the genes involved in the control of tissue remodeling (TR genes) are expressed very early in lung after Mtb infection, and are involved in other key processes including leukocyte recruitment and granuloma formation. Consistent with this, we have demonstrated that: 1) Mtb Erdman bacilli and isolated cell wall components of Mtb induce the expression of TR genes encoding for extracellular matrices, matrix-degrading proteases, and pro-fibrotic growth factors in vitro (i.e., human monocyte/macrophages) and in vivo (C57BL/6 mice). In mice, the induction of TR genes correlated both spatially and temporally with the inflammatory response. 2) The induction of TR genes in monocyte/macrophages by Mtb occurs via receptormediated protein kinase pathways and requires the induction of specific transcription factors (e.g., AP-1). 3) The injection of trehalose-6,6'-dimycolate (previously called mycobacterial cord factor) or live Mtb Erdman strain into mice with knockout mutations in a TR gene (Matrix Metalloproteinase-9) resulted in increased inflammation and granuloma formation. Together, this information suggests that the interaction between Mtb and host cells triggers TR gene expression; in turn, the products of TR genes play important roles in the host response to Mtb. The overall goal of this application is to identify the TR genes that are differentially expressed in pulmonary tuberculosis and study their function. This will be accomplished in 3 specific aims designed to: 1) Identify host TR genes differentially expressed in vitro in human monocyte/macrophages after infection with Mtb using High Density Oligonucleotide Array or HDOA. 2) Identify the TR genes differentially expressed in the lungs of infected mice and in the lungs of humans with pulmonary tuberculosis using HDOA. 3) Determine the function of specific TR genes identified in Specific Aims I and II by infection of mice with gene knockout mutations. We propose to study the function of 3 (at the most 4) TR genes. We will begin exploring the function of 2 TR genes encoding for matrix metalloproteinases which we have demonstrated to be differentially expressed in Mtb-infected lungs and for which knockout animals are already available in our laboratory. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF CHEMOKINES IN ANTHRAX PATHOGENESIS Principal Investigator & Institution: Peters, Wendy; J. David Gladstone Institutes Box 419100, 365 Vermont St San Francisco, Ca 94103

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Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): The recent deliberate dissemination of anthrax spores has revealed significant gaps in our knowledge of anthrax pathogenesis. In anthrax infection, as in other inflammatory diseases, the macrophage can play opposing roles. Macrophages serve to limit the infection by ingesting and eliminating the spores and vegetative bacilli, but they can also be a reservoir for replication and dissemination of the bacteria. In this grant we will use recently developed murine genetic models to clarify the role of the macrophage in anthrax pathogenesis. We will establish the time course of leukocyte migration to the lungs and draining mediastinal lymph nodes of mice infected with pulmonary anthrax, and we will identify the signals responsible for this recruitment. Previous work from our group has established that the monocyte chemoattractant protein (MCP) family of chemokines and their receptor, chemokine receptor 2 (CCR2), play pivotal roles in the migration of macrophages and dendritic cells to sites of inflammation, and that they are essential for host survival after infection with Mycobacterium tuberculosis. Unlike M. tuberculosis, a prominent feature of infection with Bacillus anthracis is the systemic effects produced by anthrax toxin (ATX) acting on the macrophages. Thus in the case of anthrax, it is unclear if impaired macrophage trafficking would be detrimental, or perhaps even beneficial to the host. We will take advantage of our CCR2-/- mice to directly address these possibilities in a model of pulmonary anthrax. These experiments will reveal whether paradigms established for the pathogenesis of M. tuberculosis apply to B. anthracis. We will also compare the responses of CCR2-/- and CCR2+/+ mice to lethal toxin a component of ATX. Finally, we will attempt to produce a mouse model of cutaneous anthrax infection. Completion of the specific aims of this pilot grant will establish the kinetics of leukocyte trafficking in pulmonary anthrax, will determine if chemokines such as MCP-1 play an important role in macrophage trafficking and host survival in pulmonary anthrax, and may provide a rationale for the use of chemokine/chemokine receptor antagonists in the treatment of anthrax. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SIV/MYCOBACTERIUM COINFECTION Principal Investigator & Institution: Chen, Zheng W.; Associate Professor; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 01-JUN-1998; Project End 31-MAY-2004 Summary: (Adapted from Investigator's Abstract): Coinfection with HIV and Mycobacterium tuberculosis (M. tb) is associated with high rates of active tuberculosis, and possibly an acceleration of the progression of clinical AIDS. Elucidating the interplay of immunopathogenic events that occur as a result of HIV/M. tb coinfection is, therefore, of central importance for understanding the immune sequlae of this coinfection. The simian immunodeficiency virus (SIV)-infected macaque monkey has proven to be an important model for the study of the pathogenesis and treatment of AIDS. The investigators have recently shown that macaques coinfected with SIV and BCG develop a syndrome similar to AIDS virus-related tuberculosis. Employing this SIV/mycobacterium coinfection model, the immunopathogenesis of AIDS virus interactions with mycobacterium and the evolution of tuberculosis will be evaluated. In these studies, the following will be assessed: I. Disease pathogenesis in SIV/BCG coinfected rhesus monkeys. II. CD4+ responses in BCG-infected and SIV/BCG coinfected monkeys. III. CD8+ responses in BCG-infected and SIV/BCG infected monkeys. IV. T gd+ cell responses in BCG-infected and SIV/BCG coinfected monkeys. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SP-A PHAGOCYTOSIS

RECEPTOR

MODULATION

OF

MACROPHAGE

Principal Investigator & Institution: Chroneos, Zissis C.; Biochemistry; University of Texas Hlth Ctr at Tyler 11937 Us Highway 271 Tyler, Tx 75708 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-MAY-2005 Summary: Pulmonary mycobacterial infections affect approximately one third of the world's population and claim millions of lives annually. Infectious organisms that are inhaled into the airspaces encounter alveolar macrophages in the context of immune proteins in the alveolar lining fluid. Specifically, surfactant protein A (SP-A), a lungspecific collectin, orchestrates macrophage activation, phagocytosis and killing of mycobacteria via a 210 kDa (SP-8210) receptor. The long term objective of this application is to elucidate the mechanisms by which SP-A and its receptor direct alveolar macrophage host defense functions in the lung fn vivo. This proposal is based on these new findings: 1) the SP-A receptor is a heterooligomer of 210 kDa (SP-8210) and 240 kDa (SP-8240) cell- surface, and 78 kDa (SP-R78) intracellular proteins. Both SP-8210 and SP-R78 have been sequenced by mass spectrometry.2) The composition of the SP-A receptor heterooligomer may vary based on the state of macrophage differentiation. The central hypothesis of this proposal is that the interaction of SP-A with its receptor coordinates macrophage activation and mycobacterial clearance via distinct SP-A receptor- directed mechanisms. To test this hypothesis we will study SP-A receptor structure and function in the context of mycobacterial infection. The Specific Aims are: 1) reconstitute a functional SP-A receptor in COS.cells and use a panel of recombinant wild type and mutant SP-A proteins to determine mechanisms of SP-A-binding and function in the phagocytosis of mycobacteria, 2) determine the role of the intracellular SP-R78 in the activation of an SP-A-specific pathway for intracellular targeting of mycobacteria, and 3) study the relative expression of the SP- A receptor components during macrophage differentiation to understand how the structure of the SP-A receptor directs SP-A-mediated mycobacterial clearance and activation of macrophages. To facilitate these studies we will utilize immature alveolar macrophages that we have isolated, and Mycobacterium bovis BCG and Mycobacterium tuberculosis Ra reporter strains that express green fluorescent protein. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STEROL/HOPANOID BIOSYNTHESIS: AN ANTI-TB DRUG TARGET Principal Investigator & Institution: Crick, Dean C.; Microbiol, Immunology & Path (Mip); Colorado State University-Fort Collins Fort Collins, Co 80523 Timing: Fiscal Year 2002; Project Start 15-JUN-2001; Project End 31-MAY-2005 Summary: (provided by applicant): Multi-drug resistant tuberculosis is increasing in prevalence worldwide; therefore, a greater understanding of the basic biochemistry of Mycobacterium tuberculosis is of utmost importance. Analysis of the M. tuberculosis genome suggests that there may be a biosynthetic pathway analogous to eukaryotic sterol synthesis in this organism. Preliminary evidence indicates that the M. tuberculosis genome encodes enzymes with structural homology to several eukaryotic sterol synthesis enzymes including farnesyl diphosphate synthase, squalene synthase, squalene epoxidase, oxidosqualene cyclase and lanosterol 14a-demethylase. It has been shown that both the M. tuberculosis farnesyl diphosphate synthase and lanosterol 14ademethylase are functional as well as structural homologs of the eukaryotic enzymes. More importantly, commercial anti-fungal drugs that are known inhibitors of sterol synthesis (specifically oxidosqualene cyclase and lanosterol 14a-demethylase) effectively

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inhibit the growth of M. tuberculosis in culture. It is hypothesized that M. tuberculosis synthesizes cyclic isoprenoid compounds, perhaps sterols or hopanoids, which are essential to the viability of the organism. Therefore, the specific aims of this proposal are to: 1) identify and characterize cyclic isoprenoid compounds in M. tuberculosis. 2) isolate, enzymatically characterize and determine the essentiality of the sterol synthesis homologs expressed by M. tuberculosis. 3) identify and characterize the active site of the oxidosqualene cyclase homolog. The identification of a sterol/hopanoid biosynthetic pathway in M. tuberculosis and characterization of relevant enzymes represents a novel approach to the identification of previously unsuspected antituberculosis drug targets. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SULFATE ADENYLATION -- BIOCHEMISTRY & ENZYMOLOGY Principal Investigator & Institution: Leyh, Thomas S.; Professor; Biochemistry; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2004; Project Start 02-SEP-1995; Project End 31-MAR-2008 Summary: (provided by applicant): The entry of sulfate into metabolism requires that it be chemically activated. The only known metabolic means of activating sulfate is the formation of the very high-energy phosphoric-sulfuric acid anhydride bond (?Go= -19 kcal/mole). This bond is the chemical hallmark of activated sulfate (APS or PAPS), and it is from this high-energy environment that the sulfuryl-moiety (-SO3) passes quickly and favorably into its subsequent metabolic biochemistry. The activated bond is formed in a transfer reaction, catalyzed by ATP sulfurylase, in which the adenylyl-moiety (AMP~) of ATP is transferred to sulfate. In mammals, sulfuryl-group transfer to proteins and small molecule metabolites regulates a wide-variety of metabolic processes including neuropeptide- and steroid-hormone action, growth-factor recognition, and lymph cell circulation. This proposal outlines structurally-based mechanistic inquires designed to address central issues regarding the function and evolution of the mammalian class of ATP sulfurylases. Bacterial ATP sulfurylases harbor a GTPase subunit (discovered in this laboratory) that is an evolutionary descendant of elongation factor Tu. The conformational changes that this subunit undergoes as a consequence of GTP hydrolysis accelerate turnover of the adenylyl-transferase subunit, and couple the chemical potentials of GTP hydrolysis and APS synthesis. We have recently discovered that ATP sulfurylase forms a complex with another enzyme in the cysteine biosynthetic pathway (O-acetly-l-serine sulfhydrylase), and that their interactions produce "new" catalytic function - the hydrolysis of ATP. These enzymes organize into a metabolic pump, each stroke of which delivers one molecule of APS into the pathway. The mechanism of the pump will be explored in this grant. Working with an as yet uncharacterized and novel ATP sulfurylase from Mycobacterium tuberculosis, our preliminary data extends these finding to include five of the seven enzymes in the pathway. We will define and study the cysteine metabolon with the goal of understanding the hierarchical functions that emerge from the self-organization of this pathway. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SURFACTANT AND TUBERCULOSIS PATHOGENESIS Principal Investigator & Institution: Ferguson, J Scott.; Internal Medicine; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-AUG-1998; Project End 31-JUL-2003

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Summary: (Adapted from applicant's abstract) Tuberculosis is the leading cause of death due to an infectious disease in the world. As a pulmonary pathogen, the initial interaction between the causative bacterium Mycobacterium tuberculosis (M.tb) and the human host is in the lung where surfactant, epithelial cells, and alveolar macrophages are located. This initial interaction between these components of the alveolus and M.tb dictate the outcome of infection. The understanding of this process is limited, but critical in this disease. This five year award will provide insight into the pathogenesis of tuberculosis, specifically in the role that surfactant components play in the early host response to this host-adapted microorganism. The specific aims are to: characterize the binding of surfactant protein D (SP-D) to virulent and attenuated M.tb strains, and their major surface components, and to determine the impact of this binding on bacterial agglutination; determine if SP-D alone or in conjunction with surfactant protein A (SP-A), and the major surfactant phospholipid, dipalmitoyl phosphatidylcholine (DPPC), influences the phagocytosis of M.tb by macrophages; determine if SP-D, SP-A, and DPPC influence the intracellular survival of M.tb in the macrophage, and to examine whether this is the result of altered cellular responses such as phagosome-lysosome fusion or the oxidative burst; and, determine if SP-D, SP-A, and DPPC influence the M.tb-pulmonary epithelial cell interaction. These specific aims will be accomplished using in vitro techniques available at the primary laboratory and through collaborative efforts. The candidate is a fellow in the Division of Pulmonary, Critical Care, and Occupational Medicine. Through an intense course of didactic and laboratory study, he will define the essential role that surfactant components play in the host defense response to M.tb using methods of microbiology, immunology, biochemistry, molecular biology, and cell physiology. He will determine the role that SP-A, SP-D, and DPPC, have in regulating the immune response of macrophages and epithelial cells to this intracellular pathogen. The proposed work will be performed at the University of Iowa, a well-known leader in biomedical research. The work to be performed encompasses the Division of Infectious Diseases and the Division of Pulmonary, Critical Care, and Occupational Medicine, as well as various departments from the College of Medicine. Laboratory facilities are at the Iowa City Veterans Administration Center, and the University of Iowa. The candidate, mentors, advisory committee, and collaborators will work closely to achieve the goals of this proposed award: to define critical interactions between the human pathogen M.tb and the host, and for the principal investigator to become an accomplished independent biomedical investigator. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TARGETING M. TUBERCULOSIS ALANINE LIGASE FOR DRUG DESIGN Principal Investigator & Institution: Barletta, Raul G.; Veterinary & Biomedical Scis; University of Nebraska Lincoln Lincoln, Ne 685880430 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2004 Summary: (Provided by the applicant): Mycobacterium tuberculosis causes a serious chronic infection in human beings. M. tuberculosis, along with Mycobacterium avium, is a major opportunistic pathogen of AIDS patients. Although generally susceptible to antimycobacterial agents, multi-drug resistant strains of M. tuberculosis have emerged, underlying the need for new therapeutic agents. Peptidoglycan is the backbone of the mycobacterial cell wall, and drugs that inhibit its biosynthesis cause a bactericidal effect due to cell lysis. D-alanine is a required component of the mycobacteriai peptidoglycan. Thus, those biosynthetic enzymes involved in the synthesis and incorporation of D-

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alanine are attractive targets for new drug development, especially because these enzymes are not found in mammalian hosts. The terminal D-alanyl-D-alanine dipeptide of the peptidoglycan side chain is an essential component for this process and its synthesis is catalyzed by the enzyme D-alanyl-D- alanine synthetase, usually denominated D-alanine ligase (Ddl). Unfortunately, the specific characteristics of the M. tuberculosis enzyme have not been fully characterized, nor the essentiality of the gene has been elucidated. In this context, our hypothesis for the proposed project is that Dalanine ligase plays an essential role in M. tuberculosis physiology and is a useful target for drug design. To test this hypothesis, we plan to: 1) Overexpress, purify, and characterize biochemically the M. tuberculosis Ddl enzyme; and 2) Test the essential role of Ddl enzyme in M. tuberculosis physiology. These studies are expected to provide basic knowledge on key enzymes involved in the pathway of peptidoglycan biosynthesis in mycobacteria. Most importantly, we will obtain information on the physiological essentiality and biochemical parameters of the Ddl enzyme necessary to develop assays for the screening and testing of candidate compounds. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TECHNOLOGY FOR NEW TUBERCULOSIS ANTI-INFECTIVES Principal Investigator & Institution: Cunningham, Philip R.; Associate Professor; Biological Sciences; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): A genetic system was developed in Escherichia coil that uses combinatorial genetics to identify mutations in ribosomal RNA (rRNA) drug targets that might lead to antibiotic resistance. Recently, the 16S RNA from Mycobacterium tuberculosis was substituted for E. coil 16S RNA in this system but the construct produced inactive ribosomes when expressed in E. coll. Hybrid 16S rRNAs containing the 5' and central domains from E. coil and the 3' major and minor domains from M. tuberculosis, however, produce active ribosomes in E. coil This suggests that nucleotide differences in the 5' and/or central domain of M. tuberculosis 16S RNA are responsible for loss of function when expressed in E. coll. Absence of function in 30S subunits composed entirely of M. tuberculosis 16S rRNA is probably due to the inability of a nucleotide(s) in M. tuberculosis 16S RNA to interact with an E. coil 30S ligand(s). The goal of this project is to develop genetic technology for the isolation of new antiinfectives that address the issue of drug resistance in M. tuberculosis. Two aims are proposed: (1) The nucleotides in M. tuberculosis rRNA responsible for loss of function in E. coil will be identified and (2) the M. tuberculosis 30S ligand(s) required for expression of M. tuberculosis 16S RNA in E. coil will be identified and cloned. Coexpression of M. tuberculosis 16S RNA and the ligands should produce functional ribosomes containing M. tuberculosis 16S RNA in E. coil Drug resistance in M. tuberculosis is due primarily to chromosomal mutations in the drug targets. Multi-drug resistance appears to occur through sequential accumulation of such mutations. For target-site mutations to be clinically significant, the mutated target must retain most of its biological activity since loss of function decreases the fitness and virulence of the pathogen. This is especially so for functional regions of rRNA, which are critical for protein synthesis. Successful completion of this project will provide a technology to develop novel anti-infectives that recognize all possible functional forms of the target, even if not yet found in nature, and are therefore unlikely to be susceptible to the development of resistance through target modification. Once developed, this technology will allow the use of rRNA genes from other microbial pathogens in designing new antiinfectives.

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

Project Title: THE EFFECT OF ART ON RATES AND TRANSMISSION OF TB Principal Investigator & Institution: Bekker, Linda-Gail; Univ of Witwaterstrand Johannesburg, Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: Mycobacterium tuberculosis is the commonest pathogen leading to fatal opportunistic disease in sub-Saharan Africa. South Africa is one of 5 countries with HIVpositive TB > 300 cases/100,000This proposal aims at demonstrating the benefits of antiretroviral therapy on TB in the community of Masiphumelele. Because the major cause of morbidity and mortality in HIV-1 infected adults and children is TB, safeguarding the household from the disease is a public health priority Project hypothesis: The introduction of ART in HIV-positive members of a community will have an impact on the TB morbidity and mortality in both HIV negative and positive members. Masiphumelele, a well circumscribed community of 10,000 in Cape Town where 600 adults, 100 children and 60 neonates will be treated with ART (Project 1 and 2 of this CIPRA). In addition it is our hypothesis that ART will change transmission patterns of tuberculosis in this community. Specific Aims: 1. To measure the impact of community-based antiretroviral therapy (ART) on active tuberculosis case rates, TB hospitalization rates and tuberculosis death rates, of the community residents, both HIV infected and un-infected. 2. To measure the impact of ART on the proportion of active TB in HIV infected individuals due to reactivation of latent infection versus reinfection. 3. To measure the impact of ART on transmission patterns of TB within the community. Is there a reduction of cluster sizes of M. tuberculosis? 4. To measure the contribution of HIV infected individuals to the transmission of TB. 5. To type the strains of M. tuberculosis cultured from the community using restriction length polymorphism (RFLP) to determine if the introduction of ART will change the transmission patterns of tuberculosis qualitatively as well as quantitatively in this community. 6. To use a geographic information system (GIS) and RFLP database for the Masiphumelele village, identifying TB transmission locations. 7. To measure the ongoing transmission of TB using annual tuberculin skin tests (TST) in cohorts of local school children and correlate it with the successful use of ART by. the reduction in AIDS related deaths, opportunistic infections and hospitalizations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TRAINING AND RESEARCH IN HIV PREVENTION IN RUSSIA Principal Investigator & Institution: Merson, Michael H.; Dean of Public Health; Epidemiology and Public Health; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 30-SEP-1998; Project End 31-MAY-2003 Summary: This proposal is an "Administrative Supplemental Budget Request" to the Fogarty International Center (FIC) for expanded training within the Yale AITRP to further build in-country research and public health capacity in Transitional Case Management (TCM) of cases of active Mycobacterium tuberculosis infection in Russian prisoners at the time of their release. The training and research program that we propose has the following objectives: 1) To identify two psychologists or sociologists from the Departments of Psychology and/or Sociology at St. Petersburg State University and one junior physician currently working at the Tuberculosis Institute I St. Petersburg, Russia who will receive targeted training in; infectious disease epidemiology at Yale University

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School of Public Health; Transitional Case Management of prisoners at the time of their release from prison; direct observed therapy (DOTS). To provide these junior physician/scientists with re-entry grants for conducting research in St. Petersburg concerning identifying cost-effective practical methods for assuring that these recently discharged prisoners will be properly placed in an after-care situation providing adequate treatment for their Mycobacterium tuberculosis infection. This proposal links five institutions; Yale University School of Public Health; the CT Prison Association; the Tuberculosis Institute in St. Petersburg; the Departments of Psychology and Sociology at St. Petersburg State University; and the Center for Sociology, Psychology and Law Research, an NGO in St. Petersburg with experience in aftercare for individuals recently released from prison. These five institutions will collaborate in a training and research program to introduce a system of Transitional Case Management (TCM) of active cases of tuberculosis in prisoners immediately upon release from a prison in St. Petersburg, Russia. This three-year program will conduct an open search in the Departments of Psychology at St. Petersburg State University (SPSU) for two psychologists and/or sociologists and in the Tuberculosis Institute for one junior physician who will each spend 12 months in the United States; 7 months at Yale for graduate training in infectious disease epidemiology; 4 months in the Translational Linkage to the Community (TLC) Program at the Connecticut Prison Association for on-the job training in translational use management of prisoners with anti-tuberculosis treatment. Following this 12 month stay in the United States; each Fogarty Transitional Case Management Scholar will return to St. Petersburg to begin research work on a subject related to transitional case management of prisoners released with active TB. This work will be supported by his/her Re-entry Grant. A senior scientist(s) at SPSU or the TI and a senior scientist(s) at Yale will provide appropriate mentorship. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TUBERCLE BACILLI BINDING TO HOST CELLS: VACCINE DESIGN Principal Investigator & Institution: Hall-Stoodley, Luanne; Assistant Professor; Ligocyte Pharmaceuticals, Inc. 920 Technology Blvd, Ste C Bozeman, Mt 59715 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-MAR-2004 Summary: (Provided by Applicant) Three million people die each year from tuberculosis (TB) in spite of the use of the existing anti-mycobacterial antibiotics and the BCG vaccine. Clearly, a better vaccine and better ways to treat TB are needed. The purpose of this STTR Phase I feasibility study is to evaluate Mycobacterium tuberculosis-binding interactions with several human cell types and pathogen recognition molecules. Pathogens typically gain entry to a host tissue by using cell-tocell recognition and attachment mechanisms. Conversely, the innate immune system recognizes many common motifs in microbial cell walls. These motifs are present in M. tuberculosis and bacilli-host binding interactions are increasingly being identified for M. tuberculosis. The experimental aim of the proposed study is to functionally evaluate M. tuberculosis binding interactions with human host molecules and cells under shear conditions that more accurately simulate physiological conditions in the lung. By exploring adhesion events we anticipate the discovery of novel molecular targets that could be used to develop better therapies or an improved vaccine. Blocking these targets may prevent infection by abrogating initial attachment by M. tuberculosis to permissive host cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VACCINE DEVELOPMENT IN TUBERCULOSIS Principal Investigator & Institution: Campos-Neto, Antonio; Director; Infectious Disease Research Institute 1124 Columbia St, Ste 600 Seattle, Wa 98104 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-MAY-2005 Summary: This proposal is designed to identify, characterize, and clone Mycobacterium tuberculosis genes encoding proteins associated with specific T cell responses of presumed protected humans and animals. Antigens associated with both CD4+ and/or CD8+ T cell responses are the target of this proposal. The recent identification, by our group, of a novel and protective antigen opens new possibilities for vaccine development. Two other antigens/gene have been cloned, expressed, and purified. They will be evaluated for their ability to elicit T cell responses from human PBMC, primarily from non-BCG immunized PPD+ healthy individuals. The recombinant antigens alone and in combination will also be evaluated as vaccine candidates in three animal protection models, including mice, guinea pigs, and cynomolgus monkeys, all of which will be challenged by aerosol or intratracheal routes. In addition to the evaluation of these antigens, we will characterize and clone other vaccine candidates using recently developed approaches for the direct identification of both CD4 and CD8 T cell antigens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VIRULENCE FACTORS IN MYCOBACTERIA Principal Investigator & Institution: Rubin, Eric J.; Assistant Professor; Immunology/Infections Diseases; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-MAY-2006 Summary: (provided by the applicant): Tuberculosis infects much of the world's population and is responsible for millions of deaths annually. The causative organism, Mycobacterium tuberculosis, has been recognized for over a century, but little is known about the molecular mechanisms used by this bacterium to cause disease. I propose to use three methods we have recently developed in conjunction with the M tuberculosis genomic sequence to determine which genes are required by M tuberculosis to survive both in vitro and in vivo. First, we have developed a new transposon to perform saturating mutagenesis in M tuberculosis. Second, we have made a DNA microarray with which we can measure hybridization to each M tuberculosis open reading frame. Third, we have developed transposon junction hybridization (TJH), a method for mapping the sites of transposon insertions in large pools of mutants using a DNA microarray. We propose to use TJH to compare the genes required for M tuberculosis in vitro growth with those needed to survive in an animal. We will use a variation of TJH, differential length hybridization, to identify the complete set of genes that are essential for growth in defined media. We will also sequence several thousand clones from an insertion mutant library to produce a bank of defined mutants. This will allow us to test individual strains that contain mutations in candidate virulence genes identified by TJH. Since pathogens coordinately regulate expression of virulence genes, we will focus on regulatory genes required for infection and determine which downstream genes they control. This will enable us to identify both genes required for survival and for causing disease. Identification of genes important in infection should lead to the development of new strategies of tuberculosis treatment and prevention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VIRULENCE GENES IN MYCOBACTERIUM TUBERCULOSIS Principal Investigator & Institution: Yoder, Mark A.; Environmental Health Sciences; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2004 Summary: (provided by applicant): In order to identify mycobacterial genes important for survival within the host, a rabbit model of pulmonary tuberculosis will be developed. Rabbits will be infected by transthoracic injection and intrabronchial instillation of mycobacteria. Bacillary multiplication within cavities will allow for isolation of sufficient quantities of RNA for analysis using a Mycobacterium tuberculosis oligonucleotide microarray. Comparison of gene expression patterns between mycobacteria growing in culture and those growing in vivo will provide information on genes important in mycobacterial survival within the host. A second approach will be used concurrently to determine virulence genes. A Mariner-derived transposon that has been shown to insert randomly into the M. tuberculosis genome will be used to generate libraries of mycobacterial mutants. The technique of transposon site hybridization will be used to compare pools of mutants before and after animal infection. Microarray analysis will be used to determine deletion mutants which are absent from the output pools. These mutants potentially have deletions in virulence genes, and these genes, in addition to those identified by in vivo gene expression profiling, will be further characterized individually. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: WHIB3 IN M. TUBERCULOSIS VIRULENCE Principal Investigator & Institution: Steyn, Andries Jc.; Microbiology; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2004; Project Start 15-JUN-2004; Project End 31-MAY-2009 Summary: (provided by applicant): M. tuberculosis (Mtb) is one of the leading causes of death worldwide and claims millions of lives annually. Approximately 1.7 billion people worldwide are asymptomatically infected with the tubercle bacillus and constitute a major impediment to worldwide public health control measures. Previous work had shown that a point mutation (Arg515->His) in the 4.2 domain of RpoV, the principal sigma factor in Mycobacterium bovis, is attenuating. Using the yeast twohybrid system, we have established that the 4.2 domain of virulent Mtb specifically interacts with a regulatory protein WhiB3. In contrast, the attenuated RpoV allele containing the single point mutation was unable to interact with WhiB3. We constructed a Mtb whiB3 mutant (deltawhiB3) and showed that it behaved identical to the wild-type strain with respect to its ability to replicate in mice and guinea pigs in vivo. Mice infected with AwhiB3 showed significantly longer survival times than mice infected with the wild type Mtb. In addition, the lungs of AwhiB3-infected mice appeared much less adversely affected. It is notable that this virulence gene would not have been detected using conventional screens such as signature tagged mutagenesis, which screens for mutants primarily defective in growth, and not virulence. Furthermore, we have shown that a whiB3 mutant of virulent M. bovis, in contrast to AwhiB3, was completely attenuated for growth in guinea pigs. Mtb contain seven WhiB homologues that show strong homology to proteins that are critical for sporulation in Streptomyces spp. We hypothesize that WhiB3 regulates the expression of mycobacterial components that modulate the host immune system. To better understand the mechanism of whiB3 in Mtb virulence, we will use electron paramagnetic resonance spectroscopy (EPR) to biochemically characterize the WhiB3 Fe-S cluster genes, identify genes under WhiB3

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control, and characterize proteins that interact with the WhiB family. We will also demonstrate that WhiB3 is a DNA binding protein capable of activating transcription of specific target genes. We will study the in vivo expression of the whiB family and their role in virulence. These studies will characterize the WhiB family as potential targets for interventions that may abolish virulence, but not growth. These studies will also provide insight into understanding whether TB is an anomalous immunological reaction in response to the persistent bacilli, whether the bacilli themselves induce lethal immunopathology, or if it is a combination of both. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “Mycobacterium tuberculosis” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for Mycobacterium tuberculosis in the PubMed Central database: •

[beta]-Chemokines Are Induced by Mycobacterium tuberculosis and Inhibit Its Growth. by Saukkonen JJ, Bazydlo B, Thomas M, Strieter RM, Keane J, Kornfeld H.; 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127823

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A Combination of Two Genetic Markers Is Sufficient for Restriction Fragment Length Polymorphism Typing of Mycobacterium tuberculosis Complex in Areas with a High Incidence of Tuberculosis. by Rasolofo-Razanamparany V, Ramarokoto H, Auregan G, Gicquel B, Chanteau S.; 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87965

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A Family of acr-Coregulated Mycobacterium tuberculosis Genes Shares a Common DNA Motif and Requires Rv3133c (dosR or devR) for Expression. by Florczyk MA, McCue LA, Purkayastha A, Currenti E, Wolin MJ, McDonough KA.; 2003 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=187371

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A Multidrug-Resistant Tuberculosis Microepidemic Caused by Genetically Closely Related Mycobacterium tuberculosis Strains. by Kubin M, Havelkova M, Hyncicova I, Svecova Z, Kaustova J, Kremer K, van Soolingen D.; 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85324

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A new evolutionary scenario for the Mycobacterium tuberculosis complex. by Brosch R, Gordon SV, Marmiesse M, Brodin P, Buchrieser C, Eiglmeier K, Garnier T, Gutierrez C, Hewinson G, Kremer K, Parsons LM, Pym AS, Samper S, van Soolingen D, Cole ST.; 2002 Mar 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122584

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Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.

With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.

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A rapid method for screening antimicrobial agents for activities against a strain of Mycobacterium tuberculosis expressing firefly luciferase. by Cooksey RC, Crawford JT, Jacobs WR Jr, Shinnick TM.; 1993 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=187964

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A Ser315Thr Substitution in KatG Is Predominant in Genetically Heterogeneous Multidrug-Resistant Mycobacterium tuberculosis Isolates Originating from the St. Petersburg Area in Russia. by Marttila HJ, Soini H, Eerola E, Vyshnevskaya E, Vyshnevskiy BI, Otten TF, Vasilyef AV, Viljanen MK.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105851

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Activities of poloxamer CRL8131 against Mycobacterium tuberculosis in vitro and in vivo. by Jagannath C, Allaudeen HS, Hunter RL.; 1995 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=162740

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Acute infection and macrophage subversion by Mycobacterium tuberculosis require a specialized secretion system. by Stanley SA, Raghavan S, Hwang WW, Cox JS.; 2003 Oct 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=240734

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Allele-Specific rpoB PCR Assays for Detection of Rifampin-Resistant Mycobacterium tuberculosis in Sputum Smears. by Mokrousov I, Otten T, Vyshnevskiy B, Narvskaya O.; 2003 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161874

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Analysis for a Limited Number of Gene Codons Can Predict Drug Resistance of Mycobacterium tuberculosis in a High-Incidence Community. by Van Rie A, Warren R, Mshanga I, Jordaan AM, van der Spuy GD, Richardson M, Simpson J, Gie RP, Enarson DA, Beyers N, van Helden PD, Victor TC.; 2001 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87790

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Application of Spoligotyping to Noncultured Mycobacterium tuberculosis Bacteria Requires an Optimized Approach. by Parwati I, Crevel RV, Soolingen DV, Zanden AV.; 2003 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=262530

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Arabinofuranosyl-terminated and mannosylated lipoarabinomannans from Mycobacterium tuberculosis induce different levels of interleukin-12 expression in murine macrophages. by Yoshida A, Koide Y.; 1997 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=175250

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Assessment of genetic markers for species differentiation within the Mycobacterium tuberculosis complex. by Liebana E, Aranaz A, Francis B, Cousins D.; 1996 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228920

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Assessment of Morphology for Rapid Presumptive Identification of Mycobacterium tuberculosis and Mycobacterium kansasii. by Attorri S, Dunbar S, Clarridge JE III.; 2000 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86457

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Attenuation of Mycobacterium tuberculosis by Disruption of a mas-Like Gene or a Chalcone Synthase-Like Gene, Which Causes Deficiency in Dimycocerosyl

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Phthiocerol Synthesis. by Sirakova TD, Dubey VS, Cynamon MH, Kolattukudy PE.; 2003 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154080 •

Automated DNA fingerprinting analysis of Mycobacterium tuberculosis using fluorescent detection of PCR products. by Butler WR, Haas WH, Crawford JT.; 1996 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229119

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Automated High-Throughput Genotyping for Study of Global Epidemiology of Mycobacterium tuberculosis Based on Mycobacterial Interspersed Repetitive Units. by Supply P, Lesjean S, Savine E, Kremer K, van Soolingen D, Locht C.; 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88389

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Bacteriological and Molecular Analysis of Rifampin-Resistant Mycobacterium tuberculosis Strains Isolated in Australia. by Yuen LK, Leslie D, Coloe PJ.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85826

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Biochemical Function of msl5 (pks8 plus pks17) in Mycobacterium tuberculosis H37Rv: Biosynthesis of Monomethyl Branched Unsaturated Fatty Acids. by Dubey VS, Sirakova TD, Cynamon MH, Kolattukudy PE.; 2003 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=165776

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Calculation of the Stability of the IS6110 Banding Pattern in Patients with Persistent Mycobacterium tuberculosis Disease. by Warren RM, van der Spuy GD, Richardson M, Beyers N, Borgdorff MW, Behr MA, van Helden PD.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130951

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CD40 Ligand (CD154) Does Not Contribute to Lymphocyte-Mediated Inhibition of Virulent Mycobacterium tuberculosis within Human Monocytes. by Larkin R, Benjamin CD, Hsu YM, Li Q, Zukowski L, Silver RF.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128186

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Characterization by automated DNA sequencing of mutations in the gene (rpoB) encoding the RNA polymerase beta subunit in rifampin-resistant Mycobacterium tuberculosis strains from New York City and Texas. by Kapur V, Li LL, Iordanescu S, Hamrick MR, Wanger A, Kreiswirth BN, Musser JM.; 1994 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=267194

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Characterization of Auxotrophic Mutants of Mycobacterium tuberculosis and Their Potential as Vaccine Candidates. by Smith DA, Parish T, Stoker NG, Bancroft GJ.; 2001 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97996

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Characterization of Finnish Mycobacterium tuberculosis Isolates by Spoligotyping. by Puustinen K, Marjamaki M, Rastogi N, Sola C, Filliol I, Ruutu P, Holmstrom P, Viljanen MK, Soini H.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153930

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Characterization of fluoroquinolone-resistant mutant strains of Mycobacterium tuberculosis selected in the laboratory and isolated from patients. by Alangaden GJ, Manavathu EK, Vakulenko SB, Zvonok NM, Lerner SA.; 1995 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=162811

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Characterization of IS6110 Restriction Fragment Length Polymorphism Patterns and Mechanisms of Antimicrobial Resistance for Multidrug-Resistant Isolates of

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Mycobacterium tuberculosis from a Major Reference Hospital in Assiut, Egypt. by Abbadi S, Rashed HG, Morlock GP, Woodley CL, El Shanawy O, Cooksey RC.; 2001 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88138 •

Characterization of Mycobacterium tuberculosis Complex Isolates from the Cerebrospinal Fluid of Meningitis Patients at Six Fever Hospitals in Egypt. by Cooksey RC, Abbadi SH, Woodley CL, Sikes D, Wasfy M, Crawford JT, Mahoney F.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130952

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Characterization of Mycobacterium tuberculosis Isolates from Patients in Houston, Texas, by Spoligotyping. by Soini H, Pan X, Amin A, Graviss EA, Siddiqui A, Musser JM.; 2000 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86172

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Characterization of Mycobacterium tuberculosis strains from Vietnamese patients by Southern blot hybridization. by Yuen LK, Ross BC, Jackson KM, Dwyer B.; 1993 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=265589

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Characterization of rpoB Mutations in Rifampin-Resistant Clinical Isolates of Mycobacterium tuberculosis from Turkey by DNA Sequencing and Line Probe Assay. by Cavusoglu C, Hilmioglu S, Guneri S, Bilgic A.; 2002 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154651

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Characterization of Spontaneous, In Vitro-Selected, Rifampin-Resistant Mutants of Mycobacterium tuberculosis Strain H37Rv. by Morlock GP, Plikaytis BB, Crawford JT.; 2000 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90195

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Characterization of the Mycobacterium tuberculosis iniBAC Promoter, a Promoter That Responds to Cell Wall Biosynthesis Inhibition. by Alland D, Steyn AJ, Weisbrod T, Aldrich K, Jacobs WR Jr.; 2000 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101861

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Characterization of the Two Mycobacterium tuberculosis recA Promoters. by Gopaul KK, Brooks PC, Prost JF, Davis EO.; 2003 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=225015

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Clinical Evaluation of the Gen-Probe Amplified Direct Test for Detection of Mycobacterium tuberculosis Complex Organisms in Cerebrospinal Fluid. by Lang AM, Feris-Iglesias J, Pena C, Sanchez JF, Stockman L, Rys P, Roberts GD, Henry NK, Persing DH, Cockerill FR III.; 1998 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105005

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Clinical Evaluation of the Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test for Rapid Detection of Mycobacterium tuberculosis in Select Nonrespiratory Specimens. by Woods GL, Bergmann JS, Williams-Bouyer N.; 2001 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87811

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Comparative Evaluation of Initial and New Versions of the Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test for Direct Detection of Mycobacterium tuberculosis in Respiratory and Nonrespiratory Specimens. by Gamboa F, Fernandez G, Padilla E, Manterola JM, Lonca J, Cardona PJ, Matas L, Ausina V.; 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104609

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Comparative Evaluation of Ligation-Mediated PCR and Spoligotyping as Screening Methods for Genotyping of Mycobacterium tuberculosis Strains. by Bonora S,

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Gutierrez MC, Di Perri G, Brunello F, Allegranzi B, Ligozzi M, Fontana R, Concia E, Vincent V.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85507 •

Comparative Evaluation of Low-Molecular-Mass Proteins from Mycobacterium tuberculosis Identifies Members of the ESAT-6 Family as Immunodominant T-Cell Antigens. by Skjot RL, Oettinger T, Rosenkrands I, Ravn P, Brock I, Jacobsen S, Andersen P.; 2000 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97123

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Comparative Evaluation of the New Gen-Probe Mycobacterium tuberculosis Amplified Direct Test and the Semiautomated Abbott LCx Mycobacterium tuberculosis Assay for Direct Detection of Mycobacterium tuberculosis Complex in Respiratory and Extrapulmonary Specimens. by Piersimoni C, Callegaro A, Scarparo C, Penati V, Nista D, Bornigia S, Lacchini C, Scagnelli M, Santini G, De Sio G.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105247

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Comparison of Enhanced Mycobacterium tuberculosis Amplified Direct Test with COBAS AMPLICOR Mycobacterium tuberculosis Assay for Direct Detection of Mycobacterium tuberculosis Complex in Respiratory and Extrapulmonary Specimens. by Scarparo C, Piccoli P, Rigon A, Ruggiero G, Scagnelli M, Piersimoni C.; 2000 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86489

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Comparison of in vitro models for the study of Mycobacterium tuberculosis invasion and intracellular replication. by Mehta PK, King CH, White EH, Murtagh JJ Jr, Quinn FD.; 1996 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=174125

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Comparison of Methods Based on Different Molecular Epidemiological Markers for Typing of Mycobacterium tuberculosis Complex Strains: Interlaboratory Study of Discriminatory Power and Reproducibility. by Kremer K, van Soolingen D, Frothingham R, Haas WH, Hermans PW, Martin C, Palittapongarnpim P, Plikaytis BB, Riley LW, Yakrus MA, Musser JM, van Embden JD.; 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85295

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Comparison of Roche Cobas Amplicor Mycobacterium tuberculosis Assay with InHouse PCR and Culture for Detection of M. tuberculosis. by Eing BR, Becker A, Sohns A, Ringelmann R.; 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104971

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Comparison of the Construction of Unmarked Deletion Mutations in Mycobacterium smegmatis, Mycobacterium bovis Bacillus Calmette-Guerin, and Mycobacterium tuberculosis H37Rv by Allelic Exchange. by Pavelka MS Jr, Jacobs WR Jr.; 1999 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=93962

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Comparison of Variable Number Tandem Repeat and IS6110-Restriction Fragment Length Polymorphism Analyses for Discrimination of High- and Low-Copy-Number IS6110 Mycobacterium tuberculosis Isolates. by Barlow RE, Gascoyne-Binzi DM, Gillespie SH, Dickens A, Qamer S, Hawkey PM.; 2001 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88169

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Construction and Characterization of a Mycobacterium tuberculosis Mutant Lacking the Alternate Sigma Factor Gene, sigF. by Chen P, Ruiz RE, Li Q, Silver RF, Bishai WR.; 2000 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101508

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Construction and Phenotypic Characterization of an Auxotrophic Mutant of Mycobacterium tuberculosis Defective in l-Arginine Biosynthesis. by Gordhan BG, Smith DA, Alderton H, McAdam RA, Bancroft GJ, Mizrahi V.; 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127984

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Continued Low Rates of Transmission of Mycobacterium tuberculosis in Norway. by Dahle UR, Sandven P, Heldal E, Caugant DA.; 2003 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=165220

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Contribution of [beta]-Lactamases to [beta]-Lactam Susceptibilities of Susceptible and Multidrug-Resistant Mycobacterium tuberculosis Clinical Isolates. by Segura C, Salvado M, Collado I, Chaves J, Coira A.; 1998 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105638

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Contribution of kasA Analysis to Detection of Isoniazid-Resistant Mycobacterium tuberculosis in Singapore. by Lee AS, Lim IH, Tang LL, Telenti A, Wong SY.; 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89423

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Cord Formation in BACTEC Medium Is a Reliable, Rapid Method for Presumptive Identification of Mycobacterium tuberculosis Complex. by McCarter YS, Ratkiewicz IN, Robinson A.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105205

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Cord Formation in MB/BacT Medium Is a Reliable Criterion for Presumptive Identification of Mycobacterium tuberculosis Complex in Laboratories with High Prevalence of M. tuberculosis. by Badak FZ, Goksel S, Sertoz R, Guzelant A, Kizirgil A, Bilgic A.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85924

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Correlation between Pyrazinamide Activity and pncA Mutations in Mycobacterium tuberculosis Isolates in Taiwan. by Huang TS, Lee SS, Tu HZ, Huang WK, Chen YS, Huang CK, Wann SR, Lin HH, Liu YC.; 2003 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=253789

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Cost-Effectiveness Analysis of the Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test as Used Routinely on Smear-Positive Respiratory Specimens. by Dowdy DW, Maters A, Parrish N, Beyrer C, Dorman SE.; 2003 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150318

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Criteria for Identification of Cross-Contamination of Cultures of Mycobacterium tuberculosis in Routine Microbiology Laboratories. by Carroll NM, Richardson M, van Helden PD.; 2003 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154733

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Cu,Zn Superoxide Dismutase of Mycobacterium tuberculosis Contributes to Survival in Activated Macrophages That Are Generating an Oxidative Burst. by Piddington DL, Fang FC, Laessig T, Cooper AM, Orme IM, Buchmeier NA.; 2001 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98590

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Deletion of Mycobacterium tuberculosis Sigma Factor E Results in Delayed Time to Death with Bacterial Persistence in the Lungs of Aerosol-Infected Mice. by Ando M, Yoshimatsu T, Ko C, Converse PJ, Bishai WR.; 2003 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=308924

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Detection and Differentiation of Mycobacterium tuberculosis and Nontuberculous Mycobacterial Isolates by Real-Time PCR. by Shrestha NK, Tuohy MJ, Hall GS, Reischl U, Gordon SM, Procop GW.; 2003 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=262464

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Detection and identification of Mycobacterium tuberculosis directly from sputum sediments by Amplicor PCR. by Moore DF, Curry JI.; 1995 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228556

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Detection of a Point Mutation Associated with High-Level Isoniazid Resistance in Mycobacterium tuberculosis by Using Real-Time PCR Technology with 3[prime prime or minute]-Minor Groove Binder-DNA Probes. by van Doorn HR, Claas EC, Templeton KE, van der Zanden AG, te Koppele Vije A, de Jong MD, Dankert J, Kuijper EJ.; 2003 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=254323

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Detection of embB306 Mutations in Ethambutol-Susceptible Clinical Isolates of Mycobacterium tuberculosis from Northwestern Russia: Implications for Genotypic Resistance Testing. by Mokrousov I, Otten T, Vyshnevskiy B, Narvskaya O.; 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130875

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Detection of Ethambutol-Resistant Mycobacterium tuberculosis Strains by Multiplex Allele-Specific PCR Assay Targeting embB306 Mutations. by Mokrousov I, Narvskaya O, Limeschenko E, Otten T, Vyshnevskiy B.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130919

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Detection of Isoniazid-Resistant Mycobacterium tuberculosis Strains by a Multiplex Allele-Specific PCR Assay Targeting katG Codon 315 Variation. by Mokrousov I, Otten T, Filipenko M, Vyazovaya A, Chrapov E, Limeschenko E, Steklova L, Vyshnevskiy B, Narvskaya O.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=120554

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Detection of mRNA Transcripts and Active Transcription in Persistent Mycobacterium tuberculosis Induced by Exposure to Rifampin or Pyrazinamide. by Hu Y, Mangan JA, Dhillon J, Sole KM, Mitchison DA, Butcher PD, Coates AR.; 2000 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=94781

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Detection of Mycobacterium tuberculosis in cerebrospinal fluid following immunomagnetic enrichment. by Mazurek GH, Reddy V, Murphy D, Ansari T.; 1996 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228819

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Detection of Rifampin Resistance in Mycobacterium tuberculosis in a Single Tube with Molecular Beacons. by El-Hajj HH, Marras SA, Tyagi S, Kramer FR, Alland D.; 2001 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88498

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Detection of Rifampin-Resistant Mycobacterium tuberculosis in Sputa by Nested PCR-Linked Single-Strand Conformation Polymorphism and DNA Sequencing. by Kim BJ, Lee KH, Park BN, Kim SJ, Park EM, Park YG, Bai GH, Kim SJ, Kook YH.; 2001 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88194

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Detection of rpoB Mutations in Mycobacterium tuberculosis by Biprobe Analysis. by Edwards KJ, Metherell LA, Yates M, Saunders NA.; 2001 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88343

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Differences in Rate and Variability of Intracellular Growth of a Panel of Mycobacterium tuberculosis Clinical Isolates within a Human Monocyte Model. by Li Q, Whalen CC, Albert JM, Larkin R, Zukowski L, Cave MD, Silver RF.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130434

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Different Strains of Mycobacterium tuberculosis Cause Various Spectrums of Disease in the Rabbit Model of Tuberculosis. by Manabe YC, Dannenberg AM Jr, Tyagi SK, Hatem CL, Yoder M, Woolwine SC, Zook BC, Pitt ML, Bishai WR.; 2003 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=201108

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Differential Expression of Gamma Interferon mRNA Induced by Attenuated and Virulent Mycobacterium tuberculosis in Guinea Pig Cells after Mycobacterium bovis BCG Vaccination. by Jeevan A, Yoshimura T, Lee KE, McMurray DN.; 2003 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=143318

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Differentiation among Members of the Mycobacterium tuberculosis Complex by Molecular and Biochemical Features: Evidence for Two Pyrazinamide-Susceptible Subtypes of M. bovis. by Niemann S, Richter E, Rusch-Gerdes S.; 2000 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86043

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Differentiation between Mycobacterium tuberculosis and Mycobacterium avium by Amplification of the 16S-23S Ribosomal DNA Spacer. by Sansila A, Hongmanee P, Chuchottaworn C, Rienthong S, Rienthong D, Palittapongarnpim P.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105132

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Differentiation of bacterial 16S rRNA genes and intergenic regions and Mycobacterium tuberculosis katG genes by structure-specific endonuclease cleavage. by Brow MA, Oldenburg MC, Lyamichev V, Heisler LM, Lyamicheva N, Hall JG, Eagan NJ, Olive DM, Smith LM, Fors L, Dahlberg JE.; 1996 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229470

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Differentiation of Clinical Mycobacterium tuberculosis Complex Isolates by gyrB DNA Sequence Polymorphism Analysis. by Niemann S, Harmsen D, Rusch-Gerdes S, Richter E.; 2000 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87363

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Differentiation of Mycobacterium tuberculosis Complex and Nontuberculous Mycobacterial Liquid Cultures by Using Peptide Nucleic Acid-Fluorescence In Situ Hybridization Probes. by Drobniewski FA, More PG, Harris GS.; 2000 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88746

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Differentiation of Mycobacterium tuberculosis isolates by spoligotyping and IS6110 restriction fragment length polymorphism. by Goyal M, Saunders NA, van Embden JD, Young DB, Shaw RJ.; 1997 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229643

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Differentiation of strains in Mycobacterium tuberculosis complex by DNA sequence polymorphisms, including rapid identification of M. bovis BCG. by Frothingham R.; 1995 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228052

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Diminished Adherence and/or Ingestion of Virulent Mycobacterium tuberculosis by Monocyte-Derived Macrophages from Patients with Tuberculosis. by Zabaleta J, Arias M, Maya JR, Garcia LF.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95641

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Direct Detection of Multidrug-Resistant Mycobacterium tuberculosis in Clinical Specimens in Low- and High-Incidence Countries by Line Probe Assay. by Johansen IS, Lundgren B, Sosnovskaja A, Thomsen VO.; 2003 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=193855

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Direct detection of Mycobacterium tuberculosis in respiratory specimens in a clinical laboratory by polymerase chain reaction. by Forbes BA, Hicks KE.; 1993 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=265615

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Direct genotypic detection of Mycobacterium tuberculosis rifampin resistance in clinical specimens by using single-tube heminested PCR. by Whelen AC, Felmlee TA, Hunt JM, Williams DL, Roberts GD, Stockman L, Persing DH.; 1995 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=227990

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Direct identification and typing of Mycobacterium tuberculosis by PCR. by Neimark H, Ali Baig M, Carleton S.; 1996 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229292

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Discrimination of Multidrug-Resistant Mycobacterium tuberculosis IS6110 Fingerprint Subclusters by rpoB Gene Mutation Analysis. by Portugal I, Maia S, Moniz-Pereira J.; 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85442

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Discrimination of Single-Copy IS6110 DNA Fingerprints of Mycobacterium tuberculosis Isolates by High-Resolution Minisatellite-Based Typing. by Lee AS, Tang LL, Lim IH, Bellamy R, Wong SY.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153360

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Disruption of the Gene Homologous to Mammalian Nramp1 in Mycobacterium tuberculosis Does Not Affect Virulence in Mice. by Boechat N, Lagier-Roger B, Petit S, Bordat Y, Rauzier J, Hance AJ, Gicquel B, Reyrat JM.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128187

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Disruption of the Genes Encoding Antigen 85A and Antigen 85B of Mycobacterium tuberculosis H37Rv: Effect on Growth in Culture and in Macrophages. by Armitige LY, Jagannath C, Wanger AR, Norris SJ.; 2000 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97204

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Dissemination of Mycobacterium tuberculosis Is Influenced by Host Factors and Precedes the Initiation of T-Cell Immunity. by Chackerian AA, Alt JM, Perera TV, Dascher CC, Behar SM.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128141

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Distinctiveness of Mycobacterium tuberculosis Genotypes from Human Immunodeficiency Virus Type 1-Seropositive and -Seronegative Patients in Lima, Peru. by Ahmed N, Caviedes L, Alam M, Rao KR, Sangal V, Sheen P, Gilman RH, Hasnain SE.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153905

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DNA fingerprinting and phenotyping of Mycobacterium tuberculosis isolates from human immunodeficiency virus (HIV)-seropositive and HIV-seronegative patients in Tanzania. by Yang ZH, Mtoni I, Chonde M, Mwasekaga M, Fuursted K, Askgard DS, Bennedsen J, de Haas PE, van Soolingen D, van Embden JD.; 1995 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228105

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DNA fingerprinting of Mycobacterium tuberculosis strains from patients with pulmonary tuberculosis in Honduras. by Pineda-Garcia L, Ferrera A, Hoffner SE.; 1997 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229974

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DNA Typing of a Nonviable Culture of Mycobacterium tuberculosis in a Homeless Shelter Outbreak. by Driscoll JR, McGarry MA, Taber HW.; 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84237

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Double-repetitive-element PCR method for subtyping Mycobacterium tuberculosis clinical isolates. by Friedman CR, Stoeckle MY, Johnson WD Jr, Riley LW.; 1995 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228173

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Drug Targeting Mycobacterium tuberculosis Cell Wall Synthesis: Development of a Microtiter Plate-Based Screen for UDP-Galactopyranose Mutase and Identification of an Inhibitor from a Uridine-Based Library. by Scherman MS, Winans KA, Stern RJ, Jones V, Bertozzi CR, McNeil MR.; 2003 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=148999

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Drug Targeting Mycobacterium tuberculosis Cell Wall Synthesis: Genetics of dTDPRhamnose Synthetic Enzymes and Development of a Microtiter Plate-Based Screen for Inhibitors of Conversion of dTDP-Glucose to dTDP-Rhamnose. by Ma Y, Stern RJ, Scherman MS, Vissa VD, Yan W, Jones VC, Zhang F, Franzblau SG, Lewis WH, McNeil MR.; 2001 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90481

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Drug-Susceptible Mycobacterium tuberculosis Beijing Genotype Does Not Develop Mutation-Conferred Resistance to Rifampin at an Elevated Rate. by Werngren J, Hoffner SE.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153924

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Early Detection of Mycobacterium tuberculosis in BACTEC Cultures by Ligase Chain Reaction. by Tortoli E, Lavinia F, Simonetti MT.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105213

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Effect of katG Mutations on the Virulence of Mycobacterium tuberculosis and the Implication for Transmission in Humans. by Pym AS, Saint-Joanis B, Cole ST.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128294

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Effects of isoniazid on ultrastructure of Mycobacterium aurum and Mycobacterium tuberculosis and on production of secreted proteins. by Bardou F, Quemard A, Dupont MA, Horn C, Marchal G, Daffe M.; 1996 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163558

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Efficient discrimination of Mycobacterium tuberculosis strains by 16S-23S spacer region-based random amplified polymorphic DNA analysis. by Abed Y, Davin-Regli A, Bollet C, De Micco P.; 1995 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228183

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Enhanced Amplified Mycobacterium Tuberculosis Direct Test for Detection of Mycobacterium tuberculosis Complex in Positive BACTEC 12B Broth Cultures of Respiratory Specimens. by Bergmann JS, Woods GL.; 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85048

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Enhanced Production of Recombinant Mycobacterium tuberculosis Antigens in Escherichia coli by Replacement of Low-Usage Codons. by Lakey DL, Voladri RK, Edwards KM, Hager C, Samten B, Wallis RS, Barnes PF, Kernodle DS.; 2000 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97126

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Epidemiologic Usefulness of Spoligotyping for Secondary Typing of Mycobacterium tuberculosis Isolates with Low Copy Numbers of IS6110. by Cronin WA, Golub JE, Magder LS, Baruch NG, Lathan MJ, Mukasa LN, Hooper N, Razeq JH, Mulcahy D, Benjamin WH, Bishai WR.; 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88414

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ethA, inhA, and katG Loci of Ethionamide-Resistant Clinical Mycobacterium tuberculosis Isolates. by Morlock GP, Metchock B, Sikes D, Crawford JT, Cooksey RC.; 2003 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=296216

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Evaluation of a line probe assay kit for characterization of rpoB mutations in rifampin-resistant Mycobacterium tuberculosis isolates from New York City. by Cooksey RC, Morlock GP, Glickman S, Crawford JT.; 1997 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=232749

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Evaluation of a PCR-Based Universal Heteroduplex Generator Assay as a Tool for Rapid Detection of Multidrug-Resistant Mycobacterium tuberculosis in Peru. by Mayta H, Gilman RH, Arenas F, Valencia T, Caviedes L, Montenegro SH, Ticona E, Ortiz J, Chumpitaz R, Evans CA, Williams DL.; 2003 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=308991

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Evaluation of Amplicor PCR for direct detection of Mycobacterium tuberculosis from sputum specimens. by Beavis KG, Lichty MB, Jungkind DL, Giger O.; 1995 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228532

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Evaluation of Automated BACTEC MGIT 960 System for Testing Susceptibility of Mycobacterium tuberculosis to Four Major Antituberculous Drugs: Comparison with the Radiometric BACTEC 460TB Method and the Agar Plate Method of Proportion. by Tortoli E, Benedetti M, Fontanelli A, Simonetti MT.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153389

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Evaluation of Genotype MTBC Assay for Differentiation of Clinical Mycobacterium tuberculosis Complex Isolates. by Richter E, Weizenegger M, Rusch-Gerdes S, Niemann S.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156502

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Evaluation of Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test by Using Respiratory and Nonrespiratory Specimens in a Tertiary Care Center Laboratory. by O'Sullivan CE, Miller DR, Schneider PS, Roberts GD.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130650

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Evaluation of method for secondary DNA typing of Mycobacterium tuberculosis with pTBN12 in epidemiologic study of tuberculosis. by Yang Z, Chaves F, Barnes PF, Burman WJ, Koehler J, Eisenach KD, Bates JH, Cave MD.; 1996 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229457

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Evaluation of Mycobacteria Growth Indicator Tube for Direct and Indirect Drug Susceptibility Testing of Mycobacterium tuberculosis from Respiratory Specimens in a Siberian Prison Hospital. by Goloubeva V, Lecocq M, Lassowsky P, Matthys F, Portaels F, Bastian I.; 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87960

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Evaluation of mycobacteria growth indicator tube for recovery and drug susceptibility testing of Mycobacterium tuberculosis isolates from respiratory specimens. by Palaci M, Ueki SY, Sato DN, Da Silva Telles MA, Curcio M, Silva EA.; 1996 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228889

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Evaluation of Mycobacterium tuberculosis Genes Involved in Resistance to Killing by Human Macrophages. by Miller BH, Shinnick TM.; 2000 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97146

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Evaluation of the BDProbeTec ET System for Direct Detection of Mycobacterium tuberculosis in Pulmonary and Extrapulmonary Samples: a Multicenter Study. by Mazzarelli G, Rindi L, Piccoli P, Scarparo C, Garzelli C, Tortoli E.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153925

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Evaluation of the Epidemiologic Utility of Secondary Typing Methods for Differentiation of Mycobacterium tuberculosis Isolates. by Kwara A, Schiro R, Cowan LS, Hyslop NE, Wiser MF, Roahen Harrison S, Kissinger P, Diem L, Crawford JT.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156564

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Evaluation of the ESP Culture System II for Testing Susceptibilities of Mycobacterium tuberculosis Isolates to Four Primary Antituberculous Drugs. by Bergmann JS, Woods GL.; 1998 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105091

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Evaluation of the Mycobacterium bovis Restriction Fragment Length Polymorphism Probe pUCD, in Combination with the Direct Repeat Probe, for Molecular Typing of Mycobacterium tuberculosis Strains in Ireland. by Cameron H, O'Brien R, Murray A, Cryan B, Hone R, Rogers M.; 2001 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88556

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Evaluation of Three Nucleic Acid Amplification Methods for Direct Detection of Mycobacterium tuberculosis Complex in Respiratory Specimens. by Wang SX, Tay L.; 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84988

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Evaluation of tuberculosis transmission in a community by 1 year of systematic typing of Mycobacterium tuberculosis clinical isolates. by Torrea G, Offredo C, Simonet M, Gicquel B, Berche P, Pierre-Audigier C.; 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228952

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Evidence that vesicles containing living, virulent Mycobacterium tuberculosis or Mycobacterium avium in cultured human macrophages are not acidic. by Crowle AJ, Dahl R, Ross E, May MH.; 1991 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=257922

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Evolution and Clonal Traits of Mycobacterium tuberculosis Complex in GuineaBissau. by Kallenius G, Koivula T, Ghebremichael S, Hoffner SE, Norberg R, Svensson E, Dias F, Marklund BI, Svenson SB.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85833

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Evolutionary Relationships among Strains of Mycobacterium tuberculosis with Few Copies of IS6110. by Dale JW, Al-Ghusein H, Al-Hashmi S, Butcher P, Dickens AL, Drobniewski F, Forbes KJ, Gillespie SH, Lamprecht D, McHugh TD, Pitman R, Rastogi N, Smith AT, Sola C, Yesilkaya H.; 2003 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=152614

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Experimental Mycobacterium tuberculosis Infection of Cynomolgus Macaques Closely Resembles the Various Manifestations of Human M. tuberculosis Infection. by Capuano SV III, Croix DA, Pawar S, Zinovik A, Myers A, Lin PL, Bissel S, Fuhrman C, Klein E, Flynn JL.; 2003 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=201048

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Expression of a Mycobacterium tuberculosis Arabinomannan Antigen In Vitro and In Vivo. by Schwebach JR, Casadevall A, Schneerson R, Dai Z, Wang X, Robbins JB, Glatman-Freedman A.; 2001 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98683

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Expression of Mycobacterium smegmatis Pyrazinamidase in Mycobacterium tuberculosis Confers Hypersensitivity to Pyrazinamide and Related Amides. by Boshoff HI, Mizrahi V.; 2000 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110992

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Expression of Virulence of Mycobacterium tuberculosis within Human Monocytes: Virulence Correlates with Intracellular Growth and Induction of Tumor Necrosis Factor Alpha but Not with Evasion of Lymphocyte-Dependent Monocyte Effector Functions. by Silver RF, Li Q, Ellner JJ.; 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108033

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Extensive Cross-Contamination of Specimens with Mycobacterium tuberculosis in a Reference Laboratory. by de C. Ramos M, Soini H, Roscanni GC, Jaques M, Villares MC, Musser JM.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88624

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False-Positive Gen-Probe Direct Mycobacterium tuberculosis Amplification Test Results for Patients with Pulmonary M. kansasii and M. avium Infections. by Jorgensen JH, Salinas JR, Paxson R, Magnon K, Patterson JE, Patterson TF.; 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84200

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False-Positive Mycobacterium tuberculosis Cultures in 44 Laboratories in The Netherlands (1993 to 2000): Incidence, Risk Factors, and Consequences. by de Boer AS,

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Blommerde B, de Haas PE, Sebek MM, Lambregts-van Weezenbeek KS, Dessens M, van Soolingen D.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139647 •

Fluoroquinolone-Containing Third-Line Regimen against Mycobacterium tuberculosis In Vivo. by Veziris N, Truffot-Pernot C, Aubry A, Jarlier V, Lounis N.; 2003 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=201131

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Frequency of rpoB Mutations Inside and Outside the Cluster I Region in RifampinResistant Clinical Mycobacterium tuberculosis Isolates. by Heep M, Brandstatter B, Rieger U, Lehn N, Richter E, Rusch-Gerdes S, Niemann S.; 2001 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87688

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Functional Analysis of the Mycobacterium tuberculosis MprAB Two-Component Signal Transduction System. by Zahrt TC, Wozniak C, Jones D, Trevett A.; 2003 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=308901

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Genetic Biodiversity of Mycobacterium tuberculosis Complex Strains from Patients with Pulmonary Tuberculosis in Cameroon. by Niobe-Eyangoh SN, Kuaban C, Sorlin P, Cunin P, Thonnon J, Sola C, Rastogi N, Vincent V, Gutierrez MC.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156567

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Genetic Diversity of Mycobacterium tuberculosis in Sicily Based on Spoligotyping and Variable Number of Tandem DNA Repeats and Comparison with a Spoligotyping Database for Population-Based Analysis. by Sola C, Ferdinand S, Mammina C, Nastasi A, Rastogi N.; 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87970

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Genomic analysis of Mycobacterium bovis and other members of the Mycobacterium tuberculosis complex by isoenzyme analysis and pulsed-field gel electrophoresis. by Feizabadi MM, Robertson ID, Cousins DV, Hampson DJ.; 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228969

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Genomic Analysis of Mycobacterium tuberculosis Complex Strains Used for Production of Purified Protein Derivative. by Inwald J, Hinds J, Palmer S, Dale J, Butcher PD, Hewinson RG, Gordon SV.; 2003 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=179793

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Genomic Interrogation of the Dassie Bacillus Reveals It as a Unique RD1 Mutant within the Mycobacterium tuberculosis Complex. by Mostowy S, Cousins D, Behr MA.; 2004 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=303463

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Genotypic Analysis of Mycobacterium tuberculosis in Bangladesh and Prevalence of the Beijing Strain. by Banu S, Gordon SV, Palmer S, Islam R, Ahmed S, Alam KM, Cole ST, Brosch R.; 2004 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=344461

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Genotypic Analysis of Mycobacterium tuberculosis in Two Distinct Populations Using Molecular Beacons: Implications for Rapid Susceptibility Testing. by Piatek AS, Telenti A, Murray MR, El-Hajj H, Jacobs WR Jr, Kramer FR, Alland D.; 2000 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89635

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Genotypic detection of Mycobacterium tuberculosis rifampin resistance: comparison of single-strand conformation polymorphism and dideoxy fingerprinting. by Felmlee TA, Liu Q, Whelen AC, Williams D, Sommer SS, Persing DH.; 1995 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228227

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Glucan Is a Component of the Mycobacterium tuberculosis Surface That Is Expressed In Vitro and In Vivo. by Schwebach JR, Glatman-Freedman A, Gunther-Cummins L, Dai Z, Robbins JB, Schneerson R, Casadevall A.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127896

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Glutamine Synthetase GlnA1 Is Essential for Growth of Mycobacterium tuberculosis in Human THP-1 Macrophages and Guinea Pigs. by Tullius MV, Harth G, Horwitz MA.; 2003 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=162033

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Gyrase mutations in laboratory-selected, fluoroquinolone-resistant mutants of Mycobacterium tuberculosis H37Ra. by Kocagoz T, Hackbarth CJ, Unsal I, Rosenberg EY, Nikaido H, Chambers HF.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163415

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Heminested inverse PCR for IS6110 fingerprinting of Mycobacterium tuberculosis strains. by Patel S, Wall S, Saunders NA.; 1996 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229095

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Heterogeneity of Mycobacterium tuberculosis Isolates in Yangon, Myanmar. by Phyu S.; 2003 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=254380

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Heterologous Priming-Boosting Immunization of Cattle with Mycobacterium tuberculosis 85A Induces Antigen-Specific T-Cell Responses. by Taracha EL, Bishop R, Musoke AJ, Hill AV, Gilbert SC.; 2003 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=308883

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High Prevalence of KatG Ser315Thr Substitution among Isoniazid-Resistant Mycobacterium tuberculosis Clinical Isolates from Northwestern Russia, 1996 to 2001. by Mokrousov I, Narvskaya O, Otten T, Limeschenko E, Steklova L, Vyshnevskiy B.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127151

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High resolution, on-line identification of strains from the Mycobacterium tuberculosis complex based on tandem repeat typing. by Le Fleche P, Fabre M, Denoeud F, Koeck JL, Vergnaud G.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140014

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Identification and Characterization of a 29-Kilodalton Protein from Mycobacterium tuberculosis Culture Filtrate Recognized by Mouse Memory Effector Cells. by Rosenkrands I, Rasmussen PB, Carnio M, Jacobsen S, Theisen M, Andersen P.; 1998 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108262

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Identification and HLA Restriction of Naturally Derived Th1-Cell Epitopes from the Secreted Mycobacterium tuberculosis Antigen 85B Recognized by Antigen-Specific Human CD4 + T-Cell Lines. by Mustafa AS, Shaban FA, Abal AT, Al-Attiyah R, Wiker HG, Lundin KE, Oftung F, Huygen K.; 2000 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101670

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Identification of a Contaminating Mycobacterium tuberculosis Strain with a Transposition of an IS6110 Insertion Element Resulting in an Altered Spoligotype. by Benjamin WH Jr, Lok KH, Harris R, Brook N, Bond L, Mulcahy D, Robinson N, Pruitt V, Kirkpatrick DP, Kimerling ME, Dunlap NE.; 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87878

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Identification of a Mycobacterium tuberculosis Putative Classical Nitroreductase Gene Whose Expression Is Coregulated with That of the acr Gene within Macrophages, in Standing versus Shaking Cultures, and under Low Oxygen Conditions. by Purkayastha A, McCue LA, McDonough KA.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127740

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Identification of a predominant isolate of Mycobacterium tuberculosis using molecular and clinical epidemiology tools and in vitro cytokine responses. by Sharma MK, Al-Azem A, Wolfe J, Hershfield E, Kabani A.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154093

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Identification of Genes Encoding Exported Mycobacterium tuberculosis Proteins Using a Tn552[prime prime or minute]phoA In Vitro Transposition System. by Braunstein M, Griffin TJ IV, Kriakov JI, Friedman ST, Grindley ND, Jacobs WR Jr.; 2000 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101980

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Identification of Rifampin-Resistant Mycobacterium tuberculosis Strains by Hybridization, PCR, and Ligase Detection Reaction on Oligonucleotide Microchips. by Mikhailovich V, Lapa S, Gryadunov D, Sobolev A, Strizhkov B, Chernyh N, Skotnikova O, Irtuganova O, Moroz A, Litvinov V, Vladimirskii M, Perelman M, Chernousova L, Erokhin V, Zasedatelev A, Mirzabekov A.; 2001 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88181

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Identification of two Mycobacterium tuberculosis H37Rv ORFs involved in resistance to killing by human macrophages. by Miller BH, Shinnick TM.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59890

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Identifying Mycobacterium tuberculosis cultures by gas-liquid chromatography and a computer-aided pattern recognition model. by Maliwan N, Reid RW, Pliska SR, Bird TJ, Zvetina JR.; 1988 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=266248

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Implications of Low Frequency of IS6110 in Fingerprinting Field Isolates of Mycobacterium tuberculosis from Kerala, India. by Radhakrishnan I, K. MY, Kumar RA, Mundayoor S.; 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88004

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In Vitro Activities of Linezolid against Clinical Isolates of Mycobacterium tuberculosis That Are Susceptible or Resistant to First-Line Antituberculous Drugs. by Alcala L, Ruiz-Serrano MJ, Perez-Fernandez Turegano C, Garcia de Viedma D, DiazInfantes M, Marin-Arriaza M, Bouza E.; 2003 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=148996

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In Vitro Inhibition of the Mycobacterium tuberculosis [beta]-Ketoacyl-Acyl Carrier Protein Reductase MabA by Isoniazid. by Ducasse-Cabanot S, Cohen-Gonsaud M, Marrakchi H, Nguyen M, Zerbib D, Bernadou J, Daffe M, Labesse G, Quemard A.; 2004 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=310174

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Inactivation of Mycobacterium tuberculosis for DNA Typing Analysis. by BemerMelchior P, Drugeon HB.; 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85159

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Individual Mycobacterium tuberculosis Resuscitation-Promoting Factor Homologues Are Dispensable for Growth In Vitro and In Vivo. by Tufariello JM, Jacobs, Jr. WR, Chan J.; 2004 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=343985

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Inference of protein function and protein linkages in Mycobacterium tuberculosis based on prokaryotic genome organization: a combined computational approach. by Strong M, Mallick P, Pellegrini M, Thompson MJ, Eisenberg D.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=193659

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Inhibition of Mycobacterium tuberculosis Glutamine Synthetase as a Novel Antibiotic Strategy against Tuberculosis: Demonstration of Efficacy In Vivo. by Harth G, Horwitz MA.; 2003 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=143262

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Inhibitory Effect of Alpha-Tec XPR-Plus Phosphate Buffer on the Enhanced GenProbe Amplified Mycobacterium Tuberculosis Direct Test. by Della-Latta P.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88688

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Inhibitory Effect of NO-Releasing Ciprofloxacin (NCX 976) on Mycobacterium tuberculosis Survival. by Ciccone R, Mariani F, Cavone A, Persichini T, Venturini G, Ongini E, Colizzi V, Colasanti M.; 2003 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161842

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Interleukin-8 Is Differentially Expressed by Human-Derived Monocytic Cell Line U937 Infected with Mycobacterium tuberculosis H37Rv and Mycobacterium marinum. by Song CH, Lee JS, Kim HJ, Park JK, Paik TH, Jo EK.; 2003 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=201049

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Interpreting the Results of the Amplified Mycobacterium tuberculosis Direct Test for Detection of M. tuberculosis rRNA. by Middleton AM, Cullinan P, Wilson R, Kerr JR, Chadwick MV.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156505

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Invasion Activity of a Mycobacterium tuberculosis Peptide Presented by the Escherichia coli AIDA Autotransporter. by Casali N, Konieczny M, Schmidt MA, Riley LW.; 2002 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=133103

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Is Mycobacterium africanum Subtype II (Uganda I and Uganda II) a Genetically Well-Defined Subspecies of the Mycobacterium tuberculosis Complex? by Sola C, Rastogi N.; 2003 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150321

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IS6110 Transposition and Evolutionary Scenario of the Direct Repeat Locus in a Group of Closely Related Mycobacterium tuberculosis Strains. by Fang Z, Morrison N, Watt B, Doig C, Forbes KJ.; 1998 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107136

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Isoniazid Activation Defects in Recombinant Mycobacterium tuberculosis CatalasePeroxidase (KatG) Mutants Evident in InhA Inhibitor Production. by Wei CJ, Lei B, Musser JM, Tu SC.; 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151726

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Kanamycin Susceptibility Testing of Mycobacterium tuberculosis Using Mycobacterium Growth Indicator Tube and a Colorimetric Method. by Bastian I, Rigouts L, Palomino JC, Portaels F.; 2001 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90578

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Luciferase Reporter Mycobacteriophages for Detection, Identification, and Antibiotic Susceptibility Testing of Mycobacterium tuberculosis in Mexico. by Banaiee N, Bobadilla-del-Valle M, Bardarov S Jr, Riska PF, Small PM, Ponce-de-Leon A, Jacobs WR Jr, Hatfull GF, Sifuentes-Osornio J.; 2001 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88459

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Mapping of Mycobacterium tuberculosis katG Promoters and Their Differential Expression in Infected Macrophages. by Master S, Zahrt TC, Song J, Deretic V.; 2001 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95287

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Memory T cell-mediated resistance to Mycobacterium tuberculosis infection in innately susceptible and resistant mice. by Hubbard RD, Flory CM, Collins FM.; 1991 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=257958

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Method for Inactivating and Fixing Unstained Smear Preparations of Mycobacterium tuberculosis for Improved Laboratory Safety. by Chedore P, Th'ng C, Nolan DH, Churchwell GM, Sieffert DE, Hale YM, Jamieson F.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139704

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Microarray Analysis of the Mycobacterium tuberculosis Transcriptional Response to the Acidic Conditions Found in Phagosomes. by Fisher MA, Plikaytis BB, Shinnick TM.; 2002 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=135184

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Misidentification and Diagnostic Delay Caused by a False-Positive Amplified Mycobacterium tuberculosis Direct Test in an Immunocompetent Patient with a Mycobacterium celatum Infection. by Tjhie JH, van Belle AF, Dessens-Kroon M, van Soolingen D.; 2001 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88133

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Mixed-linker polymerase chain reaction: a new method for rapid fingerprinting of isolates of the Mycobacterium tuberculosis complex. by Haas WH, Butler WR, Woodley CL, Crawford JT.; 1993 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=262921

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MmpL8 is required for sulfolipid-1 biosynthesis and Mycobacterium tuberculosis virulence. by Converse SE, Mougous JD, Leavell MD, Leary JA, Bertozzi CR, Cox JS.; 2003 May 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156336

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Modeling Bacterial Evolution with Comparative-Genome-Based Marker Systems: Application to Mycobacterium tuberculosis Evolution and Pathogenesis. by Alland D, Whittam TS, Murray MB, Cave MD, Hazbon MH, Dix K, Kokoris M, Duesterhoeft A, Eisen JA, Fraser CM, Fleischmann RD.; 2003 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155390

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Modification of Results of Drug Susceptibility Tests by Coexistence of Mycobacterium avium Complex with Mycobacterium tuberculosis in a Sputum

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Molecular and Conventional Epidemiology of Mycobacterium tuberculosis in Botswana: a Population-Based Prospective Study of 301 Pulmonary Tuberculosis Patients. by Lockman S, Sheppard JD, Braden CR, Mwasekaga MJ, Woodley CL, Kenyon TA, Binkin NJ, Steinman M, Montsho F, Kesupile-Reed M, Hirschfeldt C, Notha M, Moeti T, Tappero JW.; 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87871

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Molecular and Immunological Characterization of Mycobacterium tuberculosis CFP10, an Immunodiagnostic Antigen Missing in Mycobacterium bovis BCG. by Dillon DC, Alderson MR, Day CH, Bement T, Campos-Neto A, Skeiky YA, Vedvick T, Badaro R, Reed SG, Houghton R.; 2000 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87375

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Molecular Basis of Intrinsic Macrolide Resistance in the Mycobacterium tuberculosis Complex. by Buriankova K, Doucet-Populaire F, Dorson O, Gondran A, Ghnassia JC, Weiser J, Pernodet JL.; 2004 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=310192

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Molecular Characterization and Drug Resistance Patterns of Strains of Mycobacterium tuberculosis Isolated from Patients in an AIDS Counseling Center in Port-au-Prince, Haiti: a 1-Year Study. by Ferdinand S, Sola C, Verdol B, Legrand E, Goh KS, Berchel M, Aubery A, Timothee M, Joseph P, Pape JW, Rastogi N.; 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149692

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Molecular Characterization and Human T-Cell Responses to a Member of a Novel Mycobacterium tuberculosis mtb39 Gene Family. by Dillon DC, Alderson MR, Day CH, Lewinsohn DM, Coler R, Bement T, Campos-Neto A, Skeiky YA, Orme IM, Roberts A, Steen S, Dalemans W, Badaro R, Reed SG.; 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96604

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Molecular Characterization of Isoniazid-Resistant Mycobacterium tuberculosis Clinical Isolates in Lithuania. by Bakonyte D, Baranauskaite A, Cicenaite J, Sosnovskaja A, Stakenas P.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155844

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Molecular Characterization of Mycobacterium tuberculosis H37Rv/Ra Variants: Distinguishing the Mycobacterial Laboratory Strain. by Bifani P, Moghazeh S, Shopsin B, Driscoll J, Ravikovitch A, Kreiswirth BN.; 2000 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87354

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Molecular cloning of a highly repeated DNA element from Mycobacterium tuberculosis and its use as an epidemiological tool. by Ross BC, Raios K, Jackson K, Dwyer B.; 1992 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=265190

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Molecular Epidemiology and Drug Resistance of Mycobacterium tuberculosis Isolates from Ethiopian Pulmonary Tuberculosis Patients with and without Human Immunodeficiency Virus Infection. by Bruchfeld J, Aderaye G, Palme IB, Bjorvatn B, Ghebremichael S, Hoffner S, Lindquist L.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130945

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Molecular Epidemiology of Mycobacterium tuberculosis in Norway. by Dahle UR, Sandven P, Heldal E, Caugant DA.; 2001 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88029

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Molecular Epidemiology of Mycobacterium tuberculosis Infection in Israel. by Ravins M, Bercovier H, Chemtob D, Fishman Y, Rahav G.; 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87899

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Molecular epidemiology of Mycobacterium tuberculosis strains isolated from different regions of Italy and Pakistan. by Sechi LA, Zanetti S, Delogu G, Montinaro B, Sanna A, Fadda G.; 1996 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229127

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Molecular epidemiology of Mycobacterium tuberculosis strains isolated from patients in a human immunodeficiency virus cohort in Switzerland. by Strassle A, Putnik J, Weber R, Fehr-Merhof A, Wust J, Pfyffer GE.; 1997 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229583

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Molecular Evidence for Heterogeneity of the Multiple-Drug-Resistant Mycobacterium tuberculosis Population in Scotland (1990 to 1997). by Fang Z, Doig C, Rayner A, Kenna DT, Watt B, Forbes KJ.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88639

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Molecular Fingerprinting of Mycobacterium tuberculosis Isolates Obtained in Havana, Cuba, by IS6110 Restriction Fragment Length Polymorphism Analysis and by the Double-Repetitive-Element PCR Method. by Montoro E, Valdivia J, Leao SC.; 1998 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105126

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Molecular strain typing of Mycobacterium tuberculosis to confirm crosscontamination in the mycobacteriology laboratory and modification of procedures to minimize occurrence of false-positive cultures. by Small PM, McClenny NB, Singh SP, Schoolnik GK, Tompkins LS, Mickelsen PA.; 1993 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=265613

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Molecular Typing of Mycobacterium tuberculosis Based on Variable Number of Tandem DNA Repeats Used Alone and in Association with Spoligotyping. by Filliol I, Ferdinand S, Negroni L, Sola C, Rastogi N.; 2000 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86957

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Molecular Typing of Mycobacterium tuberculosis by Using Nine Novel VariableNumber Tandem Repeats across the Beijing Family and Low-Copy-Number IS6110 Isolates. by Scott Spurgiesz R, Quitugua TN, Smith KL, Schupp J, Palmer EG, Cox RA, Keim P.; 2003 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=193784

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Monoclonal antibodies to surface antigens of Mycobacterium tuberculosis and their use in a modified enzyme-linked immunosorbent spot assay for detection of mycobacteria. by Glatman-Freedman A, Martin JM, Riska PF, Bloom BR, Casadevall A.; 1996 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229406

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Multiple Mycobacterium tuberculosis Strains in Early Cultures from Patients in a High-Incidence Community Setting. by Richardson M, Carroll NM, Engelke E, van der Spuy GD, Salker F, Munch Z, Gie RP, Warren RM, Beyers N, van Helden PD.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=120639

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Mutations in the rpoB and katG Genes Leading to Drug Resistance in Mycobacterium tuberculosis in Latvia. by Tracevska T, Jansone I, Broka L, Marga O, Baumanis V.; 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130873

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Mutations in the rpoB Gene of Multidrug-Resistant Mycobacterium tuberculosis Clinical Isolates from India. by Mani C, Selvakumar N, Narayanan S, Narayanan PR.; 2001 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88277

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Mutations in the rpoB Gene of Multidrug-Resistant Mycobacterium tuberculosis Isolates from Brazil. by Valim AR, Rossetti ML, Ribeiro MO, Zaha A.; 2000 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87207

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Mutations in the rpoB Gene of Multidrug-Resistant Mycobacterium tuberculosis Isolates from China. by Yue J, Shi W, Xie J, Li Y, Zeng E, Wang H.; 2003 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154692

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Mutations in the rpoB Gene of Rifampin-Resistant Mycobacterium tuberculosis Isolates in Spain and Their Rapid Detection by PCR --Enzyme-Linked Immunosorbent Assay. by Garcia L, Alonso-Sanz M, Rebollo MJ, Tercero JC, Chaves F.; 2001 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88031

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Mutations in the rpoB Gene of Rifampin-Resistant Mycobacterium tuberculosis Strains Isolated Mostly in Asian Countries and Their Rapid Detection by Line Probe Assay. by Hirano K, Abe C, Takahashi M.; 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85308

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Mycobacterial Interspersed Repetitive Unit Typing of Mycobacterium tuberculosis Compared to IS6110-Based Restriction Fragment Length Polymorphism Analysis for Investigation of Apparently Clustered Cases of Tuberculosis. by Hawkey PM, Smith EG, Evans JT, Monk P, Bryan G, Mohamed HH, Bardhan M, Pugh RN.; 2003 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=179797

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Mycothiol Is Essential for Growth of Mycobacterium tuberculosis Erdman. by Sareen D, Newton GL, Fahey RC, Buchmeier NA.; 2003 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=262099

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Necrosis of Lung Epithelial Cells during Infection with Mycobacterium tuberculosis Is Preceded by Cell Permeation. by Dobos KM, Spotts EA, Quinn FD, King CH.; 2000 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97713

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New Agar Medium for Testing Susceptibility of Mycobacterium tuberculosis to Pyrazinamide. by Heifets L, Sanchez T.; 2000 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86474

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New Simple and Rapid Test for Culture Confirmation of Mycobacterium tuberculosis Complex: a Multicenter Study. by Hasegawa N, Miura T, Ishii K, Yamaguchi K, Lindner TH, Merritt S, Matthews JD, Siddiqi SH.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=120276

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Novel IS6110 Insertion Sites in the Direct Repeat Locus of Mycobacterium tuberculosis Clinical Strains from the St. Petersburg Area of Russia and Evolutionary and Epidemiological Considerations. by Mokrousov I, Narvskaya O, Limeschenko E, Otten T, Vyshnevskiy B.; 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140396

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Novel Mutations in ndh in Isoniazid-Resistant Mycobacterium tuberculosis Isolates. by Lee AS, Teo AS, Wong SY.; 2001 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90621

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Novel Saccharomyces cerevisiae Screen Identifies WR99210 Analogues That Inhibit Mycobacterium tuberculosis Dihydrofolate Reductase. by Gerum A', Ulmer JE, Jacobus DP, Jensen NP, Sherman DR, Sibley CH.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128743

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Oligonucleotide (GTG)5 as a marker for Mycobacterium tuberculosis strain identification. by Wiid IJ, Werely C, Beyers N, Donald P, van Helden PD.; 1994 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=263681

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Oxidative Stress Increases Susceptibility of Mycobacterium tuberculosis to Isoniazid. by Bulatovic VM, Wengenack NL, Uhl JR, Hall L, Roberts GD, Cockerill III FR, Rusnak F.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127408

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Pathogenesis of tuberculosis: interaction of Mycobacterium tuberculosis with macrophages. by McDonough KA, Kress Y, Bloom BR.; 1993 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=280919

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PCR-Based Genotyping of Mycobacterium tuberculosis with New GC-Rich Repeated Sequences and IS6110 Inverted Repeats Used as Primers. by Kotlowski R, Shamputa IC, Abdullah El Aila N, Sajduda A, Rigouts L, van Deun A, Portaels F.; 2004 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=321654

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PCR-Based Method To Differentiate the Subspecies of the Mycobacterium tuberculosis Complex on the Basis of Genomic Deletions. by Huard RC, de Oliveira Lazzarini LC, Butler WR, van Soolingen D, Ho JL.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153936

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Performance Assessment of Two Commercial Amplification Assays for Direct Detection of Mycobacterium tuberculosis Complex from Respiratory and Extrapulmonary Specimens. by Piersimoni C, Scarparo C, Piccoli P, Rigon A, Ruggiero G, Nista D, Bornigia S.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139632

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Performance of an IS6110-Based PCR Assay and the COBAS AMPLICOR MTB PCR System for Detection of Mycobacterium tuberculosis Complex DNA in Human Lymph Node Samples. by Rimek D, Tyagi S, Kappe R.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=120681

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Persistence and Protective Efficacy of a Mycobacterium tuberculosis Auxotroph Vaccine. by Jackson M, Phalen SW, Lagranderie M, Ensergueix D, Chavarot P, Marchal G, McMurray DN, Gicquel B, Guilhot C.; 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96594

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Phospholipase Region of Mycobacterium tuberculosis Is a Preferential Locus for IS6110 Transposition. by Vera-Cabrera L, Hernandez-Vera MA, Welsh O, Johnson WM, Castro-Garza J.; 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88379

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pncA mutations in clinical Mycobacterium tuberculosis isolates from Korea. by Park SK, Lee JY, Chang CL, Lee MK, Son HC, Kim CM, Jang HJ, Park HK, Jeong SH.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33507

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PPE Antigen Rv2430c of Mycobacterium tuberculosis Induces a Strong B-Cell Response. by Choudhary RK, Mukhopadhyay S, Chakhaiyar P, Sharma N, Murthy KJ, Katoch VM, Hasnain SE.; 2003 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=219563

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Proteins released from Mycobacterium tuberculosis during growth. by Andersen P, Askgaard D, Ljungqvist L, Bennedsen J, Heron I.; 1991 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=257941

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Pyrazinamide-Monoresistant Mycobacterium tuberculosis in the United States. by Hannan MM, Desmond EP, Morlock GP, Mazurek GH, Crawford JT.; 2001 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87792

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Rapid and Inexpensive Drug Susceptibility Testing of Mycobacterium tuberculosis with a Nitrate Reductase Assay. by Angeby KA, Klintz L, Hoffner SE.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153407

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Rapid and Simple Approach for Identification of Mycobacterium tuberculosis Complex Isolates by PCR-Based Genomic Deletion Analysis. by Parsons LM, Brosch R, Cole ST, Somoskovi A, Loder A, Bretzel G, van Soolingen D, Hale YM, Salfinger M.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=120548

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Rapid and Specific Detection of Mycobacterium tuberculosis by Using the Smart Cycler Instrument and a Specific Fluorogenic Probe. by Cleary TJ, Roudel G, Casillas O, Miller N.; 2003 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=254309

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Rapid and Specific Detection of Mycobacterium tuberculosis from Acid-Fast Bacillus Smear-Positive Respiratory Specimens and BacT/ALERT MP Culture Bottles by Using Fluorogenic Probes and Real-Time PCR. by Miller N, Cleary T, Kraus G, Young AK, Spruill G, Hnatyszyn HJ.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139713

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Rapid Colorimetric Method for Testing Susceptibility of Mycobacterium tuberculosis to Isoniazid and Rifampin in Liquid Cultures. by Syre H, Phyu S, Sandven P, Bjorvatn B, Grewal HM.; 2003 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=262483

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Rapid Detection of Mycobacterium tuberculosis in Contaminated BACTEC 12B Broth Cultures by Testing with Amplified Mycobacterium Tuberculosis Direct Test. by Zheng X, Pang M, Engler HD, Tanaka S, Reppun T.; 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88416

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Rapid Detection of Pyrazinamide-Resistant Mycobacterium tuberculosis by a PCRBased In Vitro System. by Suzuki Y, Suzuki A, Tamaru A, Katsukawa C, Oda H.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153375

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Rapid Detection of Rifampin Resistance in Mycobacterium tuberculosis Isolates by Heteroduplex Analysis and Determination of Rifamycin Cross-Resistance in Rifampin-Resistant Isolates. by Sarijbas Z, Kocagoz T, Alp A, Gunalp A.; 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149690

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Rapid Detection of rpoB Gene Mutations in Rifampin-Resistant Mycobacterium tuberculosis Isolates in Shanghai by Using the Amplification Refractory Mutation System. by Fan XY, Hu ZY, Xu FH, Yan ZQ, Guo SQ, Li ZM.; 2003 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150287

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Rapid Detection of Smear-Negative Mycobacterium tuberculosis by PCR and Sequencing for Rifampin Resistance with DNA Extracted Directly from Slides. by Patnaik M, Liegmann K, Peter JB.; 2001 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87678

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Rapid Diagnosis of Mycobacterial Infections and Quantitation of Mycobacterium tuberculosis Load by Two Real-Time Calibrated PCR Assays. by Broccolo F, Scarpellini P, Locatelli G, Zingale A, Brambilla AM, Cichero P, Sechi LA, Lazzarin A, Lusso P, Malnati MS.; 2003 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=254334

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Rapid Differentiation of "Mycobacterium canettii" from Other Mycobacterium tuberculosis Complex Organisms by PCR-Restriction Analysis of the hsp65 Gene. by Goh KS, Legrand E, Sola C, Rastogi N.; 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88413

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Rapid discrimination of Mycobacterium tuberculosis complex strains by ligationmediated PCR fingerprint analysis. by Prod'hom G, Guilhot C, Gutierrez MC, Varnerot A, Gicquel B, Vincent V.; 1997 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230178

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Rapid Film-Based Determination of Antibiotic Susceptibilities of Mycobacterium tuberculosis Strains by Using a Luciferase Reporter Phage and the Bronx Box. by Riska PF, Su Y, Bardarov S, Freundlich L, Sarkis G, Hatfull G, Carriere C, Kumar V, Chan J, Jacobs WR Jr.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88662

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Rapid Identification of Laboratory Contamination with Mycobacterium tuberculosis Using Variable Number Tandem Repeat Analysis. by Gascoyne-Binzi DM, Barlow RE, Frothingham R, Robinson G, Collyns TA, Gelletlie R, Hawkey PM.; 2001 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87682

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Rapid, Efficient Detection and Drug Susceptibility Testing of Mycobacterium tuberculosis in Sputum by Microscopic Observation of Broth Cultures. by Caviedes L, Lee TS, Gilman RH, Sheen P, Spellman E, Lee EH, Berg DE, Montenegro-James S.; 2000 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86377

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Reactive Nitrogen Intermediates Have a Bacteriostatic Effect on Mycobacterium tuberculosis In Vitro. by Firmani MA, Riley LW.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130711

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Reduced immunopathology and mortality despite tissue persistence in a Mycobacterium tuberculosis mutant lacking alternative [final sigma] factor, SigH. by Kaushal D, Schroeder BG, Tyagi S, Yoshimatsu T, Scott C, Ko C, Carpenter L, Mehrotra J, Manabe YC, Fleischmann RD, Bishai WR.; 2002 Jun 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123067

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Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding [alpha]-crystallin. by Sherman DR, Voskuil M, Schnappinger D, Liao R, Harrell MI, Schoolnik GK.; 2001 Jun 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34703

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Relevance of Commercial Amplification Methods for Direct Detection of Mycobacterium tuberculosis Complex in Clinical Samples. by Piersimoni C, Scarparo C.; 2003 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=309028

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Removal of PCR Inhibitors by Silica Membranes: Evaluating the Amplicor Mycobacterium tuberculosis Kit. by Boddinghaus B, Wichelhaus TA, Brade V, Bittner T.; 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88425

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Restriction Fragment Length Polymorphism Analysis of Mycobacterium tuberculosis Isolated from Countries in the Western Pacific Region. by Park YK, Bai GH, Kim SJ.; 2000 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88694

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Reverse Dot Blot Assay (Insertion Site Typing) for Precise Detection of Sites of IS6110 Insertion in the Mycobacterium tuberculosis Genome. by Steinlein LM, Crawford JT.; 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87843

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Risk of Mycobacterium tuberculosis Transmission in a Low-Incidence Country Due to Immigration from High-Incidence Areas. by Lillebaek T, Andersen AB, Bauer J, Dirksen A, Glismann S, de Haas P, Kok-Jensen A.; 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87841

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Role of Mycobacterium tuberculosis Copper-Zinc Superoxide Dismutase. by Dussurget O, Stewart G, Neyrolles O, Pescher P, Young D, Marchal G.; 2001 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97912

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rpoB Genotypes of Mycobacterium tuberculosis Beijing Family Isolates from East Asian Countries. by Qian L, Abe C, Lin TP, Yu MC, Cho SN, Wang S, Douglas JT.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=120282

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rpoB Mutations in Multidrug-Resistant Strains of Mycobacterium tuberculosis Isolated in Italy. by Pozzi G, Meloni M, Iona E, Orru G, Thoresen OF, Ricci ML, Oggioni MR, Fattorini L, Orefici G.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88675

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Secondary Typing of Mycobacterium tuberculosis Isolates with Matching IS6110 Fingerprints from Different Geographic Regions of the United States. by Yang ZH, Bates JH, Eisenach KD, Cave MD.; 2001 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88010

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Sequence Polymorphism in the rrs Gene of Mycobacterium tuberculosis Is Deeply Rooted within an Evolutionary Clade and Is Not Associated with Streptomycin

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Resistance. by Victor TC, van Rie A, Jordaan AM, Richardson M, van der Spuy GD, Beyers N, van Helden PD, Warren R.; 2001 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88513 •

Simple and Rapid Differentiation of Mycobacterium tuberculosis H37Ra from M. tuberculosis Clinical Isolates through Two Cytochemical Tests Using Neutral Red and Nile Blue Stains. by Soto CY, Andreu N, Gibert I, Luquin M.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=120676

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Simple and Rapid Identification of the Mycobacterium tuberculosis Complex by Immunochromatographic Assay Using Anti-MPB64 Monoclonal Antibodies. by Abe C, Hirano K, Tomiyama T.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85727

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Simultaneous Identification of Mycobacterium Genus and Mycobacterium tuberculosis Complex in Clinical Samples by 5[prime prime or minute]-Exonuclease Fluorogenic PCR. by Garcia-Quintanilla A, Gonzalez-Martin J, Tudo G, Espasa M, Jimenez de Anta MT.; 2002 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154622

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Simultaneous Infection with Two Drug-Susceptible Mycobacterium tuberculosis Strains in an Immunocompetent Host. by Pavlic M, Allerberger F, Dierich MP, Prodinger WM.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85908

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Single-Tube Balanced Heminested PCR for Detecting Mycobacterium tuberculosis in Smear-Negative Samples. by Garcia-Quintanilla A, Garcia L, Tudo G, Navarro M, Gonzalez J, Jimenez de Anta MT.; 2000 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86365

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Snapshot of Moving and Expanding Clones of Mycobacterium tuberculosis and Their Global Distribution Assessed by Spoligotyping in an International Study. by Filliol I, Driscoll JR, van Soolingen D, Kreiswirth BN, Kremer K, Valetudie G, Anh DD, Barlow R, Banerjee D, Bifani PJ, Brudey K, Cataldi A, Cooksey RC, Cousins DV, Dale JW, Dellagostin OA, Drobniewski F, Engelmann G, Ferdinand S, Gascoyne-Binzi D, Gordon M, Gutierrez MC, Haas WH, Heersma H, Kassa-Kelembho E, Ly HM, Makristathis A, Mammina C, Martin G, Mostrom P, Mokrousov I, Narbonne V, Narvskaya O, Nastasi A, Niobe-Eyangoh SN, Pape JW, Rasolofo-Razanamparany V, Ridell M, Rossetti ML, Stauffer F, Suffys PN, Takiff H, Texier-Maugein J, Vincent V, de Waard JH, Sola C, Rastogi N.; 2003 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154710

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Specific Differentiation between Mycobacterium bovis BCG and Virulent Strains of the Mycobacterium tuberculosis Complex. by Magdalena J, Supply P, Locht C.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105146

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Specific identification of Mycobacterium tuberculosis with the luciferase reporter mycobacteriophage: use of p-nitro-alpha-acetylamino-beta-hydroxy propiophenone. by Riska PF, Jacobs WR Jr, Bloom BR, McKitrick J, Chan J.; 1997 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230152

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Spoligotyping and Polymorphic GC-Rich Repetitive Sequence Fingerprinting of Mycobacterium tuberculosis Strains Having Few Copies of IS6110. by Yang ZH, Ijaz K, Bates JH, Eisenach KD, Cave MD.; 2000 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87438

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Spoligotyping of Mycobacterium tuberculosis Isolates from Multiple-Drug-Resistant Tuberculosis Patients from Bombay, India. by Mistry NF, Iyer AM, D'souza DT, Taylor GM, Young DB, Antia NH.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=120599

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Spread of Drug-Resistant Mycobacterium tuberculosis Strains of the Beijing Genotype in the Archangel Oblast, Russia. by Toungoussova OS, Sandven P, Mariandyshev AO, Nizovtseva NI, Bjune G, Caugant DA.; 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130821

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Stability of Mycobacterium tuberculosis IS6110 Restriction Fragment Length Polymorphism Patterns and Spoligotypes Determined by Analyzing Serial Isolates from Patients with Drug-Resistant Tuberculosis. by Niemann S, Richter E, RuschGerdes S.; 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84323

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Sulfolipid Deficiency Does Not Affect the Virulence of Mycobacterium tuberculosis H37Rv in Mice and Guinea Pigs. by Rousseau C, Turner OC, Rush E, Bordat Y, Sirakova TD, Kolattukudy PE, Ritter S, Orme IM, Gicquel B, Jackson M.; 2003 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=165994

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Targeting the Mycobacterium tuberculosis 30 /32-kDa mycolyl transferase complex as a therapeutic strategy against tuberculosis: Proof of principle by using antisense technology. by Harth G, Horwitz MA, Tabatadze D, Zamecnik PC.; 2002 Nov 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137765

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Temperature-Mediated Heteroduplex Analysis Performed by Using Denaturing High-Performance Liquid Chromatography To Identify Sequence Polymorphisms in Mycobacterium tuberculosis Complex Organisms. by Cooksey RC, Morlock GP, Holloway BP, Limor J, Hepburn M.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130679

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Testing of susceptibility of Mycobacterium tuberculosis to isoniazid and rifampin by mycobacterium growth indicator tube method. by Walters SB, Hanna BA.; 1996 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229065

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Testing of Susceptibility of Mycobacterium tuberculosis to Pyrazinamide with the Nonradiometric BACTEC MGIT 960 System. by Pfyffer GE, Palicova F, Rusch-Gerdes S.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130957

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The 14,000-molecular-weight antigen of Mycobacterium tuberculosis is related to the alpha-crystallin family of low-molecular-weight heat shock proteins. by Verbon A, Hartskeerl RA, Schuitema A, Kolk AH, Young DB, Lathigra R.; 1992 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=206432

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The 16-kDa [alpha]-crystallin (Acr) protein of Mycobacterium tuberculosis is required for growth in macrophages. by Yuan Y, Crane DD, Simpson RM, Zhu Y, Hickey MJ, Sherman DR, Barry CE III.; 1998 Aug 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21381

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The Apa Protein of Mycobacterium tuberculosis Stimulates Gamma InterferonSecreting CD4 + and CD8 + T Cells from Purified Protein Derivative-Positive Individuals and Affords Protection in a Guinea Pig Model. by Kumar P, Amara RR, Challu VK, Chadda VK, Satchidanandam V.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=152084

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The Efficiency of the Translocation of Mycobacterium tuberculosis across a Bilayer of Epithelial and Endothelial Cells as a Model of the Alveolar Wall Is a Consequence of Transport within Mononuclear Phagocytes and Invasion of Alveolar Epithelial Cells. by Bermudez LE, Sangari FJ, Kolonoski P, Petrofsky M, Goodman J.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127600

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The IS6110 Restriction Fragment Length Polymorphism in Particular MultidrugResistant Mycobacterium tuberculosis Strains May Evolve Too Fast for Reliable Use in Outbreak Investigation. by Alito A, Morcillo N, Scipioni S, Dolmann A, Romano MI, Cataldi A, van Soolingen D.; 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84556

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The isoniazid-NAD adduct is a slow, tight-binding inhibitor of InhA, the Mycobacterium tuberculosis enoyl reductase: Adduct affinity and drug resistance. by Rawat R, Whitty A, Tonge PJ.; 2003 Nov 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=283515

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The Largest Open Reading Frame (pks12) in the Mycobacterium tuberculosis Genome Is Involved in Pathogenesis and Dimycocerosyl Phthiocerol Synthesis. by Sirakova TD, Dubey VS, Kim HJ, Cynamon MH, Kolattukudy PE.; 2003 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161999

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The Mycobacterium tuberculosis 19-Kilodalton Lipoprotein Inhibits Gamma Interferon-Regulated HLA-DR and Fc[gamma]R1 on Human Macrophages through Toll-Like Receptor 2. by Gehring AJ, Rojas RE, Canaday DH, Lakey DL, Harding CV, Boom WH.; 2003 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=166015

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The Mycobacterium tuberculosis Complex-Restricted Gene cfp32 Encodes an Expressed Protein That Is Detectable in Tuberculosis Patients and Is Positively Correlated with Pulmonary Interleukin-10. by Huard RC, Chitale S, Leung M, Lazzarini LC, Zhu H, Shashkina E, Laal S, Conde MB, Kritski AL, Belisle JT, Kreiswirth BN, Lapa e Silva JR, Ho JL.; 2003 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=308900

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The Mycobacterium tuberculosis Phagosome in Human Macrophages Is Isolated from the Host Cell Cytoplasm. by Clemens DL, Lee BY, Horwitz MA.; 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128330

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The role of RelMtb-mediated adaptation to stationary phase in long-term persistence of Mycobacterium tuberculosis in mice. by Dahl JL, Kraus CN, Boshoff HI, Doan B, Foley K, Avarbock D, Kaplan G, Mizrahi V, Rubin H, Barry CE III.; 2003 Aug 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=187750

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The salicylate-derived mycobactin siderophores of Mycobacterium tuberculosis are essential for growth in macrophages. by De Voss JJ, Rutter K, Schroeder BG, Su H, Zhu Y, Barry CE III.; 2000 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15586

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The Stringent Response of Mycobacterium tuberculosis Is Required for Long-Term Survival. by Primm TP, Andersen SJ, Mizrahi V, Avarbock D, Rubin H, Barry CE III.; 2000 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111369

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The Susceptibility of Mycobacterium tuberculosis to Isoniazid and the Arg[right arrow]Leu Mutation at Codon 463 of katG Are Not Associated. by van Doorn HR, Kuijper EJ, van der Ende A, Welten AG, van Soolingen D, de Haas PE, Dankert J.; 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87976

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Transcription of the Stationary-Phase-Associated hspX Gene of Mycobacterium tuberculosis Is Inversely Related to Synthesis of the 16-Kilodalton Protein. by Hu Y, Coates AR.; 1999 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=93524

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Transfer of a Mycobacterium tuberculosis Genotyping Method, Spoligotyping, from a Reverse Line-Blot Hybridization, Membrane-Based Assay to the Luminex Multianalyte Profiling System. by Cowan LS, Diem L, Brake MC, Crawford JT.; 2004 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=321738

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Transmission Dynamics and Molecular Characterization of Mycobacterium tuberculosis Isolates with Low Copy Numbers of IS6110. by Soini H, Pan X, Teeter L, Musser JM, Graviss EA.; 2001 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87705

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Tumor Necrosis Factor Alpha Stimulates Killing of Mycobacterium tuberculosis by Human Neutrophils. by Kisich KO, Higgins M, Diamond G, Heifets L.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128192

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Two-Dimensional Electrophoresis for Analysis of Mycobacterium tuberculosis Culture Filtrate and Purification and Characterization of Six Novel Proteins. by Weldingh K, Rosenkrands I, Jacobsen S, Rasmussen PB, Elhay MJ, Andersen P.; 1998 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108378

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Use of Equivocal Zone in Interpretation of Results of the Amplified Mycobacterium Tuberculosis Direct Test for Diagnosis of Tuberculosis. by Kerleguer A, Koeck JL, Fabre M, Gerome P, Teyssou R, Herve V.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153920

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Use of in vivo complementation in Mycobacterium tuberculosis to identify a genomic fragment associated with virulence. by Pascopella L, Collins FM, Martin JM, Lee MH, Hatfull GF, Stover CK, Bloom BR, Jacobs WR Jr.; 1994 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=186277

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Use of Molecular Methods To Identify the Mycobacterium tuberculosis Complex (MTBC) and Other Mycobacterial Species and To Detect Rifampin Resistance in MTBC Isolates following Growth Detection with the BACTEC MGIT 960 System. by Somoskovi A, Song Q, Mester J, Tanner C, Hale YM, Parsons LM, Salfinger M.; 2003 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=165292

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Use of the Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test for Early Detection of Mycobacterium tuberculosis in BACTEC 12B Medium. by Desmond EP, Loretz K.; 2001 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88067

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Usefulness of Spoligotyping To Discriminate IS6110 Low-Copy-Number Mycobacterium tuberculosis Complex Strains Cultured in Denmark. by Bauer J, Andersen AB, Kremer K, Miorner H.; 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85294

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Utility of an In-House Mycobacteriophage-Based Assay for Rapid Detection of Rifampin Resistance in Mycobacterium tuberculosis Clinical Isolates. by Gali N, Dominguez J, Blanco S, Prat C, Quesada MD, Matas L, Ausina V.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156511

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Variable-Number Tandem Repeat Typing of Mycobacterium tuberculosis Isolates with Low Copy Numbers of IS6110 by Using Mycobacterial Interspersed Repetitive Units. by Cowan LS, Mosher L, Diem L, Massey JP, Crawford JT.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130938

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Visualization and interpretation of protein networks in Mycobacterium tuberculosis based on hierarchical clustering of genome-wide functional linkage maps. by Strong M, Graeber TG, Beeby M, Pellegrini M, Thompson MJ, Yeates TO, Eisenberg D.; 2003 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=291866

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Whole-Genome Comparison of Mycobacterium tuberculosis Clinical and Laboratory Strains. by Fleischmann RD, Alland D, Eisen JA, Carpenter L, White O, Peterson J, DeBoy R, Dodson R, Gwinn M, Haft D, Hickey E, Kolonay JF, Nelson WC, Umayam LA, Ermolaeva M, Salzberg SL, Delcher A, Utterback T, Weidman J, Khouri H, Gill J, Mikula A, Bishai W, Jacobs, Jr. WR, Venter JC, Fraser CM.; 2002 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=135346

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Widespread Pyrazinamide-Resistant Mycobacterium tuberculosis Family in a LowIncidence Setting. by Nguyen D, Brassard P, Westley J, Thibert L, Proulx M, Henry K, Schwartzman K, Menzies D, Behr MA.; 2003 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=165272

The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals.

6

PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.

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To generate your own bibliography of studies dealing with Mycobacterium tuberculosis, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “Mycobacterium tuberculosis” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for Mycobacterium tuberculosis (hyperlinks lead to article summaries): •

A case of sarcoidosis following exposure to Mycobacterium tuberculosis (MTb). Author(s): Rutherford RM, Gilmartin JJ. Source: Ir Med J. 2003 February; 96(2): 58-9. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12674162

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A comparison of dual skin test with mycobacterial antigens and tuberculin skin test alone in estimating prevalence of Mycobacterium tuberculosis infection from population surveys. Author(s): Bierrenbach AL, Floyd S, Cunha SC, Dourado I, Barreto ML, Pereira SM, Hijjar MA, Rodrigues LC. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 April; 7(4): 3129. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12729335

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A family of acr-coregulated Mycobacterium tuberculosis genes shares a common DNA motif and requires Rv3133c (dosR or devR) for expression. Author(s): Florczyk MA, McCue LA, Purkayastha A, Currenti E, Wolin MJ, McDonough KA. Source: Infection and Immunity. 2003 September; 71(9): 5332-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12933881

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A fatal attraction: Mycobacterium tuberculosis and HIV-1 target DC-SIGN to escape immune surveillance. Author(s): van Kooyk Y, Appelmelk B, Geijtenbeek TB. Source: Trends in Molecular Medicine. 2003 April; 9(4): 153-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12727141

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A new high-throughput AFLP approach for identification of new genetic polymorphism in the genome of the clonal microorganism Mycobacterium tuberculosis. Author(s): van den Braak N, Simons G, Gorkink R, Reijans M, Eadie K, Kremers K, van Soolingen D, Savelkoul P, Verbrugh H, van Belkum A. Source: Journal of Microbiological Methods. 2004 January; 56(1): 49-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14706750

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A real-time PCR assay for detection of isoniazid resistance in Mycobacterium tuberculosis clinical isolates. Author(s): Rindi L, Bianchi L, Tortoli E, Lari N, Bonanni D, Garzelli C. Source: Journal of Microbiological Methods. 2003 December; 55(3): 797-800. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14607423

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A tale of two lipids: Mycobacterium tuberculosis phagosome maturation arrest. Author(s): Chua J, Vergne I, Master S, Deretic V. Source: Current Opinion in Microbiology. 2004 February; 7(1): 71-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15036144

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Accurate mapping of mutations of pyrazinamide-resistant Mycobacterium tuberculosis strains with a scanning-frame oligonucleotide microarray. Author(s): Wade MM, Volokhov D, Peredelchuk M, Chizhikov V, Zhang Y. Source: Diagnostic Microbiology and Infectious Disease. 2004 June; 49(2): 89-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15183857

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Activated THP-1 cells: an attractive model for the assessment of intracellular growth rates of Mycobacterium tuberculosis isolates. Author(s): Theus SA, Cave MD, Eisenach KD. Source: Infection and Immunity. 2004 February; 72(2): 1169-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14742569

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Advances in antibody-mediated immunity against Mycobacterium tuberculosis: implications for a novel vaccine strategy. Author(s): Glatman-Freedman A. Source: Fems Immunology and Medical Microbiology. 2003 October 24; 39(1): 9-16. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14556990

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Allele-specific rpoB PCR assays for detection of rifampin-resistant Mycobacterium tuberculosis in sputum smears. Author(s): Mokrousov I, Otten T, Vyshnevskiy B, Narvskaya O. Source: Antimicrobial Agents and Chemotherapy. 2003 July; 47(7): 2231-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12821473

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Alveolar macrophages from HIV-infected subjects are resistant to Mycobacterium tuberculosis in vitro. Author(s): Day RB, Wang Y, Knox KS, Pasula R, Martin WJ 2nd, Twigg HL 3rd. Source: American Journal of Respiratory Cell and Molecular Biology. 2004 March; 30(3): 403-10. Epub 2003 September 11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12972398

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Amplified-fragment length polymorphism as a complement to IS6110-based restriction fragment length polymorphism analysis for molecular typing of Mycobacterium tuberculosis. Author(s): Ruiz M, Rodriguez JC, Rodriguez-Valera F, Royo G. Source: Journal of Clinical Microbiology. 2003 October; 41(10): 4820-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14532231

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Analysis of genetic polymorphisms affecting the four phospholipase C (plc) genes in Mycobacterium tuberculosis complex clinical isolates. Author(s): Viana-Niero C, de Haas PE, van Soolingen D, Leao SC. Source: Microbiology (Reading, England). 2004 April; 150(Pt 4): 967-78. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15073306

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Analysis of the allelic diversity of the mycobacterial interspersed repetitive units in Mycobacterium tuberculosis strains of the Beijing family: practical implications and evolutionary considerations. Author(s): Mokrousov I, Narvskaya O, Limeschenko E, Vyazovaya A, Otten T, Vyshnevskiy B. Source: Journal of Clinical Microbiology. 2004 June; 42(6): 2438-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15184416

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Antibody response to Mycobacterium tuberculosis 30 and 16kDa antigens in pulmonary tuberculosis with human immunodeficiency virus coinfection. Author(s): Uma Devi KR, Ramalingam B, Raja A. Source: Diagnostic Microbiology and Infectious Disease. 2003 July; 46(3): 205-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12867096

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Antimicrobial susceptibility determined by the E test, Lowenstein-Jensen proportion, and DNA sequencing methods among Mycobacterium tuberculosis isolates discrepancies, preliminary results. Author(s): Freixo MI, Caldas PC, Said A, Martins F, Brito RC, Fonseca Lde S, Saad MH. Source: Memorias Do Instituto Oswaldo Cruz. 2004 February; 99(1): 107-10. Epub 2004 March 31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15057357

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Apoptosis genes in human alveolar macrophages infected with virulent or attenuated Mycobacterium tuberculosis: a pivotal role for tumor necrosis factor. Author(s): Spira A, Carroll JD, Liu G, Aziz Z, Shah V, Kornfeld H, Keane J. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 November; 29(5): 545-51. Epub 2003 May 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12748057

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93

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Assessment of laboratory performance of nucleic acid amplification tests for detection of Mycobacterium tuberculosis. Author(s): Ridderhof JC, Williams LO, Legois S, Shult PA, Metchock B, Kubista LN, Handsfield JH, Fehd RJ, Robinson PH. Source: Journal of Clinical Microbiology. 2003 November; 41(11): 5258-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14605177

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Bacillarity at autopsy in pulmonary tuberculosis. Mycobacterium tuberculosis is often disseminated. Author(s): Lillebaek T, Kok-Jensen A, Viskum K. Source: Apmis : Acta Pathologica, Microbiologica, Et Immunologica Scandinavica. 2002 September; 110(9): 625-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12529015

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Bacteremia due to Mycobacterium tuberculosis or M. bovis, Bacille Calmette-Guerin (BCG) among HIV- positive children and adults in Zambia. Author(s): Waddell RD, Lishimpi K, von Reyn CF, Chintu C, Baboo KS, Kreiswirth B, Talbot EA, Karagas MR; Dartmouth/UCLMS/UNZA Collaborative Study Group. Source: Aids (London, England). 2001 January 5; 15(1): 55-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11192868

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Bacterial endocarditis: a role for Mycobacterium tuberculosis? Author(s): Fumagalli J, Bonifacio C, Gulotta H, Shinzato R, Troncoso A. Source: Aids (London, England). 2002 September 6; 16(13): 1845-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12218405

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Bactericidal activities of commonly used antiseptics against multidrug-resistant Mycobacterium tuberculosis. Author(s): Rikimaru T, Kondo M, Kajimura K, Hashimoto K, Oyamada K, Sagawa K, Tanoue S, Oizumi K. Source: Dermatology (Basel, Switzerland). 2002; 204 Suppl 1: 15-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12011515

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Bactericidal activities of the pyrrole derivative BM212 against multidrug-resistant and intramacrophagic Mycobacterium tuberculosis strains. Author(s): Deidda D, Lampis G, Fioravanti R, Biava M, Porretta GC, Zanetti S, Pompei R. Source: Antimicrobial Agents and Chemotherapy. 1998 November; 42(11): 3035-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9797251

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Bacteriological and molecular analysis of rifampin-resistant Mycobacterium tuberculosis strains isolated in Australia. Author(s): Yuen LK, Leslie D, Coloe PJ. Source: Journal of Clinical Microbiology. 1999 December; 37(12): 3844-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10565894

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Bartonella quintana and Mycobacterium tuberculosis coinfection in an HIV-infected patient with lymphadenitis. Author(s): Bernit E, Veit V, La Scola B, Tissot-Dupont H, Gachon J, Raoult D, Harle JR. Source: The Journal of Infection. 2003 May; 46(4): 244-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12799150

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Batimastat reduces Mycobacterium tuberculosis-induced apoptosis in macrophages. Author(s): Santucci MB, Ciaramella A, Mattei M, Sumerska T, Fraziano M. Source: International Immunopharmacology. 2003 November; 3(12): 1657-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14555290

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Beijing/W Mycobacterium tuberculosis in Italy. Author(s): Lari N, Rindi L, Bonanni D, Tortoli E, Garzelli C. Source: Emerging Infectious Diseases. 2004 May; 10(5): 958-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15216844

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Benefits of screening for latent Mycobacterium tuberculosis infection. Author(s): Rose DN. Source: Archives of Internal Medicine. 2000 May 22; 160(10): 1513-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10826467

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beta-1,3-Glucan reduces growth of Mycobacterium tuberculosis in macrophage cultures. Author(s): Hetland G, Sandven P. Source: Fems Immunology and Medical Microbiology. 2002 March 25; 33(1): 41-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11985967

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Beta-chemokines are induced by Mycobacterium tuberculosis and inhibit its growth. Author(s): Saukkonen JJ, Bazydlo B, Thomas M, Strieter RM, Keane J, Kornfeld H. Source: Infection and Immunity. 2002 April; 70(4): 1684-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11895930

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95

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Binding and activation of human plasminogen by Mycobacterium tuberculosis. Author(s): Monroy V, Amador A, Ruiz B, Espinoza-Cueto P, Xolalpa W, Mancilla R, Espitia C. Source: Infection and Immunity. 2000 July; 68(7): 4327-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10858253

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Biochemical and genetic evidence for the transfer of Mycobacterium tuberculosis subsp. caprae Aranaz et al. 1999 to the species Mycobacterium bovis Karlson and Lessel 1970 (approved lists 1980) as Mycobacterium bovis subsp. caprae comb. nov. Author(s): Niemann S, Richter E, Rusch-Gerdes S. Source: International Journal of Systematic and Evolutionary Microbiology. 2002 March; 52(Pt 2): 433-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11931153

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Biochemical interaction of human neutrophil peptide-1 with Mycobacterium tuberculosis H37Ra. Author(s): Sharma S, Verma I, Khuller GK. Source: Archives of Microbiology. 1999 April; 171(5): 338-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10382264

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Blood agar and Mycobacterium tuberculosis: the end of a dogma. Author(s): Drancourt M, Carrieri P, Gevaudan MJ, Raoult D. Source: Journal of Clinical Microbiology. 2003 April; 41(4): 1710-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12682165

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B-lymphocytes and co-stimulatory molecules in Mycobacterium tuberculosis infection. Author(s): Corominas M, Cardona V, Gonzalez L, Cayla JA, Rufi G, Mestre M, Buendia E. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2004 January; 8(1): 98-105. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14974752

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Bone marrow samples from patients with aplastic anemia are not infected with parvovirus B19 and Mycobacterium tuberculosis. Author(s): Hsu HC, Lee YM, Su WJ, Huang CY, Yang CF, Ho CK, Ho CH, Wang SY, Liu WT. Source: American Journal of Clinical Pathology. 2002 January; 117(1): 36-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11789728

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CD8+ T cell-mediated suppression of intracellular Mycobacterium tuberculosis growth in activated human macrophages. Author(s): Brookes RH, Pathan AA, McShane H, Hensmann M, Price DA, Hill AV. Source: European Journal of Immunology. 2003 December; 33(12): 3293-302. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14635037

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Cell-wall alterations as an attribute of Mycobacterium tuberculosis in latent infection. Author(s): Seiler P, Ulrichs T, Bandermann S, Pradl L, Jorg S, Krenn V, Morawietz L, Kaufmann SH, Aichele P. Source: The Journal of Infectious Diseases. 2003 November 1; 188(9): 1326-31. Epub 2003 October 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14593589

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Changes in avidity and level of immunoglobulin G antibodies to Mycobacterium tuberculosis in sera of patients undergoing treatment for pulmonary tuberculosis. Author(s): Arias-Bouda LM, Kuijper S, Van der Werf A, Nguyen LN, Jansen HM, Kolk AH. Source: Clinical and Diagnostic Laboratory Immunology. 2003 July; 10(4): 702-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12853408

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Characteristics associated with reported sputum culture conversion in the era of reemergent Mycobacterium tuberculosis in the State of North Carolina, 1993-1998. Author(s): Salihu HM, Aliyu MH, Ratard R, Pierre-Louis BJ. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 November; 7(11): 1070-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14598967

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Characterization of clinical isolates of Mycobacterium tuberculosis resistant to drugs and detection of RpoB mutation in multidrug-resistant tuberculosis in the Philippines. Author(s): Agdamag DM, Kageyama S, Solante R, Espantaleon AS, Sangco JC, Suzuki Y. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 November; 7(11): 1104-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14598972

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Characterization of the Manila family of Mycobacterium tuberculosis. Author(s): Douglas JT, Qian L, Montoya JC, Musser JM, Van Embden JD, Van Soolingen D, Kremer K. Source: Journal of Clinical Microbiology. 2003 June; 41(6): 2723-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12791915

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Clinical evaluation of the semiautomated BDProbeTec ET System for the detection of Mycobacterium tuberculosis in respiratory and nonrespiratory specimens. Author(s): Rusch-Gerdes S, Richter E. Source: Diagnostic Microbiology and Infectious Disease. 2004 April; 48(4): 265-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15062919

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Comparative analysis of B- and T-cell epitopes of Mycobacterium leprae and Mycobacterium tuberculosis culture filtrate protein 10. Author(s): Spencer JS, Kim HJ, Marques AM, Gonzalez-Juarerro M, Lima MC, Vissa VD, Truman RW, Gennaro ML, Cho SN, Cole ST, Brennan PJ. Source: Infection and Immunity. 2004 June; 72(6): 3161-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15155617

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Comparative antimicrobial activities of gatifloxacin, sitafloxacin and levofloxacin against Mycobacterium tuberculosis replicating within Mono Mac 6 human macrophage and A-549 type II alveolar cell lines. Author(s): Sato K, Tomioka H, Sano C, Shimizu T, Sano K, Ogasawara K, Cai S, Kamei T. Source: The Journal of Antimicrobial Chemotherapy. 2003 August; 52(2): 199-203. Epub 2003 July 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12865388

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Comparative study of purine and pyrimidine nucleoside analogues acting on the thymidylate kinases of Mycobacterium tuberculosis and of humans. Author(s): Pochet S, Dugue L, Labesse G, Delepierre M, Munier-Lehmann H. Source: Chembiochem : a European Journal of Chemical Biology. 2003 August 4; 4(8): 742-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12898625

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Comparison of a whole-blood interferon-gamma assay and tuberculin skin testing in patients with active tuberculosis and individuals at high or low risk of Mycobacterium tuberculosis infection. Author(s): Fietta A, Meloni F, Cascina A, Morosini M, Marena C, Troupioti P, Mangiarotti P, Casali L. Source: American Journal of Infection Control. 2003 October; 31(6): 347-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14608301

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Comparison of sodium carbonate, cetyl-pyridinium chloride, and sodium borate for preservation of sputa for culture of Mycobacterium tuberculosis. Author(s): Bobadilla-del-Valle M, Ponce-de-Leon A, Kato-Maeda M, Hernandez-Cruz A, Calva-Mercado JJ, Chavez-Mazari B, Caballero-Rivera BA, Nolasco-Garcia JC, SifuentesOsornio J. Source: Journal of Clinical Microbiology. 2003 September; 41(9): 4487-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12958303

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Comparison of the BDProbeTec ET system with the roche COBAS AMPLICOR System for detection of Mycobacterium tuberculosis complex in the respiratory and pleural fluid specimens. Author(s): Kim SY, Park YJ, Kang SJ, Kim BK, Kang CS. Source: Diagnostic Microbiology and Infectious Disease. 2004 May; 49(1): 13-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15135494

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Complement protein C3 binding to Mycobacterium tuberculosis is initiated by the classical pathway in human bronchoalveolar lavage fluid. Author(s): Ferguson JS, Weis JJ, Martin JL, Schlesinger LS. Source: Infection and Immunity. 2004 May; 72(5): 2564-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15102764

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Complementary analysis of the Mycobacterium tuberculosis proteome by twodimensional electrophoresis and isotope-coded affinity tag technology. Author(s): Schmidt F, Donahoe S, Hagens K, Mattow J, Schaible UE, Kaufmann SH, Aebersold R, Jungblut PR. Source: Molecular & Cellular Proteomics : Mcp. 2004 January; 3(1): 24-42. Epub 2003 October 13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14557599

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Computer-assisted prediction of HLA-DR binding and experimental analysis for human promiscuous Th1-cell peptides in the 24 kDa secreted lipoprotein (LppX) of Mycobacterium tuberculosis. Author(s): Al-Attiyah R, Mustafa AS. Source: Scandinavian Journal of Immunology. 2004 January; 59(1): 16-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14723617

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Concomitant Mycobacterium tuberculosis and Aspergillus niger infection in a patient with acute myeloid leukemia. Author(s): Aksoy DY, Turker A, Altundag MK, Abali H, Durusu M, Erman M, Uner A, Sungur AA, Unal S, Uzun O. Source: Chemotherapy. 2003 September; 49(5): 264-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14504439

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Cough-generated aerosols of Mycobacterium tuberculosis: a new method to study infectiousness. Author(s): Fennelly KP, Martyny JW, Fulton KE, Orme IM, Cave DM, Heifets LB. Source: American Journal of Respiratory and Critical Care Medicine. 2004 March 1; 169(5): 604-9. Epub 2003 December 04. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14656754

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Critical use of nucleic acid amplification techniques to test for Mycobacterium tuberculosis in respiratory tract samples. Author(s): Van den Wijngaert S, Dediste A, VanLaethem Y, Gerard M, Vandenberg O, Zissis G. Source: Journal of Clinical Microbiology. 2004 February; 42(2): 837-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14766866

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Cytokine profile, HLA restriction and TCR sequence analysis of human CD4+ T clones specific for an immunodominant epitope of Mycobacterium tuberculosis 16kDa protein. Author(s): Caccamo N, Barera A, Di Sano C, Meraviglia S, Ivanyi J, Hudecz F, Bosze S, Dieli F, Salerno A. Source: Clinical and Experimental Immunology. 2003 August; 133(2): 260-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12869033

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Deficiency in mycolipenate- and mycosanoate-derived acyltrehaloses enhances early interactions of Mycobacterium tuberculosis with host cells. Author(s): Rousseau C, Neyrolles O, Bordat Y, Giroux S, Sirakova TD, Prevost MC, Kolattukudy PE, Gicquel B, Jackson M. Source: Cellular Microbiology. 2003 June; 5(6): 405-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12780778

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Deletion of Mycobacterium tuberculosis sigma factor E results in delayed time to death with bacterial persistence in the lungs of aerosol-infected mice. Author(s): Ando M, Yoshimatsu T, Ko C, Converse PJ, Bishai WR. Source: Infection and Immunity. 2003 December; 71(12): 7170-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14638810

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Design of Mycobacterium tuberculosis thymidine monophosphate kinase inhibitors. Author(s): Munier-Lehmann H, Pochet S, Dugue L, Dutruel O, Labesse G, Douget D. Source: Nucleosides, Nucleotides & Nucleic Acids. 2003 May-August; 22(5-8): 801-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14565282

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Detection and differentiation of Mycobacterium tuberculosis and nontuberculous mycobacterial isolates by real-time PCR. Author(s): Shrestha NK, Tuohy MJ, Hall GS, Reischl U, Gordon SM, Procop GW. Source: Journal of Clinical Microbiology. 2003 November; 41(11): 5121-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14605148

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Detection of a point mutation associated with high-level isoniazid resistance in Mycobacterium tuberculosis by using real-time PCR technology with 3'-minor groove binder-DNA probes. Author(s): van Doorn HR, Claas EC, Templeton KE, van der Zanden AG, te Koppele Vije A, de Jong MD, Dankert J, Kuijper EJ. Source: Journal of Clinical Microbiology. 2003 October; 41(10): 4630-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14532194

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Detection of isoniazid and rifampin resistance in Mycobacterium tuberculosis strains by single-strand conformation polymorphism analysis and restriction fragment length polymorphism. Author(s): Piana A, Orru M, Masia MD, Sotgiu G, Muresu E, Maida A. Source: New Microbiol. 2003 October; 26(4): 375-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14596348

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Detection of katG Ser315Thr substitution in respiratory specimens from patients with isoniazid-resistant Mycobacterium tuberculosis using PCR-RFLP. Author(s): Leung ET, Kam KM, Chiu A, Ho PL, Seto WH, Yuen KY, Yam WC. Source: Journal of Medical Microbiology. 2003 November; 52(Pt 11): 999-1003. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14532345

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Detection of Mycobacterium tuberculosis in gastric aspirate and sputum collected from Ethiopian HIV-positive and HIV-negative children in a mixed in- and outpatient setting. Author(s): Berggren Palme I, Gudetta B, Bruchfeld J, Eriksson M, Giesecke J. Source: Acta Paediatrica (Oslo, Norway : 1992). 2004 March; 93(3): 311-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15124831

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Detection of resistance to isoniazid by denaturing gradient-gel electrophoresis DNA sequencing in Mycobacterium tuberculosis clinical isolates. Author(s): Scarpellini P, Carrera P, Cichero P, Gelfi C, Gori A, Ferrari M, Zingale A, Lazzarin A. Source: New Microbiol. 2003 October; 26(4): 345-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14596345

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Detection of rifampin-resistant Mycobacterium tuberculosis strains by using a specialized oligonucleotide microarray. Author(s): Yue J, Shi W, Xie J, Li Y, Zeng E, Liang L, Wang H. Source: Diagnostic Microbiology and Infectious Disease. 2004 January; 48(1): 47-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14761721

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Differential gene expression identifies novel markers of CD4+ and CD8+ T cell activation following stimulation by Mycobacterium tuberculosis. Author(s): Cliff JM, Andrade IN, Mistry R, Clayton CL, Lennon MG, Lewis AP, Duncan K, Lukey PT, Dockrell HM. Source: Journal of Immunology (Baltimore, Md. : 1950). 2004 July 1; 173(1): 485-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15210809

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Differential identification of Mycobacterium tuberculosis complex and nontuberculous mycobacteria by duplex PCR assay using the RNA polymerase gene (rpoB). Author(s): Kim BJ, Hong SK, Lee KH, Yun YJ, Kim EC, Park YG, Bai GH, Kook YH. Source: Journal of Clinical Microbiology. 2004 March; 42(3): 1308-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15004105

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Direct colorimetric assay for rapid detection of rifampin-resistant Mycobacterium tuberculosis. Author(s): Abate G, Aseffa A, Selassie A, Goshu S, Fekade B, WoldeMeskal D, Miorner H. Source: Journal of Clinical Microbiology. 2004 February; 42(2): 871-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14766876

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Direct detection of Mycobacterium tuberculosis in clinical specimens using singletube biotinylated nested polymerase chain reaction-enzyme linked immunoassay (PCR-ELISA). Author(s): Yam WC, Cheng VC, Hui WT, Wang LN, Seto WH, Yuen KY. Source: Diagnostic Microbiology and Infectious Disease. 2004 April; 48(4): 271-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15062920

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Direct detection of rifampin- and isoniazid-resistant Mycobacterium tuberculosis in auramine-rhodamine-positive sputum specimens by real-time PCR. Author(s): Ruiz M, Torres MJ, Llanos AC, Arroyo A, Palomares JC, Aznar J. Source: Journal of Clinical Microbiology. 2004 April; 42(4): 1585-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15071008

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Direct identification of Mycobacterium tuberculosis from sputum on Ziehl-Neelsen acid fast stained slides by use of silica-based filter combined with polymerase chain reaction assay. Author(s): Tansuphasiri U, Boonrat P, Rienthong S. Source: J Med Assoc Thai. 2004 February; 87(2): 180-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15061302

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Disruption of response regulator gene, devR, leads to attenuation in virulence of Mycobacterium tuberculosis. Author(s): Malhotra V, Sharma D, Ramanathan VD, Shakila H, Saini DK, Chakravorty S, Das TK, Li Q, Silver RF, Narayanan PR, Tyagi JS. Source: Fems Microbiology Letters. 2004 February 16; 231(2): 237-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14987770

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Drug resistance among Mycobacterium tuberculosis strains in immigrants: is there a real threat everywhere? Author(s): Esteban J, Granizo JJ, Alvarez-Castillo MC, Soriano F. Source: Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 2004 April; 10(4): 335-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15059124

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Drug susceptibility testing of Mycobacterium tuberculosis by the broth microdilution method with 7H9 broth. Author(s): Coban AY, Birinci A, Ekinci B, Durupinar B. Source: Memorias Do Instituto Oswaldo Cruz. 2004 February; 99(1): 111-3. Epub 2004 March 31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15057358

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Dual infection with Streptococcus pneumoniae and Mycobacterium tuberculosis in HIV-seropositive patients with community acquired pneumonia. Author(s): Schleicher GK, Feldman C. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 December; 7(12): 1207-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14677897

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Effect of clinical and socio-economic factors on the rate of clustering of Mycobacterium tuberculosis clinical isolates in Elche (Spain). Author(s): Ruiz M, Navarro JF, Rodriguez JC, Larrosa JA, Royo G. Source: Epidemiology and Infection. 2003 December; 131(3): 1077-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14959773

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Effect of neutralizing transforming growth factor beta1 on the immune response against Mycobacterium tuberculosis in guinea pigs. Author(s): Allen SS, Cassone L, Lasco TM, McMurray DN. Source: Infection and Immunity. 2004 March; 72(3): 1358-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14977939

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Effect of rpoB mutations conferring rifampin resistance on fitness of Mycobacterium tuberculosis. Author(s): Mariam DH, Mengistu Y, Hoffner SE, Andersson DI. Source: Antimicrobial Agents and Chemotherapy. 2004 April; 48(4): 1289-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15047531

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ethA, inhA, and katG loci of ethionamide-resistant clinical Mycobacterium tuberculosis isolates. Author(s): Morlock GP, Metchock B, Sikes D, Crawford JT, Cooksey RC. Source: Antimicrobial Agents and Chemotherapy. 2003 December; 47(12): 3799-805. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14638486

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Eukaryotic genes in Mycobacterium tuberculosis? Possible alternative explanations. Author(s): Kinsella RJ, McInerney JO. Source: Trends in Genetics : Tig. 2003 December; 19(12): 687-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14642748

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Evaluation of a high-throughput repetitive-sequence-based PCR system for DNA fingerprinting of Mycobacterium tuberculosis and Mycobacterium avium complex strains. Author(s): Cangelosi GA, Freeman RJ, Lewis KN, Livingston-Rosanoff D, Shah KS, Milan SJ, Goldberg SV. Source: Journal of Clinical Microbiology. 2004 June; 42(6): 2685-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15184453

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Evaluation of a PCR-based universal heteroduplex generator assay as a tool for rapid detection of multidrug-resistant Mycobacterium tuberculosis in Peru. Author(s): Mayta H, Gilman RH, Arenas F, Valencia T, Caviedes L, Montenegro SH, Ticona E, Ortiz J, Chumpitaz R, Evans CA, Williams DL; Tuberculosis Working Group in Peru. Source: Journal of Clinical Microbiology. 2003 December; 41(12): 5774-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14662980

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Evaluation of genotype MTBC assay for differentiation of clinical Mycobacterium tuberculosis complex isolates. Author(s): Richter E, Weizenegger M, Rusch-Gerdes S, Niemann S. Source: Journal of Clinical Microbiology. 2003 June; 41(6): 2672-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12791901

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Evaluation of indirect susceptibility testing of Mycobacterium tuberculosis to the first- and second-line, and alternative drugs by the newer MB/BacT system. Author(s): Barreto AM, Araujo JB, de Melo Medeiros RF, de Souza Caldas PC. Source: Memorias Do Instituto Oswaldo Cruz. 2003 September; 98(6): 827-30. Epub 2003 October 29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14595463

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Evaluation of sputum decontamination methods for Mycobacterium tuberculosis using viable colony counts and flow cytometry. Author(s): Burdz TV, Wolfe J, Kabani A. Source: Diagnostic Microbiology and Infectious Disease. 2003 November; 47(3): 503-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14596969

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Evaluation of T-cell responses to novel RD1- and RD2-encoded Mycobacterium tuberculosis gene products for specific detection of human tuberculosis infection. Author(s): Liu XQ, Dosanjh D, Varia H, Ewer K, Cockle P, Pasvol G, Lalvani A. Source: Infection and Immunity. 2004 May; 72(5): 2574-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15102765

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Evaluation of the BacT/ALERT 3D system for recovery and drug susceptibility testing of Mycobacterium tuberculosis. Author(s): Angeby KA, Werngren J, Toro JC, Hedstrom G, Petrini B, Hoffner SE. Source: Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 2003 November; 9(11): 1148-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14616736

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Evaluation of the BDProbeTec ET system as screening tool in the direct detection of Mycobacterium tuberculosis complex in respiratory specimens. Author(s): Jesus de la Calle I, Jesus de la Calle MA, Rodriguez-Iglesias M. Source: Diagnostic Microbiology and Infectious Disease. 2003 December; 47(4): 573-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14711478

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Evaluation of the epidemiologic utility of secondary typing methods for differentiation of Mycobacterium tuberculosis isolates. Author(s): Kwara A, Schiro R, Cowan LS, Hyslop NE, Wiser MF, Roahen Harrison S, Kissinger P, Diem L, Crawford JT. Source: Journal of Clinical Microbiology. 2003 June; 41(6): 2683-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12791904

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105

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Evaluation of the fully automated BACTEC MGIT 960 system for testing susceptibility of Mycobacterium tuberculosis to pyrazinamide, streptomycin, isoniazid, rifampin, and ethambutol and comparison with the radiometric BACTEC 460TB method. Author(s): Scarparo C, Ricordi P, Ruggiero G, Piccoli P. Source: Journal of Clinical Microbiology. 2004 March; 42(3): 1109-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15004061

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Evaluation of the fully automated Bactec MGIT 960 system for the susceptibility testing of Mycobacterium tuberculosis to first-line drugs: a multicenter study. Author(s): Kontos F, Maniati M, Costopoulos C, Gitti Z, Nicolaou S, Petinaki E, Anagnostou S, Tselentis I, Maniatis AN. Source: Journal of Microbiological Methods. 2004 February; 56(2): 291-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14744458

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Expanded geographical distribution of the N family of Mycobacterium tuberculosis strains within the United States. Author(s): Milan SJ, Hauge KA, Kurepina NE, Lofy KH, Goldberg SV, Narita M, Nolan CM, McElroy PD, Kreiswirth BN, Cangelosi GA. Source: Journal of Clinical Microbiology. 2004 March; 42(3): 1064-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15004054

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Experimental Mycobacterium tuberculosis infection of cynomolgus macaques closely resembles the various manifestations of human M. tuberculosis infection. Author(s): Capuano SV 3rd, Croix DA, Pawar S, Zinovik A, Myers A, Lin PL, Bissel S, Fuhrman C, Klein E, Flynn JL. Source: Infection and Immunity. 2003 October; 71(10): 5831-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14500505

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Expression of SA5K, a secretion antigen of Mycobacterium tuberculosis, inside human macrophages and in sputum from tuberculosis patients. Author(s): Bottai D, Batoni G, Esin S, Maisetta G, Pardini M, Florio W, Rindi L, Garzelli C, Campa M. Source: Fems Microbiology Letters. 2003 September 26; 226(2): 229-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14553916

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Expression, secretion, and glycosylation of the 45- and 47-kDa glycoprotein of Mycobacterium tuberculosis in Streptomyces lividans. Author(s): Lara M, Servin-Gonzalez L, Singh M, Moreno C, Cohen I, Nimtz M, Espitia C. Source: Applied and Environmental Microbiology. 2004 February; 70(2): 679-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14766542

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Facial granulomatous diseases: a study of four cases tested for the presence of Mycobacterium tuberculosis DNA using nested polymerase chain reaction. Author(s): Ferrara G, Cannone M, Scalvenzi M, Delfino M, Staibano S, De Rosa G, Barberis MC. Source: The American Journal of Dermatopathology. 2001 February; 23(1): 8-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11176046

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Failure of commercial ligase chain reaction to detect Mycobacterium tuberculosis DNA in sputum samples from a patient with smear-positive pulmonary tuberculosis due to a deletion of the target region. Author(s): Gilpin CM, Dawson DJ, O'Kane G, Armstrong JG, Coulter C. Source: Journal of Clinical Microbiology. 2002 June; 40(6): 2305-7. Erratum In: J Clin Microbiol 2002 October; 40(10): 3887. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12037118

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Failure of osteosynthesis and prosthetic joint infection due to Mycobacterium tuberculosis following a subtrochanteric fracture: a case report and review of the literature. Author(s): Krappel FA, Harland U. Source: Archives of Orthopaedic and Trauma Surgery. 2000; 120(7-8): 470-2. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10968544

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False molecular clusters due to nonrandom association of IS6110 with Mycobacterium tuberculosis. Author(s): Gillespie SH, Dickens A, McHugh TD. Source: Journal of Clinical Microbiology. 2000 June; 38(6): 2081-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10834957

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False-positive growth of Mycobacterium tuberculosis attributable to laboratory contamination confirmed by restriction fragment length polymorphism analysis. Author(s): Chang CL, Kim HH, Son HC, Park SS, Lee MK, Park SK, Park WW, Jeon CH. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2001 September; 5(9): 861-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11573899

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False-positive Mycobacterium tuberculosis culture revealed by restriction fragment length polymorphism analysis. Author(s): Schoch OD, Pfyffer GE, Buhl D, Paky A. Source: Infection. 2003 June; 31(3): 189-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12789481

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False-positive Mycobacterium tuberculosis cultures in 44 laboratories in The Netherlands (1993 to 2000): incidence, risk factors, and consequences. Author(s): de Boer AS, Blommerde B, de Haas PE, Sebek MM, Lambregts-van Weezenbeek KS, Dessens M, van Soolingen D. Source: Journal of Clinical Microbiology. 2002 November; 40(11): 4004-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12409366

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False-positive results for Mycobacterium celatum with the AccuProbe Mycobacterium tuberculosis complex assay. Author(s): Somoskovi A, Hotaling JE, Fitzgerald M, Jonas V, Stasik D, Parsons LM, Salfinger M. Source: Journal of Clinical Microbiology. 2000 July; 38(7): 2743-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10878076

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Familial Mediterranean fever. No role of Mycobacterium tuberculosis in ten patients. Author(s): Akcan Y, Tuncer S, Unal S, Sokmensuer C, Haznedaroglu CI, Arslan S. Source: European Journal of Medical Research. 1999 April 27; 4(4): 161-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10205292

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Fatal mycobacteremia caused by Mycobacterium tuberculosis in a patient with acute leukemia. Author(s): Ker CC, Hung CC, Sheng WH, Chang SC, Luh KT. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1999 April; 13(4): 646-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10214876

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Fatal Mycobacterium tuberculosis brain abscess in an immunocompetent patient. Author(s): Megarbane B, Lebrun L, Marchal P, Axler O, Brivet FG. Source: Scandinavian Journal of Infectious Diseases. 2000; 32(6): 702-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11200388

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Fatal sepsis due to Mycobacterium tuberculosis after allogeneic bone marrow transplantation. Author(s): Kindler T, Schindel C, Brass U, Fischer T. Source: Bone Marrow Transplantation. 2001 January; 27(2): 217-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11281394

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Fluoroquinolone action against clinical isolates of Mycobacterium tuberculosis: effects of a C-8 methoxyl group on survival in liquid media and in human macrophages. Author(s): Zhao BY, Pine R, Domagala J, Drlica K. Source: Antimicrobial Agents and Chemotherapy. 1999 March; 43(3): 661-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10049284

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Folding requirements are different between sterol 14alpha-demethylase (CYP51) from Mycobacterium tuberculosis and human or fungal orthologs. Author(s): Lepesheva GI, Podust LM, Bellamine A, Waterman MR. Source: The Journal of Biological Chemistry. 2001 July 27; 276(30): 28413-20. Epub 2001 May 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11373285

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Four-year experience of use of the Cobas Amplicor system for rapid detection of Mycobacterium tuberculosis complex in respiratory and nonrespiratory specimens in Greece. Author(s): Levidiotou S, Vrioni G, Galanakis E, Gesouli E, Pappa C, Stefanou D. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2003 June; 22(6): 349-56. Epub 2003 June 03. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12783277

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Frequency of rpoB mutations inside and outside the cluster I region in rifampinresistant clinical Mycobacterium tuberculosis isolates. Author(s): Heep M, Brandstatter B, Rieger U, Lehn N, Richter E, Rusch-Gerdes S, Niemann S. Source: Journal of Clinical Microbiology. 2001 January; 39(1): 107-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11136757

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Functional analysis of the Mycobacterium tuberculosis MprAB two-component signal transduction system. Author(s): Zahrt TC, Wozniak C, Jones D, Trevett A. Source: Infection and Immunity. 2003 December; 71(12): 6962-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14638785

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Functional similarities between the small heat shock proteins Mycobacterium tuberculosis HSP 16.3 and human alphaB-crystallin. Author(s): Valdez MM, Clark JI, Wu GJ, Muchowski PJ. Source: European Journal of Biochemistry / Febs. 2002 April; 269(7): 1806-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11952782

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Further investigations on the association of Mycobacterium tuberculosis with Eales' disease. Author(s): Madhavan HN, Therese KL, Doraiswamy K. Source: Indian J Ophthalmol. 2002 March; 50(1): 35-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12090085

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Gamma/delta T cell subsets in patients with active Mycobacterium tuberculosis infection and tuberculin anergy. Author(s): Szereday L, Baliko Z, Szekeres-Bartho J. Source: Clinical and Experimental Immunology. 2003 February; 131(2): 287-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12562390

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Gas chromatographic detection of Mycobacterium tuberculosis complex in pure cultures from respiratory specimens. Author(s): Dorneanu O, Wittmer A, Diculencu D, Pelz K. Source: Rev Med Chir Soc Med Nat Iasi. 2000 October-December; 104(4): 161-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12089947

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Gene expression profiling detects patterns of human macrophage responses following Mycobacterium tuberculosis infection. Author(s): Wang JP, Rought SE, Corbeil J, Guiney DG. Source: Fems Immunology and Medical Microbiology. 2003 November 28; 39(2): 163-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14625100

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Genetic and phenotypic characterization of pyrazinamide-resistant Mycobacterium tuberculosis complex isolates in Japan. Author(s): Miyagi C, Yamane N, Yogesh B, Ano H, Takashima T. Source: Diagnostic Microbiology and Infectious Disease. 2004 February; 48(2): 111-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14972380

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Genetic biodiversity of Mycobacterium tuberculosis complex strains from patients with pulmonary tuberculosis in Cameroon. Author(s): Niobe-Eyangoh SN, Kuaban C, Sorlin P, Cunin P, Thonnon J, Sola C, Rastogi N, Vincent V, Gutierrez MC. Source: Journal of Clinical Microbiology. 2003 June; 41(6): 2547-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12791879

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Genetic diversity and population structure of Mycobacterium tuberculosis in Casablanca, a Moroccan city with high incidence of tuberculosis. Author(s): Tazi L, El Baghdadi J, Lesjean S, Locht C, Supply P, Tibayrenc M, Banuls AL. Source: Journal of Clinical Microbiology. 2004 January; 42(1): 461-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14715806

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Genetic polymorphism in Mycobacterium tuberculosis isolates from patients with chronic multidrug-resistant tuberculosis. Author(s): Post FA, Willcox PA, Mathema B, Steyn LM, Shean K, Ramaswamy SV, Graviss EA, Shashkina E, Kreiswirth BN, Kaplan G. Source: The Journal of Infectious Diseases. 2004 July 1; 190(1): 99-106. Epub 2004 May 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15195248

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Genome structure in the vole bacillus, Mycobacterium microti, a member of the Mycobacterium tuberculosis complex with a low virulence for humans. Author(s): Frota CC, Hunt DM, Buxton RS, Rickman L, Hinds J, Kremer K, van Soolingen D, Colston MJ. Source: Microbiology (Reading, England). 2004 May; 150(Pt 5): 1519-27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15133113

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Genome-wide analysis of synonymous single nucleotide polymorphisms in Mycobacterium tuberculosis complex organisms: resolution of genetic relationships among closely related microbial strains. Author(s): Gutacker MM, Smoot JC, Migliaccio CA, Ricklefs SM, Hua S, Cousins DV, Graviss EA, Shashkina E, Kreiswirth BN, Musser JM. Source: Genetics. 2002 December; 162(4): 1533-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12524330

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Genomewide pattern of synonymous nucleotide substitution in two complete genomes of Mycobacterium tuberculosis. Author(s): Hughes AL, Friedman R, Murray M. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1342-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12453367

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Genomic deletions suggest a phylogeny for the Mycobacterium tuberculosis complex. Author(s): Mostowy S, Cousins D, Brinkman J, Aranaz A, Behr MA. Source: The Journal of Infectious Diseases. 2002 July 1; 186(1): 74-80. Epub 2002 May 30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12089664

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Genomic study of Mycobacterium tuberculosis and its clinical applications. Author(s): Tyagi JS, Sharma D. Source: Indian J Pediatr. 2002 November; 69 Suppl 1: S29-38. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12501923

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Genotype analysis of Mycobacterium tuberculosis isolates from a sentinel surveillance population. Author(s): Cowan LS, Crawford JT. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1294-302. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12453359

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Genotypic analysis of multidrug-resistant Mycobacterium tuberculosis isolates from Monterrey, Mexico. Author(s): Ramaswamy SV, Dou SJ, Rendon A, Yang Z, Cave MD, Graviss EA. Source: Journal of Medical Microbiology. 2004 February; 53(Pt 2): 107-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14729930

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Genotypic analysis of Mycobacterium tuberculosis in Bangladesh and prevalence of the Beijing strain. Author(s): Banu S, Gordon SV, Palmer S, Islam MR, Ahmed S, Alam KM, Cole ST, Brosch R. Source: Journal of Clinical Microbiology. 2004 February; 42(2): 674-82. Erratum In: J Clin Microbiol. 2004 April; 42(4): 1861. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14766836

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Genotypic and phenotypic characterization of drug-resistant Mycobacterium tuberculosis isolates from rural districts of the Western Cape Province of South Africa. Author(s): Streicher EM, Warren RM, Kewley C, Simpson J, Rastogi N, Sola C, van der Spuy GD, van Helden PD, Victor TC. Source: Journal of Clinical Microbiology. 2004 February; 42(2): 891-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14766882

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Genotypic and phenotypic resistance of Mycobacterium tuberculosis to rifamycins and fluoroquinolones. Author(s): Yew WW, Chan E, Chan CY, Cheng AF. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 October; 6(10): 936-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12365583

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Genotyping of the Mycobacterium tuberculosis complex using MIRUs: association with VNTR and spoligotyping for molecular epidemiology and evolutionary genetics. Author(s): Sola C, Filliol I, Legrand E, Lesjean S, Locht C, Supply P, Rastogi N. Source: Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases. 2003 July; 3(2): 125-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12809807

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Glutamine synthetase GlnA1 is essential for growth of Mycobacterium tuberculosis in human THP-1 macrophages and guinea pigs. Author(s): Tullius MV, Harth G, Horwitz MA. Source: Infection and Immunity. 2003 July; 71(7): 3927-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12819079

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Guidelines for using the QuantiFERON-TB test for diagnosing latent Mycobacterium tuberculosis infection. Centers for Disease Control and Prevention. Author(s): Mazurek GH, Villarino ME; CDC. Source: Mmwr. Recommendations and Reports : Morbidity and Mortality Weekly Report. Recommendations and Reports / Centers for Disease Control. 2003 January 31; 52(Rr-2): 15-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12583541

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Healthy individuals that control a latent infection with Mycobacterium tuberculosis express high levels of Th1 cytokines and the IL-4 antagonist IL-4delta2. Author(s): Demissie A, Abebe M, Aseffa A, Rook G, Fletcher H, Zumla A, Weldingh K, Brock I, Andersen P, Doherty TM; VACSEL Study Group. Source: Journal of Immunology (Baltimore, Md. : 1950). 2004 June 1; 172(11): 6938-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15153513

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Heterogeneity of Mycobacterium tuberculosis isolates in Yangon, Myanmar. Author(s): Phyu S, Jureen R, Ti T, Dahle UR, Grewal HM. Source: Journal of Clinical Microbiology. 2003 October; 41(10): 4907-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14532259

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Heteroresistance in Mycobacterium tuberculosis. Author(s): Rinder H, Mieskes KT, Loscher T. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2001 April; 5(4): 33945. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11334252

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High prevalence of KatG Ser315Thr substitution among isoniazid-resistant Mycobacterium tuberculosis clinical isolates from northwestern Russia, 1996 to 2001. Author(s): Mokrousov I, Narvskaya O, Otten T, Limeschenko E, Steklova L, Vyshnevskiy B. Source: Antimicrobial Agents and Chemotherapy. 2002 May; 46(5): 1417-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11959577

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Histopathologic features of cerebral vasculitis associated with Mycobacterium tuberculosis. Author(s): Blanco Garcia FJ, Sanchez Blas M, Freire Gonzalez M. Source: Arthritis and Rheumatism. 1999 February; 42(2): 383. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10025934

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Historic and recent events contribute to the disease dynamics of Beijing-like Mycobacterium tuberculosis isolates in a high incidence region. Author(s): Richardson M, van Lill SW, van der Spuy GD, Munch Z, Booysen CN, Beyers N, van Helden PD, Warren RM. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 November; 6(11): 1001-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12475147

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HIV infection and sputum-culture conversion in patients diagnosed with Mycobacterium tuberculosis: a population-based study. Author(s): Aliyu MH, Salihu HM, Ratard R. Source: Wiener Klinische Wochenschrift. 2003 May 30; 115(10): 340-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12800448

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HLA-A2-restricted CD8+-cytotoxic-T-cell responses to novel epitopes in Mycobacterium tuberculosis superoxide dismutase, alanine dehydrogenase, and glutamine synthetase. Author(s): Dong Y, Demaria S, Sun X, Santori FR, Jesdale BM, De Groot AS, Rom WN, Bushkin Y. Source: Infection and Immunity. 2004 April; 72(4): 2412-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15039371

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HLA-B*35-restricted CD8(+)-T-cell epitope in Mycobacterium tuberculosis Rv2903c. Author(s): Klein MR, Hammond AS, Smith SM, Jaye A, Lukey PT, McAdam KP. Source: Infection and Immunity. 2002 February; 70(2): 981-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11796635

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Host defense responses to infection by Mycobacterium tuberculosis. Induction of IRF-1 and a serine protease inhibitor. Author(s): Qiao Y, Prabhakar S, Coccia EM, Weiden M, Canova A, Giacomini E, Pine R. Source: The Journal of Biological Chemistry. 2002 June 21; 277(25): 22377-85. Epub 2002 April 10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11948194

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Human CD8(+) T cells specific for Mycobacterium tuberculosis secreted antigens in tuberculosis patients and healthy BCG-vaccinated controls in The Gambia. Author(s): Smith SM, Klein MR, Malin AS, Sillah J, Huygen K, Andersen P, McAdam KP, Dockrell HM. Source: Infection and Immunity. 2000 December; 68(12): 7144-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11083843

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Human CD8+ T cells recognize epitopes of the 28-kDa hemolysin and the 38-kDa antigen of Mycobacterium tuberculosis. Author(s): Shams H, Barnes PF, Weis SE, Klucar P, Wizel B. Source: Journal of Leukocyte Biology. 2003 December; 74(6): 1008-14. Epub 2003 September 12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12972510

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Human dendritic cells presenting adenovirally expressed antigen elicit Mycobacterium tuberculosis--specific CD8+ T cells. Author(s): Lewinsohn DA, Lines RA, Lewinsohn DM. Source: American Journal of Respiratory and Critical Care Medicine. 2002 September 15; 166(6): 843-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12231495

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Human eosinophil peroxidase induces surface alteration, killing, and lysis of Mycobacterium tuberculosis. Author(s): Borelli V, Vita F, Shankar S, Soranzo MR, Banfi E, Scialino G, Brochetta C, Zabucchi G. Source: Infection and Immunity. 2003 February; 71(2): 605-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12540536

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Human exposure following Mycobacterium tuberculosis infection of multiple animal species in a Metropolitan Zoo. Author(s): Oh P, Granich R, Scott J, Sun B, Joseph M, Stringfield C, Thisdell S, Staley J, Workman-Malcolm D, Borenstein L, Lehnkering E, Ryan P, Soukup J, Nitta A, Flood J. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1290-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12453358

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Human immunodeficiency virus type 1 (HIV-1) quasispecies at the sites of Mycobacterium tuberculosis infection contribute to systemic HIV-1 heterogeneity. Author(s): Collins KR, Quinones-Mateu ME, Wu M, Luzze H, Johnson JL, Hirsch C, Toossi Z, Arts EJ. Source: Journal of Virology. 2002 February; 76(4): 1697-706. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11799165

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Human leucocyte antigen-A2 restricted and Mycobacterium tuberculosis 19-kDa antigen-specific CD8+ T-cell responses are oligoclonal and exhibit a T-cell cytotoxic type 2 response cytokine-secretion pattern. Author(s): Hohn H, Kortsik C, Nilges K, Necker A, Freitag K, Tully G, Neukirch C, Maeurer MJ. Source: Immunology. 2001 November; 104(3): 278-88. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11722642

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115

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Human macrophage gamma interferon decreases gene expression but not replication of Mycobacterium tuberculosis: analysis of the host-pathogen reciprocal influence on transcription in a comparison of strains H37Rv and CMT97. Author(s): Cappelli G, Volpe P, Sanduzzi A, Sacchi A, Colizzi V, Mariani F. Source: Infection and Immunity. 2001 December; 69(12): 7262-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11705896

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Human T-cell responses to the RD1-encoded protein TB27.4 (Rv3878) from Mycobacterium tuberculosis. Author(s): Agger EM, Brock I, Okkels LM, Arend SM, Aagaard CS, Weldingh KN, Andersen P. Source: Immunology. 2003 December; 110(4): 507-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14632649

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Human Th1 cell lines recognize the Mycobacterium tuberculosis ESAT-6 antigen and its peptides in association with frequently expressed HLA class II molecules. Author(s): Mustafa AS, Shaban FA, Al-Attiyah R, Abal AT, El-Shamy AM, Andersen P, Oftung F. Source: Scandinavian Journal of Immunology. 2003 February; 57(2): 125-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12588658

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Identification and characterization of a unique adenosine kinase from Mycobacterium tuberculosis. Author(s): Long MC, Escuyer V, Parker WB. Source: Journal of Bacteriology. 2003 November; 185(22): 6548-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14594827

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Identification of a Mycobacterium tuberculosis strain with stable, low-level resistance to isoniazid. Author(s): Madison BM, Siddiqi SH, Heifets L, Gross W, Higgins M, Warren N, Thompson A, Morlock G, Ridderhof JC. Source: Journal of Clinical Microbiology. 2004 March; 42(3): 1294-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15004099

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Identification of the new T-cell-stimulating antigens from Mycobacterium tuberculosis culture filtrate. Author(s): Lim JH, Kim HJ, Lee KS, Jo EK, Song CH, Jung SB, Kim SY, Lee JS, Paik TH, Park JK. Source: Fems Microbiology Letters. 2004 March 12; 232(1): 51-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15019734

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Immunization with a DNA vaccine cocktail protects mice lacking CD4 cells against an aerogenic infection with Mycobacterium tuberculosis. Author(s): Derrick SC, Repique C, Snoy P, Yang AL, Morris S. Source: Infection and Immunity. 2004 March; 72(3): 1685-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14977976

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Immunoglobulin A (IgA) and IgG immune responses against P-90 antigen for diagnosis of pulmonary tuberculosis and screening for Mycobacterium tuberculosis infection. Author(s): Conde MB, Suffys P, Lapa E Silva JR, Kritski AL, Dorman SE. Source: Clinical and Diagnostic Laboratory Immunology. 2004 January; 11(1): 94-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14715551

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Immunological crossreactivity of the Mycobacterium leprae CFP-10 with its homologue in Mycobacterium tuberculosis. Author(s): Geluk A, van Meijgaarden KE, Franken KL, Wieles B, Arend SM, Faber WR, Naafs B, Ottenhoff TH. Source: Scandinavian Journal of Immunology. 2004 January; 59(1): 66-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14723623

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Impact of drug-resistant Mycobacterium tuberculosis on treatment outcome of culture-positive cases of tuberculosis in the Archangel oblast, Russia, in 1999. Author(s): Toungoussova OS, Nizovtseva NI, Mariandyshev AO, Caugant DA, Sandven P, Bjune G. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2004 March; 23(3): 174-9. Epub 2004 January 20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14735405

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In situ study of abundant expression of proinflammatory chemokines and cytokines in pulmonary granulomas that develop in cynomolgus macaques experimentally infected with Mycobacterium tuberculosis. Author(s): Fuller CL, Flynn JL, Reinhart TA. Source: Infection and Immunity. 2003 December; 71(12): 7023-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14638792

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Increased sensitivity of Mycobacterium tuberculosis Cobas Amplicor PCR following brief incubation of tissue samples on Lowenstein-Jensen substrate. Author(s): Fernstrom MC, Dahlgren L, Ranby M, Forsgren A, Petrini B. Source: Apmis : Acta Pathologica, Microbiologica, Et Immunologica Scandinavica. 2003 December; 111(12): 1114-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14678020

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Individual Mycobacterium tuberculosis resuscitation-promoting factor homologues are dispensable for growth in vitro and in vivo. Author(s): Tufariello JM, Jacobs WR Jr, Chan J. Source: Infection and Immunity. 2004 January; 72(1): 515-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14688133

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Individual RD1-region genes are required for export of ESAT-6/CFP-10 and for virulence of Mycobacterium tuberculosis. Author(s): Guinn KM, Hickey MJ, Mathur SK, Zakel KL, Grotzke JE, Lewinsohn DM, Smith S, Sherman DR. Source: Molecular Microbiology. 2004 January; 51(2): 359-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14756778

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Induction of nitric oxide release from the human alveolar epithelial cell line A549: an in vitro correlate of innate immune response to Mycobacterium tuberculosis. Author(s): Roy S, Sharma S, Sharma M, Aggarwal R, Bose M. Source: Immunology. 2004 July; 112(3): 471-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15196216

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Inhibition of HIV-1 replication in monocyte-derived macrophages by Mycobacterium tuberculosis. Author(s): Goletti D, Carrara S, Vincenti D, Giacomini E, Fattorini L, Garbuglia AR, Capobianchi MR, Alonzi T, Fimia GM, Federico M, Poli G, Coccia E. Source: The Journal of Infectious Diseases. 2004 February 15; 189(4): 624-33. Epub 2004 Feb 04. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14767815

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Innate inhibition of adaptive immunity: Mycobacterium tuberculosis-induced IL-6 inhibits macrophage responses to IFN-gamma. Author(s): Nagabhushanam V, Solache A, Ting LM, Escaron CJ, Zhang JY, Ernst JD. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 November 1; 171(9): 4750-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14568951

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Interaction of a Mycobacterium tuberculosis repetitive DNA sequence with eukaryotic proteins. Author(s): Liu X, Tiwari RK, Geliebter J, Wu JM, Godfrey HP. Source: Biochemical and Biophysical Research Communications. 2004 July 30; 320(3): 966-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15240143

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Interferon-gamma and skin test responses of schoolchildren in southeast England to purified protein derivatives from Mycobacterium tuberculosis and other species of mycobacteria. Author(s): Weir RE, Fine PE, Nazareth B, Floyd S, Black GF, King E, Stanley C, Bliss L, Branson K, Dockrell HM. Source: Clinical and Experimental Immunology. 2003 November; 134(2): 285-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14616789

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Interleukin-12 therapy reduces the number of immune cells and pathology in lungs of mice infected with Mycobacterium tuberculosis. Author(s): Nolt D, Flynn JL. Source: Infection and Immunity. 2004 May; 72(5): 2976-88. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15102810

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Interpreting the results of the amplified Mycobacterium tuberculosis direct test for detection of M. tuberculosis rRNA. Author(s): Middleton AM, Cullinan P, Wilson R, Kerr JR, Chadwick MV. Source: Journal of Clinical Microbiology. 2003 June; 41(6): 2741-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12791919

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Intracellular expression of interleukin-4 and interferon-gamma by a Mycobacterium tuberculosis antigen-stimulated CD4+ CD57+ T-cell subpopulation with memory phenotype in tuberculosis patients. Author(s): Jimenez-Martinez MC, Linares M, Baez R, Montano LF, Martinez-Cairo S, Gorocica P, Chavez R, Zenteno E, Lascurain R. Source: Immunology. 2004 January; 111(1): 100-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14678204

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Investigation of Laboratory cross-contamination of Mycobacterium tuberculosis cultures. Author(s): Fitzpatrick L, Braden C, Cronin W, English J, Campbell E, Valway S, Onorato I. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2004 March 15; 38(6): E52-4. Epub 2004 February 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14999647

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Koch's bacillus - a look at the first isolate of Mycobacterium tuberculosis from a modern perspective. Author(s): Taylor GM, Stewart GR, Cooke M, Chaplin S, Ladva S, Kirkup J, Palmer S, Young DB. Source: Microbiology (Reading, England). 2003 November; 149(Pt 11): 3213-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14600233

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Laboratory cross-contamination of Mycobacterium tuberculosis: an investigation and analysis of causes and consequences. Author(s): Poynten M, Andresen DN, Gottlieb T. Source: Internal Medicine Journal. 2002 November; 32(11): 512-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12412933

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Laboratory methods for diagnosis and detection of drug resistant Mycobacterium tuberculosis complex with reference to developing countries: a review. Author(s): Githui WA. Source: East Afr Med J. 2002 May; 79(5): 242-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12638807

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Large-scale evaluation of enzyme-linked immunospot assay and skin test for diagnosis of Mycobacterium tuberculosis infection against a gradient of exposure in The Gambia. Author(s): Hill PC, Brookes RH, Fox A, Fielding K, Jeffries DJ, Jackson-Sillah D, Lugos MD, Owiafe PK, Donkor SA, Hammond AS, Otu JK, Corrah T, Adegbola RA, McAdam KP. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2004 April 1; 38(7): 966-73. Epub 2004 March 16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15034828

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Latent Mycobacterium tuberculosis-persistence, patience, and winning by waiting. Author(s): Manabe YC, Bishai WR. Source: Nature Medicine. 2000 December; 6(12): 1327-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11100115

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LCx Mycobacterium tuberculosis assay is valuable with respiratory specimens, but provides little help in the diagnosis of extrapulmonary tuberculosis. Author(s): Rantakokko-Jalava K, Marjamaki M, Marttila H, Makela L, Valtonen V, Viljanen MK. Source: Annals of Medicine. 2001 February; 33(1): 55-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11310940

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LCx: a diagnostic alternative for the early detection of Mycobacterium tuberculosis complex. Author(s): Ruiz-Serrano MJ, Albadalejo J, Martinez-Sanchez L, Bouza E. Source: Diagnostic Microbiology and Infectious Disease. 1998 December; 32(4): 259-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9934542

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Length of time to laboratory diagnosis of Mycobacterium tuberculosis infection: comparison of in-house methods with reference laboratory results. Author(s): Davies AP, Newport LE, Billington OJ, Gillespie SH. Source: The Journal of Infection. 1999 November; 39(3): 205-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10714796

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Life on the inside for Mycobacterium tuberculosis. Author(s): McKinney JD, Gomez JE. Source: Nature Medicine. 2003 November; 9(11): 1356-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14595429

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Life on the inside: probing Mycobacterium tuberculosis gene expression during infection. Author(s): Triccas JA, Gicquel B. Source: Immunology and Cell Biology. 2000 August; 78(4): 311-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10947854

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Limits of detection of Mycobacterium tuberculosis in spiked cerebrospinal fluid using the polymerase chain reaction in tuberculous meningitis. Author(s): Baran J Jr, Riederer KM, Khatib R. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2000 January; 19(1): 47-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10706180

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Line probe assay in the rapid detection of rifampin-resistant Mycobacterium tuberculosis directly from clinical specimens. Author(s): Marttila HJ, Soini H, Vyshnevskaya E, Vyshnevskiy BI, Otten TF, Vasilyef AV, Viljanen MK. Source: Scandinavian Journal of Infectious Diseases. 1999; 31(3): 269-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10482056

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Linkage disequilibrium between minisatellite loci supports clonal evolution of Mycobacterium tuberculosis in a high tuberculosis incidence area. Author(s): Supply P, Warren RM, Banuls AL, Lesjean S, Van Der Spuy GD, Lewis LA, Tibayrenc M, Van Helden PD, Locht C. Source: Molecular Microbiology. 2003 January; 47(2): 529-38. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12519202

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Lipid modification of the Cu,Zn superoxide dismutase from Mycobacterium tuberculosis. Author(s): D'orazio M, Folcarelli S, Mariani F, Colizzi V, Rotilio G, Battistoni A. Source: The Biochemical Journal. 2001 October 1; 359(Pt 1): 17-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11563965

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Lipoarabinomannan from Mycobacterium tuberculosis promotes macrophage survival by phosphorylating Bad through a phosphatidylinositol 3-kinase/Akt pathway. Author(s): Maiti D, Bhattacharyya A, Basu J. Source: The Journal of Biological Chemistry. 2001 January 5; 276(1): 329-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11020382

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Longitudinal analysis of Mycobacterium tuberculosis 19-kDa antigen-specific T cells in patients with pulmonary tuberculosis: association with disease activity and crossreactivity to a peptide from HIVenv gp120. Author(s): Hohn H, Kortsik C, Tully G, Nilges K, Necker A, Freitag K, Neukirch C, Galle P, Lohr H, Maeurer MJ. Source: European Journal of Immunology. 2003 June; 33(6): 1613-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12778479

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Loop-mediated isothermal amplification for direct detection of Mycobacterium tuberculosis complex, M. avium, and M. intracellulare in sputum samples. Author(s): Iwamoto T, Sonobe T, Hayashi K. Source: Journal of Clinical Microbiology. 2003 June; 41(6): 2616-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12791888

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Low prevalence and increased household clustering of Mycobacterium tuberculosis infection in high altitude villages in Peru. Author(s): Olender S, Saito M, Apgar J, Gillenwater K, Bautista CT, Lescano AG, Moro P, Caviedes L, Hsieh EJ, Gilman RH. Source: The American Journal of Tropical Medicine and Hygiene. 2003 June; 68(6): 721-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12887034

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Low-stringency single-specific-primer PCR as a tool for detection of mutations in the rpoB gene of rifampin-resistant Mycobacterium tuberculosis. Author(s): Carvalho WS, Spindola de Miranda S, Costa KM, Araujo JG, Augusto CJ, Pesquero JB, Pesquero JL, Gomes MA. Source: Journal of Clinical Microbiology. 2003 July; 41(7): 3384-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12843099

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Luciferase reporter mycobacteriophages for detection, identification, and antibiotic susceptibility testing of Mycobacterium tuberculosis in Mexico. Author(s): Banaiee N, Bobadilla-Del-Valle M, Bardarov S Jr, Riska PF, Small PM, PonceDe-Leon A, Jacobs WR Jr, Hatfull GF, Sifuentes-Osornio J. Source: Journal of Clinical Microbiology. 2001 November; 39(11): 3883-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11682502

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Lymph node infection by Trichomonas tenax: report of a case with co-infection by Mycobacterium tuberculosis. Author(s): Duboucher C, Farto-Bensasson F, Cheron M, Peltier JY, Beaufils F, Perie G. Source: Human Pathology. 2000 October; 31(10): 1317-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11070125

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Mapping immune reactivity toward Rv2653 and Rv2654: two novel low-molecularmass antigens found specifically in the Mycobacterium tuberculosis complex. Author(s): Aagaard C, Brock I, Olsen A, Ottenhoff TH, Weldingh K, Andersen P. Source: The Journal of Infectious Diseases. 2004 March 1; 189(5): 812-9. Epub 2004 February 13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14976597

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Molecular characterization of Mycobacterium tuberculosis isolates presenting various drug susceptibility from Greece using three DNA typing methods. Author(s): Vrioni G, Levidiotou S, Matsiota-Bernard P, Marinis E. Source: The Journal of Infection. 2004 April; 48(3): 253-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15001304

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Molecular epidemiology of Mycobacterium tuberculosis in western Sweden. Author(s): Brudey K, Gordon M, Mostrom P, Svensson L, Jonsson B, Sola C, Ridell M, Rastogi N. Source: Journal of Clinical Microbiology. 2004 July; 42(7): 3046-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15243058

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Molecular fingerprinting of multidrug-resistant Mycobacterium tuberculosis strains in Beirut reveals genetic diversity and father to daughter transmission. Author(s): Ahmad S, Itani LY, Araj GF. Source: J Med Liban. 2003 January-March; 51(1): 4-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15181954

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Multicenter evaluation of reverse line blot assay for detection of drug resistance in Mycobacterium tuberculosis clinical isolates. Author(s): Mokrousov I, Bhanu NV, Suffys PN, Kadival GV, Yap SF, Cho SN, Jordaan AM, Narvskaya O, Singh UB, Gomes HM, Lee H, Kulkarni SP, Lim KC, Khan BK, van Soolingen D, Victor TC, Schouls LM. Source: Journal of Microbiological Methods. 2004 June; 57(3): 323-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15134881

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Multicenter evaluation of the MB/BACT system for susceptibility testing of Mycobacterium tuberculosis. Author(s): Bemer P, Bodmer T, Munzinger J, Perrin M, Vincent V, Drugeon H. Source: Journal of Clinical Microbiology. 2004 March; 42(3): 1030-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15004049

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Multicentre quality control study for detection of Mycobacterium tuberculosis in clinical samples by nucleic amplification methods. Author(s): Noordhoek GT, Mulder S, Wallace P, van Loon AM. Source: Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 2004 April; 10(4): 295-301. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15059117

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Mutant prevention concentration: comparison of fluoroquinolones and linezolid with Mycobacterium tuberculosis. Author(s): Rodriguez JC, Cebrian L, Lopez M, Ruiz M, Jimenez I, Royo G. Source: The Journal of Antimicrobial Chemotherapy. 2004 March; 53(3): 441-4. Epub 2004 February 12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14963069

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Mycobacterium bovis versus Mycobacterium tuberculosis as a cause of acute cervical lymphadenitis without pulmonary disease. Author(s): Fennelly GJ. Source: The Pediatric Infectious Disease Journal. 2004 June; 23(6): 590-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15194851

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Mycobacterium celatum, an emerging pathogen and cause of false positive amplified Mycobacterium tuberculosis direct test. Author(s): Christiansen DC, Roberts GD, Patel R. Source: Diagnostic Microbiology and Infectious Disease. 2004 May; 49(1): 19-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15135495

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Mycobacterium tuberculosis and the cause of consumption: from discovery to fact. Author(s): Murray JF. Source: American Journal of Respiratory and Critical Care Medicine. 2004 May 15; 169(10): 1086-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15132958

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Mycobacterium tuberculosis complex drug resistance in Italy. Author(s): Migliori GB, Centis R, Fattorini L, Besozzi G, Saltini C, Scarparo C, Cirillo D, Gori A, Cassone A, Piersimoni C. Source: Emerging Infectious Diseases. 2004 April; 10(4): 752-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15211998

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Mycobacterium tuberculosis diverts alpha interferon-induced monocyte differentiation from dendritic cells into immunoprivileged macrophage-like host cells. Author(s): Mariotti S, Teloni R, Iona E, Fattorini L, Romagnoli G, Gagliardi MC, Orefici G, Nisini R. Source: Infection and Immunity. 2004 August; 72(8): 4385-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15271894

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Mycobacterium tuberculosis H37Rv: Delta RD1 is more virulent than M. bovis bacille Calmette-Guerin in long-term murine infection. Author(s): Sherman DR, Guinn KM, Hickey MJ, Mathur SK, Zakel KL, Smith S. Source: The Journal of Infectious Diseases. 2004 July 1; 190(1): 123-6. Epub 2004 June 11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15195251

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Mycobacterium tuberculosis isolate with a distinct genomic identity overexpresses a tap-like efflux pump. Author(s): Siddiqi N, Das R, Pathak N, Banerjee S, Ahmed N, Katoch VM, Hasnain SE. Source: Infection. 2004 April; 32(2): 109-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15057575

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Mycobacterium tuberculosis lipomannan induces apoptosis and interleukin-12 production in macrophages. Author(s): Dao DN, Kremer L, Guerardel Y, Molano A, Jacobs WR Jr, Porcelli SA, Briken V. Source: Infection and Immunity. 2004 April; 72(4): 2067-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15039328

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Mycobacterium tuberculosis resides in nonacidified vacuoles in endocytically competent alveolar macrophages from patients with tuberculosis and HIV infection. Author(s): Mwandumba HC, Russell DG, Nyirenda MH, Anderson J, White SA, Molyneux ME, Squire SB. Source: Journal of Immunology (Baltimore, Md. : 1950). 2004 April 1; 172(7): 4592-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15034077

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Mycobacterium tuberculosis/HIV-1 coinfection and disease: role of human leukocyte antigen variation. Author(s): Louie LG, Hartogensis WE, Jackman RP, Schultz KA, Zijenah LS, Yiu CH, Nguyen VD, Sohsman MY, Katzenstein DK, Mason PR. Source: The Journal of Infectious Diseases. 2004 March 15; 189(6): 1084-90. Epub 2004 February 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14999612

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Negative transcriptional regulation of the mce3 operon in Mycobacterium tuberculosis. Author(s): Santangelo MP, Goldstein J, Alito A, Gioffre A, Caimi K, Zabal O, Zumarraga M, Romano MI, Cataldi AA, Bigi F. Source: Microbiology (Reading, England). 2002 October; 148(Pt 10): 2997-3006. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12368433

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Nested polymerase chain reaction for Mycobacterium tuberculosis DNA detection in aqueous and vitreous of patients with uveitis. Author(s): Ortega-Larrocea G, Bobadilla-del-Valle M, Ponce-de-Leon A, SifuentesOsornio J. Source: Archives of Medical Research. 2003 March-April; 34(2): 116-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12700006

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Nested polymerase chain reaction in the diagnosis of negative Ziehl-Neelsen stained Mycobacterium tuberculosis fistula-in-ano: report of four cases. Author(s): Shan YS, Yan JJ, Sy ED, Jin YT, Lee JC. Source: Diseases of the Colon and Rectum. 2002 December; 45(12): 1685-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12473896

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New drug targets for Mycobacterium tuberculosis. Author(s): Chopra P, Meena LS, Singh Y. Source: The Indian Journal of Medical Research. 2003 January; 117: 1-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12866819

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Nicotinamide: an oral antimicrobial agent with activity against both Mycobacterium tuberculosis and human immunodeficiency virus. Author(s): Murray MF. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 February 15; 36(4): 453-60. Epub 2003 January 31. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12567303

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Nitric oxide scavenging and detoxification by the Mycobacterium tuberculosis haemoglobin, HbN in Escherichia coli. Author(s): Pathania R, Navani NK, Gardner AM, Gardner PR, Dikshit KL. Source: Molecular Microbiology. 2002 September; 45(5): 1303-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12207698

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No association between Helicobacter pylori and Mycobacterium tuberculosis infections among gastrointestinal clinic attendees in Lima, Peru. Author(s): Torres MA, Passaro DJ, Watanabe J, Parsonnet J, Small P, Miyagu J, Rodriquez C, Astete M, Gilman RH. Source: Epidemiology and Infection. 2003 February; 130(1): 87-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12613749

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Nosocomial outbreak of multidrug-resistant tuberculosis caused by a strain of Mycobacterium tuberculosis W-Beijing family in St. Petersburg, Russia. Author(s): Narvskaya O, Otten T, Limeschenko E, Sapozhnikova N, Graschenkova O, Steklova L, Nikonova A, Filipenko ML, Mokrousov I, Vyshnevskiy B. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2002 August; 21(8): 596602. Epub 2002 August 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12226690

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Nosocomial transmission of Mycobacterium tuberculosis found through screening for severe acute respiratory syndrome--Taipei, Taiwan, 2003. Author(s): Centers for Disease Control and Prevention (CDC). Source: Mmwr. Morbidity and Mortality Weekly Report. 2004 April 23; 53(15): 321-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15103296

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Novel mutations in ndh in isoniazid-resistant Mycobacterium tuberculosis isolates. Author(s): Lee AS, Teo AS, Wong SY. Source: Antimicrobial Agents and Chemotherapy. 2001 July; 45(7): 2157-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11408244

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Observational study of the use of infection control interventions for Mycobacterium tuberculosis in pediatric facilities. Author(s): Kellerman SE, Saiman L, San Gabriel P, Besser R, Jarvis WR. Source: The Pediatric Infectious Disease Journal. 2001 June; 20(6): 566-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11419496

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Occupational exposure to Mycobacterium tuberculosis. Legal issues in workers' compensation. Author(s): Evenson W. Source: Aaohn Journal : Official Journal of the American Association of Occupational Health Nurses. 1999 August; 47(8): 373-80; Quiz 381-2. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10703290

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Occupational transmission of Mycobacterium tuberculosis to health care workers in a university hospital in Lima, Peru. Author(s): Alonso-Echanove J, Granich RM, Laszlo A, Chu G, Borja N, Blas R, Olortegui A, Binkin NJ, Jarvis WR. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2001 September 1; 33(5): 589-96. Epub 2001 July 25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11477527

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Overexpression of heat-shock proteins reduces survival of Mycobacterium tuberculosis in the chronic phase of infection. Author(s): Stewart GR, Snewin VA, Walzl G, Hussell T, Tormay P, O'Gaora P, Goyal M, Betts J, Brown IN, Young DB. Source: Nature Medicine. 2001 June; 7(6): 732-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11385512

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Oxidative stress response genes in Mycobacterium tuberculosis: role of ahpC in resistance to peroxynitrite and stage-specific survival in macrophages. Author(s): Master SS, Springer B, Sander P, Boettger EC, Deretic V, Timmins GS. Source: Microbiology (Reading, England). 2002 October; 148(Pt 10): 3139-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12368447

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Oxygenated mycolic acids are necessary for virulence of Mycobacterium tuberculosis in mice. Author(s): Dubnau E, Chan J, Raynaud C, Mohan VP, Laneelle MA, Yu K, Quemard A, Smith I, Daffe M. Source: Molecular Microbiology. 2000 May; 36(3): 630-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10844652

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PCR Enhances acid-fast bacillus stain-based rapid detection of Mycobacterium tuberculosis. Author(s): Tang YW, Meng S, Li H, Stratton CW, Koyamatsu T, Zheng X. Source: Journal of Clinical Microbiology. 2004 April; 42(4): 1849-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15071068

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PCR-based methodology for detecting multidrug-resistant strains of Mycobacterium tuberculosis Beijing family circulating in Russia. Author(s): Mokrousov I, Otten T, Vyazovaya A, Limeschenko E, Filipenko ML, Sola C, Rastogi N, Steklova L, Vyshnevskiy B, Narvskaya O. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2003 June; 22(6): 342-8. Epub 2003 June 03. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12783278

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Phylogenetic reconstruction of Mycobacterium tuberculosis within four settings of the Caribbean region: tree comparative analyse and first appraisal on their phylogeography. Author(s): Duchene V, Ferdinand S, Filliol I, Guegan JF, Rastogi N, Sola C. Source: Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases. 2004 March; 4(1): 5-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15019584

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Polymerase chain reaction for Mycobacterium tuberculosis: impact on clinical management of refugees with pulmonary infiltrates. Author(s): Laifer G, Widmer AF, Frei R, Zimmerli W, Fluckiger U. Source: Chest. 2004 March; 125(3): 981-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15006957

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Polymerase chain reaction used for the detection of airborne Mycobacterium tuberculosis in health care settings. Author(s): Wan GH, Lu SC, Tsai YH. Source: American Journal of Infection Control. 2004 February; 32(1): 17-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14755230

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Possible role of Mycobacterium tuberculosis complex in Melkersson-Rosenthal syndrome demonstrated with Gen-Probe amplified Mycobacterium tuberculosis direct test. Author(s): Apaydin R, Bahadir S, Kakklikkaya N, Bilen N, Bayramgurler D. Source: The Australasian Journal of Dermatology. 2004 May; 45(2): 94-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15068454

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Posttranscriptional inhibition of gene expression by Mycobacterium tuberculosis offsets transcriptional synergism with IFN-gamma and posttranscriptional upregulation by IFN-gamma. Author(s): Qiao Y, Prabhakar S, Canova A, Hoshino Y, Weiden M, Pine R. Source: Journal of Immunology (Baltimore, Md. : 1950). 2004 March 1; 172(5): 2935-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14978096

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Practical strategies for performance optimization of the enhanced gen-probe amplified Mycobacterium tuberculosis direct test. Author(s): Sloutsky A, Han LL, Werner BG. Source: Journal of Clinical Microbiology. 2004 April; 42(4): 1547-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15071002

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Primary drug resistance and molecular epidemiology of Mycobacterium tuberculosis isolates from patients in a population with high tuberculosis incidence in Turkey. Author(s): Durmaz R, Ozerol IH, Durmaz B, Gunal S, Senoglu A, Evliyaoglu E. Source: Microbial Drug Resistance (Larchmont, N.Y.). 2003 Winter; 9(4): 361-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15000742

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Pulmonary delivery of chitosan-DNA nanoparticles enhances the immunogenicity of a DNA vaccine encoding HLA-A*0201-restricted T-cell epitopes of Mycobacterium tuberculosis. Author(s): Bivas-Benita M, van Meijgaarden KE, Franken KL, Junginger HE, Borchard G, Ottenhoff TH, Geluk A. Source: Vaccine. 2004 April 16; 22(13-14): 1609-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15068842

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Quality assessment of Mycobacterium tuberculosis genotyping in a large laboratory network. Author(s): Braden CR, Crawford JT, Schable BA. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1210-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12453344

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Quantitative bacillary response to treatment in Mycobacterium tuberculosis infected and M. africanum infected adults with pulmonary tuberculosis. Author(s): Joloba ML, Johnson JL, Namale A, Morrissey A, Assegghai AE, Rusch-Gerdes S, Mugerwa RD, Ellner JJ, Eisenach KD. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2001 June; 5(6): 57982. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11409588

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Rapid colorimetric method for testing susceptibility of Mycobacterium tuberculosis to isoniazid and rifampin in liquid cultures. Author(s): Syre H, Phyu S, Sandven P, Bjorvatn B, Grewal HM. Source: Journal of Clinical Microbiology. 2003 November; 41(11): 5173-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14605155

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Rapid serodiagnosis of active pulmonary Mycobacterium tuberculosis by analysis of results from multiple antigen-specific tests. Author(s): Okuda Y, Maekura R, Hirotani A, Kitada S, Yoshimura K, Hiraga T, Yamamoto Y, Itou M, Ogura T, Ogihara T. Source: Journal of Clinical Microbiology. 2004 March; 42(3): 1136-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15004065

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Relevance of commercial amplification methods for direct detection of Mycobacterium tuberculosis complex in clinical samples. Author(s): Piersimoni C, Scarparo C. Source: Journal of Clinical Microbiology. 2003 December; 41(12): 5355-65. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14662911

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Requirement of gene fadD33 for the growth of Mycobacterium tuberculosis in a hepatocyte cell line. Author(s): Rindi L, Bonanni D, Lari N, Garzelli C. Source: New Microbiol. 2004 April; 27(2): 125-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15164622

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Respiratory protection against Mycobacterium tuberculosis: quantitative fit test outcomes for five type N95 filtering-facepiece respirators. Author(s): Lee K, Slavcev A, Nicas M. Source: J Occup Environ Hyg. 2004 January; 1(1): 22-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15202153

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Risk factors for recent transmission of Mycobacterium tuberculosis. Author(s): Heldal E, Dahle UR, Sandven P, Caugant DA, Brattaas N, Waaler HT, Enarson DA, Tverdal A, Kongerud J. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2003 October; 22(4): 637-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14582917

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Risk of infection with Mycobacterium tuberculosis in Malawi: national tuberculin survey 1994. Author(s): Salaniponi FM, Kwanjana J, Veen J, Misljenovic O, Borgdorff MW. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2004 June; 8(6): 71823. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15182141

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Role of cellular activation and tumor necrosis factor-alpha in the early expression of Mycobacterium tuberculosis 85B mRNA in human alveolar macrophages. Author(s): Islam N, Kanost AR, Teixeira L, Johnson J, Hejal R, Aung H, Wilkinson RJ, Hirsch CS, Toossi Z. Source: The Journal of Infectious Diseases. 2004 July 15; 190(2): 341-51. Epub 2004 June 18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15216471

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Role of mitogen-activated protein kinase pathways in the production of tumor necrosis factor-alpha, interleukin-10, and monocyte chemotactic protein-1 by Mycobacterium tuberculosis H37Rv-infected human monocytes. Author(s): Song CH, Lee JS, Lee SH, Lim K, Kim HJ, Park JK, Paik TH, Jo EK. Source: Journal of Clinical Immunology. 2003 May; 23(3): 194-201. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12797541

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Rv1818c-encoded PE_PGRS protein of Mycobacterium tuberculosis is surface exposed and influences bacterial cell structure. Author(s): Delogu G, Pusceddu C, Bua A, Fadda G, Brennan MJ, Zanetti S. Source: Molecular Microbiology. 2004 May; 52(3): 725-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15101979

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Specific T-cell epitopes for immunoassay-based diagnosis of Mycobacterium tuberculosis infection. Author(s): Brock I, Weldingh K, Leyten EM, Arend SM, Ravn P, Andersen P. Source: Journal of Clinical Microbiology. 2004 June; 42(6): 2379-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15184408

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Stability of DNA patterns and evidence of Mycobacterium tuberculosis reactivation occurring decades after the initial infection. Author(s): Lillebaek T, Dirksen A, Vynnycky E, Baess I, Thomsen VO, Andersen AB. Source: The Journal of Infectious Diseases. 2003 October 1; 188(7): 1032-9. Epub 2003 September 11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14513424

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Stability of polymorphic GC-rich repeat sequence-containing regions of Mycobacterium tuberculosis. Author(s): Richardson M, van der Spuy GD, Sampson SL, Beyers N, van Helden PD, Warren RM. Source: Journal of Clinical Microbiology. 2004 March; 42(3): 1302-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15004103

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Stable association between strains of Mycobacterium tuberculosis and their human host populations. Author(s): Hirsh AE, Tsolaki AG, DeRiemer K, Feldman MW, Small PM. Source: Proceedings of the National Academy of Sciences of the United States of America. 2004 April 6; 101(14): 4871-6. Epub 2004 March 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15041743

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Standardisation and evaluation of DNA-lanthanide fluorescence spectroscopy for determining rifampicin resistance in Mycobacterium tuberculosis clinical isolates. Author(s): Mani C, Selvakumar N, Gajendiran N, Panigrahi B, Venkatesan P, Narayanan PR. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 September; 7(9): 873-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12971672

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Surveillance of Mycobacterium tuberculosis susceptibility to second-line drugs in Hong Kong, 1995-2002, after the implementation of DOTS-plus. Author(s): Kam KM, Yip CW. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2004 June; 8(6): 760-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15182147

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Survival perspectives from the world's most successful pathogen, Mycobacterium tuberculosis. Author(s): Hingley-Wilson SM, Sambandamurthy VK, Jacobs WR Jr. Source: Nature Immunology. 2003 October; 4(10): 949-55. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14515128

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Susceptibility of Mycobacterium tuberculosis to isoniazid and its derivative, 1isonicotinyl-2-nonanoyl hydrazine: investigation at cellular level. Author(s): Mohamad S, Ibrahim P, Sadikun A. Source: Tuberculosis (Edinburgh, Scotland). 2004; 84(1-2): 56-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14670346

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Suspected small-scale interpersonal transmission of Mycobacterium tuberculosis in wards of an urban hospital in Delhi, India. Author(s): Bhanu NV, Banavalikar JN, Kapoor SK, Seth P. Source: The American Journal of Tropical Medicine and Hygiene. 2004 May; 70(5): 52731. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15155985

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SWR mice are highly susceptible to pulmonary infection with Mycobacterium tuberculosis. Author(s): Turner OC, Keefe RG, Sugawara I, Yamada H, Orme IM. Source: Infection and Immunity. 2003 September; 71(9): 5266-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12933873

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Temperature-mediated heteroduplex analysis for detection of pncA mutations associated with pyrazinamide resistance and differentiation between Mycobacterium tuberculosis and Mycobacterium bovis by denaturing high- performance liquid chromatography. Author(s): Mohamed AM, Bastola DR, Morlock GP, Cooksey RC, Hinrichs SH. Source: Journal of Clinical Microbiology. 2004 March; 42(3): 1016-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15004047

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The human immune response to Mycobacterium tuberculosis in lung and lymph node. Author(s): Marino S, Kirschner DE. Source: Journal of Theoretical Biology. 2004 April 21; 227(4): 463-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15038983

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The hydrophobic domain of the Mycobacterial Erp protein is not essential for the virulence of Mycobacterium tuberculosis. Author(s): Kocincova D, Sonden B, Bordat Y, Pivert E, de Mendonca-Lima L, Gicquel B, Reyrat JM. Source: Infection and Immunity. 2004 April; 72(4): 2379-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15039363

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The MspA porin promotes growth and increases antibiotic susceptibility of both Mycobacterium bovis BCG and Mycobacterium tuberculosis. Author(s): Mailaender C, Reiling N, Engelhardt H, Bossmann S, Ehlers S, Niederweis M. Source: Microbiology (Reading, England). 2004 April; 150(Pt 4): 853-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15073295

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The nature of extracellular iron influences iron acquisition by Mycobacterium tuberculosis residing within human macrophages. Author(s): Olakanmi O, Schlesinger LS, Ahmed A, Britigan BE. Source: Infection and Immunity. 2004 April; 72(4): 2022-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15039322

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The principal sigma factor sigA mediates enhanced growth of Mycobacterium tuberculosis in vivo. Author(s): Wu S, Howard ST, Lakey DL, Kipnis A, Samten B, Safi H, Gruppo V, Wizel B, Shams H, Basaraba RJ, Orme IM, Barnes PF. Source: Molecular Microbiology. 2004 March; 51(6): 1551-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15009884

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The production of tumour necrosis factor-alpha is decreased in peripheral blood mononuclear cells from multidrug-resistant tuberculosis patients following stimulation with the 30-kDa antigen of Mycobacterium tuberculosis. Author(s): Lee JS, Song CH, Lim JH, Kim HJ, Park JK, Paik TH, Kim CH, Kong SJ, Shon MH, Jung SS, Jo EK. Source: Clinical and Experimental Immunology. 2003 June; 132(3): 443-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12780691

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The vitro efficacy of beta-lactam and beta-lactamase inhibitors against multidrug resistant clinical strains of Mycobacterium tuberculosis. Author(s): Dincer I, Ergin A, Kocagoz T. Source: International Journal of Antimicrobial Agents. 2004 April; 23(4): 408-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15081094

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Tumour-like ear lesion due to Mycobacterium tuberculosis diagnosed by polymerase chain reaction-reverse hybridization. Author(s): Garcovich A, Romano L, Zampetti A, Garcovich S, Ardito F, Posteraro B, Sanguinetti M, Fadda G. Source: The British Journal of Dermatology. 2004 February; 150(2): 370-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14996117

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Typing of drug resistant isolates of Mycobacterium tuberculosis from India using the IS6110 element reveals substantive polymorphism. Author(s): Siddiqi N, Shamim M, Amin A, Chauhan DS, Das R, Srivastava K, Singh D, Sharma VD, Katoch VM, Sharma SK, Hanief M, Hasnain SE. Source: Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases. 2001 December; 1(2): 109-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12798025

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Use of a high-density DNA probe array for detecting mutations involved in rifampicin resistance in Mycobacterium tuberculosis. Author(s): Sougakoff W, Rodrigue M, Truffot-Pernot C, Renard M, Durin N, Szpytma M, Vachon R, Troesch A, Jarlier V. Source: Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 2004 April; 10(4): 289-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15059116

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Use of DNA extracts from Ziehl-Neelsen-stained slides for molecular detection of rifampin resistance and spoligotyping of Mycobacterium tuberculosis. Author(s): Van Der Zanden AG, Te Koppele-Vije EM, Vijaya Bhanu N, Van Soolingen D, Schouls LM. Source: Journal of Clinical Microbiology. 2003 March; 41(3): 1101-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12624036

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Use of equivocal zone in interpretation of results of the amplified Mycobacterium tuberculosis direct test for diagnosis of tuberculosis. Author(s): Kerleguer A, Koeck JL, Fabre M, Gerome P, Teyssou R, Herve V. Source: Journal of Clinical Microbiology. 2003 April; 41(4): 1783-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12682187

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Use of genetic distance as a measure of ongoing transmission of Mycobacterium tuberculosis. Author(s): van der Spuy GD, Warren RM, Richardson M, Beyers N, Behr MA, van Helden PD. Source: Journal of Clinical Microbiology. 2003 December; 41(12): 5640-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14662954

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Use of MGIT 960 for rapid quantitative measurement of the susceptibility of Mycobacterium tuberculosis complex to ciprofloxacin and ethionamide. Author(s): Huang TS, Lee SS, Tu HZ, Huang WK, Chen YS, Huang CK, Wann SR, Lin HH, Liu YC. Source: The Journal of Antimicrobial Chemotherapy. 2004 April; 53(4): 600-3. Epub 2004 February 18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14973155

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Use of molecular methods to identify the Mycobacterium tuberculosis complex (MTBC) and other mycobacterial species and to detect rifampin resistance in MTBC isolates following growth detection with the BACTEC MGIT 960 system. Author(s): Somoskovi A, Song Q, Mester J, Tanner C, Hale YM, Parsons LM, Salfinger M. Source: Journal of Clinical Microbiology. 2003 July; 41(7): 2822-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12843007

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Use of receiver operating characteristic curves to assess the performance of a microdilution assay for determination of drug susceptibility of clinical isolates of Mycobacterium tuberculosis. Author(s): Luna-Herrera J, Martinez-Cabrera G, Parra-Maldonado R, Enciso-Moreno JA, Torres-Lopez J, Quesada-Pascual F, Delgadillo-Polanco R, Franzblau SG. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2003 January; 22(1): 21-7. Epub 2003 January 25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12582740

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Use of the hupB gene encoding a histone-like protein of Mycobacterium tuberculosis as a target for detection and differentiation of M. tuberculosis and M. bovis. Author(s): Prabhakar S, Mishra A, Singhal A, Katoch VM, Thakral SS, Tyagi JS, Prasad HK. Source: Journal of Clinical Microbiology. 2004 June; 42(6): 2724-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15184459

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Utility of an in-house mycobacteriophage-based assay for rapid detection of rifampin resistance in Mycobacterium tuberculosis clinical isolates. Author(s): Gali N, Dominguez J, Blanco S, Prat C, Quesada MD, Matas L, Ausina V. Source: Journal of Clinical Microbiology. 2003 June; 41(6): 2647-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12791894

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Utility of polymerase chain reaction for detecting Mycobacterium tuberculosis in specimens from percutaneous transthoracic needle aspiration. Author(s): Kang EY, Choi JA, Seo BK, Oh YW, Lee CK, Shim JJ. Source: Radiology. 2002 October; 225(1): 205-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12355006

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Value of Mycobacterium tuberculosis fingerprinting as a tool in a rural state surveillance program. Author(s): Dobbs KG, Lok KH, Bruce F, Mulcahy D, Benjamin WH, Dunlap NE. Source: Chest. 2001 December; 120(6): 1877-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11742916

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Valvular endocarditis due to Mycobacterium tuberculosis. Author(s): Klingler K, Brandli O, Doerfler M, Schluger N, Rom WN. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 1998 May; 2(5): 435-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9613642

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Variable human minisatellite-like regions in the Mycobacterium tuberculosis genome. Author(s): Supply P, Mazars E, Lesjean S, Vincent V, Gicquel B, Locht C. Source: Molecular Microbiology. 2000 May; 36(3): 762-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10844663

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Variable-number tandem repeat typing of Mycobacterium tuberculosis isolates with low copy numbers of IS6110 by using mycobacterial interspersed repetitive units. Author(s): Cowan LS, Mosher L, Diem L, Massey JP, Crawford JT. Source: Journal of Clinical Microbiology. 2002 May; 40(5): 1592-602. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11980927

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Variations in the occurrence of the S315T mutation within the katG gene in isoniazidresistant clinical Mycobacterium tuberculosis isolates from Kuwait. Author(s): Abal AT, Ahmad S, Mokaddas E. Source: Microbial Drug Resistance (Larchmont, N.Y.). 2002 Summer; 8(2): 99-105. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12118524

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Vertical transmission of Mycobacterium tuberculosis in KwaZulu Natal: impact of HIV-1 co-infection. Author(s): Pillay T, Sturm AW, Khan M, Adhikari M, Moodley J, Connolly C, Moodley D, Padayatchi N, Ramjee A, Coovadia HM, Sullivan JL. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2004 January; 8(1): 59-69. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14974747

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Vgamma9/Vdelta2 T lymphocytes reduce the viability of intracellular Mycobacterium tuberculosis. Author(s): Dieli F, Troye-Blomberg M, Ivanyi J, Fournie JJ, Bonneville M, Peyrat MA, Sireci G, Salerno A. Source: European Journal of Immunology. 2000 May; 30(5): 1512-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10820400

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Virulence of Mycobacterium tuberculosis affects interleukin-8, monocyte chemoattractant protein-1 and interleukin-10 production by human mononuclear phagocytes. Author(s): Fietta A, Meloni F, Francioli C, Morosini M, Bulgheroni A, Casali L, Gialdroni Grassi G. Source: Int J Tissue React. 2001; 23(4): 113-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11771775

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Virulent Mycobacterium tuberculosis strains evade apoptosis of infected alveolar macrophages. Author(s): Keane J, Remold HG, Kornfeld H. Source: Journal of Immunology (Baltimore, Md. : 1950). 2000 February 15; 164(4): 201620. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10657653

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What we can learn from the Mycobacterium tuberculosis genome sequencing projects. Author(s): Manabe YC, Dannenberg AM Jr, Bishai WR. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2000 February; 4(2 Suppl 1): S18-23. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10688144

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Whole blood assay to access T cell-immune responses to Mycobacterium tuberculosis antigens in healthy Brazilian individuals. Author(s): Antas PR, Cardoso FL, Oliveira EB, Gomes PK, Cunha KS, Sarno EN, Sampaio EP. Source: Memorias Do Instituto Oswaldo Cruz. 2004 February; 99(1): 53-5. Epub 2004 March 31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15057347

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Whole-genome comparison of Mycobacterium tuberculosis clinical and laboratory strains. Author(s): Fleischmann RD, Alland D, Eisen JA, Carpenter L, White O, Peterson J, DeBoy R, Dodson R, Gwinn M, Haft D, Hickey E, Kolonay JF, Nelson WC, Umayam LA, Ermolaeva M, Salzberg SL, Delcher A, Utterback T, Weidman J, Khouri H, Gill J, Mikula A, Bishai W, Jacobs Jr WR Jr, Venter JC, Fraser CM. Source: Journal of Bacteriology. 2002 October; 184(19): 5479-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12218036

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Widespread bronchogenic dissemination makes DBA/2 mice more susceptible than C57BL/6 mice to experimental aerosol infection with Mycobacterium tuberculosis. Author(s): Cardona PJ, Gordillo S, Diaz J, Tapia G, Amat I, Pallares A, Vilaplana C, Ariza A, Ausina V. Source: Infection and Immunity. 2003 October; 71(10): 5845-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14500506

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Widespread occurrence of Mycobacterium tuberculosis DNA from 18th-19th century Hungarians. Author(s): Fletcher HA, Donoghue HD, Holton J, Pap I, Spigelman M. Source: American Journal of Physical Anthropology. 2003 February; 120(2): 144-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12541332

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Widespread pyrazinamide-resistant Mycobacterium tuberculosis family in a lowincidence setting. Author(s): Nguyen D, Brassard P, Westley J, Thibert L, Proulx M, Henry K, Schwartzman K, Menzies D, Behr MA. Source: Journal of Clinical Microbiology. 2003 July; 41(7): 2878-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12843016

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Worldwide occurrence of Beijing/W strains of Mycobacterium tuberculosis: a systematic review. Author(s): Glynn JR, Whiteley J, Bifani PJ, Kremer K, van Soolingen D. Source: Emerging Infectious Diseases. 2002 August; 8(8): 843-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12141971

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CHAPTER 2. NUTRITION AND MYCOBACTERIUM TUBERCULOSIS Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and Mycobacterium tuberculosis.

Finding Nutrition Studies on Mycobacterium Tuberculosis The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail: [email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “Mycobacterium tuberculosis” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

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Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.

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The following information is typical of that found when using the “Full IBIDS Database” to search for “Mycobacterium tuberculosis” (or a synonym): •

Antifungal, antibacterial, antiviral and cytotoxic activity of novel thio- and selenoazoles. Author(s): Cattedra di Microbiologia Applicata, Istituto di Medicina Interna, Universita degli studi di Cagliari, 09124 Cagliari (Italy) Source: Deidda, D. Lampis, G. Maullu, C. Pompei, R. Isaia, F. Lippolis, V. Verani, G. Pharmacological-Research (United Kingdom). (1997). volume 36(3) page 193-197.

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MICs [Minimum inhibitory concentration] of betel oil against common clinical pathogens. Author(s): United Lab. Inc., Mandaluyong City (Philippines). Medical Affairs Source: Ontengco, D.C. Talaue, M. Cruz, L.J. Capal, T.V. Dayap, L.A. Acta-Manilana (Philippines). (1999). volume 47 page 61-66. Issued May 2000.

Additional physician-oriented references include: •

A comparative study on the activation of J-774 macrophage-like cells by gammainterferon, 1,25-dihydroxyvitamin D3 and lipopeptide RP-56142: ability to kill intracellularly multiplying Mycobacterium tuberculosis and Mycobacterium avium. Author(s): Unite de la Tuberculose et des Mycobacteries, Institut Pasteur, Paris, France. Source: Rastogi, N Blom Potar, M C Zentralbl-Bakteriol. 1990 August; 273(3): 344-61 0934-8840

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A parallel intraphagosomal survival strategy shared by Mycobacterium tuberculosis and Salmonella enterica. Author(s): Department of Pathology, University of California, San Diego, La Jolla, CA 92093-0640, USA. [email protected] Source: Buchmeier, N Blanc Potard, A Ehrt, S Piddington, D Riley, L Groisman, E A Mol-Microbiol. 2000 March; 35(6): 1375-82 0950-382X

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Activity against Mycobacterium tuberculosis of alkaloid constituents of Angostura bark, Galipea officinalis. Author(s): Department of Pharmacy, King's College London, U.K. [email protected] Source: Houghton, P J Woldemariam, T Z Watanabe, Y Yates, M Planta-Med. 1999 April; 65(3): 250-4 0032-0943

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ahpC, a gene involved in isoniazid resistance of the Mycobacterium tuberculosis complex. Source: Wilson, T.M. Collins, D.M. Mol-microbiol. Oxford : Blackwell Scientific Publications,. March 1996. volume 19 (5) page 1025-1034. 0950-382X

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Antimicrobial susceptibility testing of Mycobacterium tuberculosis to first-line drugs: comparisons of the MGIT 960 and BACTEC 460 systems. Author(s): Section of Microbiology and Infectious Diseases, Kaohsiung Veterans General Hospital, Taiwan, Republic of China. [email protected] Source: Huang, T S Tu, H Z Lee, S S Huang, W K Liu, Y C Ann-Clin-Lab-Sci. 2002 Spring; 32(2): 142-7 0091-7370

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Arylamine N-acetyltransferase of Mycobacterium tuberculosis is a polymorphic enzyme and a site of isoniazid metabolism. Author(s): Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK. [email protected]

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Source: Upton, A M Mushtaq, A Victor, T C Sampson, S L Sandy, J Smith, D M van Helden, P V Sim, E Mol-Microbiol. 2001 October; 42(2): 309-17 0950-382X •

Crystal structure of Rv2118c: an AdoMet-dependent methyltransferase from Mycobacterium tuberculosis H37Rv. Author(s): Molecular and Structural Biology Division, Central Drug Research Institute, Chattar Manzil Palace, Mahatma Gandhi Marg, Lucknow 226001, India. Source: Gupta, A KuMarch, P H Dineshkumar, T K Varshney, U Subramanya, H S JMol-Biol. 2001 Sep14; 312(2): 381-91 0022-2836

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Drug resistance of Mycobacterium tuberculosis strains isolated from patients with pulmonary tuberculosis in Archangels, Russia. Author(s): Department of International Health, the Faculty of Medicine, University of Oslo, Blindern, Norway. [email protected] Source: Toungoussova, S Caugant, D A Sandven, P Mariandyshev, A O Bjune, G Int-JTuberc-Lung-Dis. 2002 May; 6(5): 406-14 1027-3719

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Drug resistance of strains of Mycobacterium tuberculosis isolated in Brazil. Author(s): Departamento de Patologia, Universidade Federal do (FURG), Rio Grande, Brazil. [email protected] Source: Almeida da Silva, P E Osorio, M Reinhardt, M C de Souza Fonseca, L Dellagostin, O A Microbes-Infect. 2001 November; 3(13): 1111-3 1286-4579

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Identification of iron-regulated proteins of Mycobacterium tuberculosis and cloning of tandem genes encoding a low iron-induced protein and a metal transporting ATPase with similarities to two-component metal transport systems. Author(s): Department of Medicine, School of Medicine, University of California, Los Angeles, California, 90095, USA. Source: Calder, K M Horwitz, M A Microb-Pathog. 1998 March; 24(3): 133-43 0882-4010

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Infection of the macrophage cell line NR8383 with Mycobacterium tuberculosis (H37Ra) leads to an increase in oligodeoxynucleotide accumulation. Author(s): Department of Pharmaceutics, University of Florida, Gainesville 32610, USA. Source: Rosenblatt, M N Burns, J R Duncan, V E Hughes, J A Antisense-Nucleic-AcidDrug-Devolume 2000 February; 10(1): 1-9 1087-2906

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Iron and Mycobacterium tuberculosis infection. Author(s): Laboratoire de Bacteriologie, Faculte de Medecine Pitie-Salpetriere, Paris, France. Source: Lounis, N Truffot Pernot, C Grosset, J Gordeuk, V R Boelaert, J R J-Clin-Virol. 2001 February; 20(3): 123-6 1386-6532

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Ovalbumin (OVA) and Mycobacterium tuberculosis bacilli cooperatively polarize anti-OVA T-helper (Th) cells toward a Th1-dominant phenotype and ameliorate murine tracheal eosinophilia. Author(s): First Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan. [email protected] Source: Sano, K Haneda, K Tamura, G Shirato, K Am-J-Respir-Cell-Mol-Biol. 1999 June; 20(6): 1260-7 1044-1549

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Quality assurance programme for drug susceptibility testing of Mycobacterium tuberculosis in the WHO/IUATLD Supranational Reference Laboratory Network: five rounds of proficiency testing, 1994-1998. Author(s): Laboratory Centre for Disease Control, Health Canada, Ottawa. [email protected] Source: Laszlo, A Rahman, M Espinal, M Raviglione, M Int-J-Tuberc-Lung-Dis. 2002 September; 6(9): 748-56 1027-3719

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Rapid cultivation of Mycobacterium tuberculosis in liquid medium. Author(s): Voluntary Health Services, Adyar, Chennai. Source: Sarma, L V Indian-J-Med-Sci. 1998 August; 52(8): 352-6 0019-5359

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Reactivity studies of the tyrosyl radical in ribonucleotide reductase from Mycobacterium tuberculosis and Arabidopsis thaliana--comparison with Escherichia coli and mouse. Author(s): Laboratoire de Chimie et Biochimie des Centres Redox Biologiques, DBMSCEA/CNRS/Universite Joseph Fourier, Grenoble, France. Source: Elleingand, E Gerez, C Un, S Knupling, M Lu, G Salem, J Rubin, H Sauge Merle, S Laulhere, J P Fontecave, M Eur-J-Biochem. 1998 December 1; 258(2): 485-90 0014-2956

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Recombinant Mycobacterium tuberculosis protein associated with mammalian cell entry. Author(s): Department of Medicine, Weill Medical College of Cornell University New York, NY, USA. Source: Chitale, S Ehrt, S Kawamura, I Fujimura, T Shimono, N Anand, N Lu, S Cohen Gould, L Riley, L W Cell-Microbiol. 2001 April; 3(4): 247-54 1462-5814

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Regulation of IL-10 secretion after phagocytosis of Mycobacterium tuberculosis by human monocytic cells. Author(s): Department of Infectious Diseases, Imperial College of Science, Technology and Medicine, London, UK. Source: Shaw, T C Thomas, L H Friedland, J S Cytokine. 2000 May; 12(5): 483-6 10434666

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Rifampin and isoniazid resistance associated mutations in Mycobacterium tuberculosis clinical isolates in Seville, Spain. Author(s): Department of Microbiology, University of Seville School of Medicine, Spain. [email protected] Source: Torres, M J Criado, A Gonzalez, N Palomares, J C Aznar, J Int-J-Tuberc-LungDis. 2002 February; 6(2): 160-3 1027-3719

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Surveillance of Mycobacterium tuberculosis drug resistance in Hong Kong, 1986-1999, after the implementation of directly observed treatment. Author(s): Tuberculosis Reference Laboratory, Yung Fung Shee Memorial Center, Department of Health, Kwun Tong, Kowloon, Hong Kong. [email protected] Source: Kam, K M Yip, C W Int-J-Tuberc-Lung-Dis. 2001 September; 5(9): 815-23 10273719

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Trace elements incorporated into the culture medium of Mycobacterium tuberculosis promote the presence of tuberculoprotein C in the preparation of purified protein derivatives. Author(s): Department of Microbiology, George Washington University School of Medicine and Health Sciences, Washington, D.C. 20037. Source: Affronti, L F Porrello, V Gupta, S Microbios. 1990; 63(255): 101-7 0026-2633

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Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •

healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0

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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov

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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov

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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/

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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/

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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/

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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/

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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/

Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats

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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html

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Google: http://directory.google.com/Top/Health/Nutrition/

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Healthnotes: http://www.healthnotes.com/

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Open Directory Project: http://dmoz.org/Health/Nutrition/

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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/

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WebMDHealth: http://my.webmd.com/nutrition

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

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CHAPTER 3. ALTERNATIVE MEDICINE AND MYCOBACTERIUM TUBERCULOSIS Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to Mycobacterium tuberculosis. At the conclusion of this chapter, we will provide additional sources.

National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to Mycobacterium tuberculosis and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “Mycobacterium tuberculosis” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to Mycobacterium tuberculosis: •

(+)-Totarol from Chamaecyparis nootkatensis and activity against Mycobacterium tuberculosis. Author(s): Constantine GH, Karchesy JJ, Franzblau SG, LaFleur LE. Source: Fitoterapia. 2001 June; 72(5): 572-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11429259

•

Activation of human neutrophils by Mycobacterium tuberculosis H37Ra involves phospholipase C gamma 2, Shc adapter protein, and p38 mitogen-activated protein kinase. Author(s): Perskvist N, Zheng L, Stendahl O. Source: Journal of Immunology (Baltimore, Md. : 1950). 2000 January 15; 164(2): 959-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10623845

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Activation of phospholipase D is tightly coupled to the phagocytosis of Mycobacterium tuberculosis or opsonized zymosan by human macrophages. Author(s): Kusner DJ, Hall CF, Schlesinger LS. Source: The Journal of Experimental Medicine. 1996 August 1; 184(2): 585-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8760812

•

Activity against multidrug-resistant Mycobacterium tuberculosis in Mexican plants used to treat respiratory diseases. Author(s): Jimenez-Arellanes A, Meckes M, Ramirez R, Torres J, Luna-Herrera J. Source: Phytotherapy Research : Ptr. 2003 September; 17(8): 903-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13680821

•

Activity against Mycobacterium tuberculosis of alkaloid constituents of Angostura bark, Galipea officinalis. Author(s): Houghton PJ, Woldemariam TZ, Watanabe Y, Yates M. Source: Planta Medica. 1999 April; 65(3): 250-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10232071

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Activity of bromhexine and ambroxol, semi-synthetic derivatives of vasicine from the Indian shrub Adhatoda vasica, against Mycobacterium tuberculosis in vitro. Author(s): Grange JM, Snell NJ. Source: Journal of Ethnopharmacology. 1996 January; 50(1): 49-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8778507

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Differential regulation of MMP-1/9 and TIMP-1 secretion in human monocytic cells in response to Mycobacterium tuberculosis. Author(s): Friedland JS, Shaw TC, Price NM, Dayer JM. Source: Matrix Biology : Journal of the International Society for Matrix Biology. 2002 January; 21(1): 103-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11827797

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Diminished adherence and/or ingestion of virulent Mycobacterium tuberculosis by monocyte-derived macrophages from patients with tuberculosis. Author(s): Zabaleta J, Arias M, Maya JR, Garcia LF. Source: Clinical and Diagnostic Laboratory Immunology. 1998 September; 5(5): 690-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9729537

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Direct ex vivo analysis of antigen-specific IFN-gamma-secreting CD4 T cells in Mycobacterium tuberculosis-infected individuals: associations with clinical disease state and effect of treatment. Author(s): Pathan AA, Wilkinson KA, Klenerman P, McShane H, Davidson RN, Pasvol G, Hill AV, Lalvani A.

Alternative Medicine 147

Source: Journal of Immunology (Baltimore, Md. : 1950). 2001 November 1; 167(9): 521725. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11673535 •

Effect of decalcifying agents on the staining of Mycobacterium tuberculosis. Author(s): Anderson G, Coup AJ. Source: Journal of Clinical Pathology. 1975 September; 28(9): 744-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=51859

•

Effect of mitochondrial stabilizers on the immunogenicity of the particulate fraction isolated from Mycobacterium tuberculosis. Author(s): YOUMANS AS, YOUMANS GP. Source: Journal of Bacteriology. 1964 June; 87: 1346-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14188712

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Effect of oxygen tension on the aldolases of Mycobacterium tuberculosis H37Rv. Author(s): Bai NJ, Pai MR, Murthy PS, Venkitasubramanian TA. Source: Febs Letters. 1974 September 1; 45(1): 68-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4213059

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Effect of trypsin and ribonuclease on the immunogenic activity of ribosomes and ribonucleic acid isolated from Mycobacterium tuberculosis. Author(s): Youmans AS, Youmans GP. Source: Journal of Bacteriology. 1966 June; 91(6): 2146-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4957610

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Effects of panax ginseng extracts on the growth of Mycobacterium tuberculosis H37Rv. Author(s): Chang MW, Tasaka H, Kuwabara M, Watanabe T, Matsuo Y. Source: Hiroshima J Med Sci. 1979 June; 28(2): 115-8. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=113372

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Fatty acid nature and adjuvant activity of wax D from Mycobacterium tuberculosis. Author(s): Hiu IJ, Amiel JL. Source: J Gen Microbiol. 1971 May; 66(2): 239-41. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4999074

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First-line tuberculosis therapy and drug-resistant Mycobacterium tuberculosis in prisons. Author(s): Coninx R, Mathieu C, Debacker M, Mirzoev F, Ismaelov A, de Haller R, Meddings DR.

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Source: Lancet. 1999 March 20; 353(9157): 969-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10459906 •

Formation of spheroplasts of Mycobacterium tuberculosis by lysozyme. Author(s): THACORE H, WILLETT HP. Source: Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N. Y.). 1963 October; 114: 43-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14076908

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Hydrogen peroxide and superoxide release by alveolar macrophages from normal and BCG-vaccinated guinea-pigs after intravenous challenge with Mycobacterium tuberculosis. Author(s): Jackett PS, Andrew PW, Aber VR, Lowrie DB. Source: Br J Exp Pathol. 1981 August; 62(4): 419-28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6271160

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Identification of acidic, alkaline, and neutral sphingomyelinase activities in Mycobacterium tuberculosis. Author(s): Vargas-Villarreal J, Mata-Cardenas BD, Deslauriers M, Quinn FD, CastroGarza J, Martinez-Rodrlguez HG, Said-Fernandez S. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2003 June; 9(6): Br225-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12824945

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Identification of Mycobacterium tuberculosis and Mycobacterium avium-M. intracellulare directly from primary BACTEC cultures by using acridinium-esterlabeled DNA probes. Author(s): Evans KD, Nakasone AS, Sutherland PA, de la Maza LM, Peterson EM. Source: Journal of Clinical Microbiology. 1992 September; 30(9): 2427-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1401010

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In vitro inhibition of drug-resistant and drug-sensitive strains of Mycobacterium tuberculosis by ethnobotanically selected South African plants. Author(s): Lall N, Meyer JJ. Source: Journal of Ethnopharmacology. 1999 September; 66(3): 347-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10473184

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Inhibition of drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis by diospyrin, isolated from Euclea natalensis. Author(s): Lall N, Meyer JJ. Source: Journal of Ethnopharmacology. 2001 December; 78(2-3): 213-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11694367


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Inhibition of Mycobacterium tuberculosis growth by saringosterol from Lessonia nigrescens. Author(s): Wachter GA, Franzblau SG, Montenegro G, Hoffmann JJ, Maiese WM, Timmermann BN. Source: Journal of Natural Products. 2001 November; 64(11): 1463-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11720535

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Inhibitory effect of sterols from Ruprechtia triflora and diterpenes from Calceolaria pinnifolia on the growth of Mycobacterium tuberculosis. Author(s): Woldemichael GM, Franzblau SG, Zhang F, Wang Y, Timmermann BN. Source: Planta Medica. 2003 July; 69(7): 628-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12898418

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Interleukin-8 secretion from Mycobacterium tuberculosis-infected monocytes is regulated by protein tyrosine kinases but not by ERK1/2 or p38 mitogen-activated protein kinases. Author(s): Ameixa C, Friedland JS. Source: Infection and Immunity. 2002 August; 70(8): 4743-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12117995

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Intracellular expression of Mycobacterium tuberculosis-specific 10-kDa antigen down-regulates macrophage B7.1 expression and nitric oxide release. Author(s): Singh B, Singh G, Trajkovic V, Sharma P. Source: Clinical and Experimental Immunology. 2003 October; 134(1): 70-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12974757

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Isoniazid-resistant mutants of Mycobacterium tuberculosis H37RV: uptake of isoniazid and the properties of NADase inhibitor. Author(s): Sriprakash KS, Ramakrishnan T. Source: J Gen Microbiol. 1970 January; 60(1): 125-32. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4992269

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Metal ions modulate the plastic nature of Mycobacterium tuberculosis chaperonin-10. Author(s): Taneja B, Mande SC. Source: Protein Engineering. 2001 June; 14(6): 391-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11477217

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Mode of action of pyrazinamide: disruption of Mycobacterium tuberculosis membrane transport and energetics by pyrazinoic acid. Author(s): Zhang Y, Wade MM, Scorpio A, Zhang H, Sun Z.

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Source: The Journal of Antimicrobial Chemotherapy. 2003 November; 52(5): 790-5. Epub 2003 October 16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14563891 •

Molecular cloning and expression of an alpha-mannosidase gene in Mycobacterium tuberculosis. Author(s): Rivera-Marrero CA, Ritzenthaler JD, Roman J, Moremen KW. Source: Microbial Pathogenesis. 2001 January; 30(1): 9-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11162181

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Mycobacterium tuberculosis growth inhibition by constituents of Sapium haematospermum. Author(s): Woldemichael GM, Gutierrez-Lugo MT, Franzblau SG, Wang Y, Suarez E, Timmermann BN. Source: Journal of Natural Products. 2004 April; 67(4): 598-603. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15104489

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Mycobacterium tuberculosis responsible for cutaneous disease after percutaneal inoculation of solutions: a case report. Author(s): Diaz Betancourt ML, Olano AM, Klinger JC. Source: International Journal of Dermatology. 2003 July; 42(7): 564-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12839613

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Oxidative stress increases susceptibility of Mycobacterium tuberculosis to isoniazid. Author(s): Bulatovic VM, Wengenack NL, Uhl JR, Hall L, Roberts GD, Cockerill FR 3rd, Rusnak F. Source: Antimicrobial Agents and Chemotherapy. 2002 September; 46(9): 2765-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12183226

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Partial purification and characterization of an alcohol dehydrogenase of Mycobacterium tuberculosis var. bovis (BCG). Author(s): De Bruyn J, Johannes A, Weckx M, Beumer-Jochmans MP. Source: J Gen Microbiol. 1981 June; 124(Pt 2): 359-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7035614

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Plants from Puerto Rico with anti-Mycobacterium tuberculosis properties. Author(s): Frame AD, Rios-Olivares E, De Jesus L, Ortiz D, Pagan J, Mendez S. Source: P R Health Sci J. 1998 September; 17(3): 243-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9883470

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Polyphosphate-glucose phosphotransferase. Purification tuberculosis H37Ra enzyme to apparent homogeneity. Author(s): Szymona M, Kowalska H, Pastuszak I.

of

Mycobacterium


Source: Acta Biochimica Polonica. 1977; 24(2): 133-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=406755 •

Protective effect of green tea extract against the erythrocytic oxidative stress injury during Mycobacterium tuberculosis infection in mice. Author(s): Guleria RS, Jain A, Tiwari V, Misra MK. Source: Molecular and Cellular Biochemistry. 2002 July; 236(1-2): 173-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12190117

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Purification and properties of the transglucosylase inhibitor of Mycobacterium tuberculosis. Author(s): LORNITZO FA, GOLDMAN DS. Source: The Journal of Biological Chemistry. 1964 September; 239: 2730-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14216421

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Purification of serologically active phosphoinositides of Mycobacterium tuberculosis. Author(s): Pangborn MC, McKinney JA. Source: Journal of Lipid Research. 1966 September; 7(5): 627-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4291253

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Purification, characterization, and genetic analysis of Mycobacterium tuberculosis urease, a potentially critical determinant of host-pathogen interaction. Author(s): Clemens DL, Lee BY, Horwitz MA. Source: Journal of Bacteriology. 1995 October; 177(19): 5644-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7559354

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Recombinant expression and characterization of the major beta-lactamase of Mycobacterium tuberculosis. Author(s): Voladri RK, Lakey DL, Hennigan SH, Menzies BE, Edwards KM, Kernodle DS. Source: Antimicrobial Agents and Chemotherapy. 1998 June; 42(6): 1375-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9624479

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Regulation of IL-10 secretion after phagocytosis of Mycobacterium tuberculosis by human monocytic cells. Author(s): Shaw TC, Thomas LH, Friedland JS. Source: Cytokine. 2000 May; 12(5): 483-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10857763

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The antigens of Mycobacterium tuberculosis, H37Rv, studied by crossed immunoelectrophoresis. Comparison with a reference system for Mycobacterium bovis, BCG. Author(s): Wiker HG, Harboe M, Bennedsen J, Closs O.

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Source: Scandinavian Journal of Immunology. 1988 February; 27(2): 223-39. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3124264 •

The contribution of hydrogen peroxide resistance to virulence of Mycobacterium tuberculosis during the first six days after intravenous infection of normal and BCGvaccinated guinea-pigs. Author(s): Jackett PS, Aber VR, Mitchison DA, Lowrie DB. Source: Br J Exp Pathol. 1981 February; 62(1): 34-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6784743

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The induction by lysozyme of an L-type growth in Mycobacterium tuberculosis. Author(s): Willett HP, Thacore H. Source: Canadian Journal of Microbiology. 1966 February; 12(1): 11-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4958824

Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •

Alternative Medicine Foundation, Inc.: http://www.herbmed.org/

•


•

Chinese Medicine: http://www.newcenturynutrition.com/

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drkoop.com: http://www.drkoop.com/InteractiveMedicine/IndexC.html

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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm

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Google: http://directory.google.com/Top/Health/Alternative/

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Healthnotes: http://www.healthnotes.com/

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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine

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Open Directory Project: http://dmoz.org/Health/Alternative/

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HealthGate: http://www.tnp.com/

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WebMDHealth: http://my.webmd.com/drugs_and_herbs

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

•

Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/


The following is a specific Web list relating to Mycobacterium tuberculosis; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

General Overview Tuberculosis Source: Integrative Medicine Communications; www.drkoop.com

•

Herbs and Supplements Berberis Alternative names: Barberry; Berberis sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Centella Alternative names: Gotu Kola; Centella asiatica (Linn.) Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Hydrastis Alternative names: Goldenseal; Hydrastis canadensis L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Matricaria Alternative names: Chamomile; Matricaria chamomilla Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Momordica Alternative names: Bitter Gourd, Karela; Momordica charantia Linn. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Swertia Alternative names: Swertia sp Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Syzygium Clove Alternative names: Clove, Jamun; Syzygium sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Tanacetum Alternative names: Feverfew; Tanacetum parthenium (L.) Schultz-Bip. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Thymus Alternative names: Thyme; Thymus vulgaris Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org

General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page

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dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.

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CHAPTER 4. DISSERTATIONS ON MYCOBACTERIUM TUBERCULOSIS Overview In this chapter, we will give you a bibliography on recent dissertations relating to Mycobacterium tuberculosis. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “Mycobacterium tuberculosis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on Mycobacterium tuberculosis, we have not necessarily excluded non-medical dissertations in this bibliography.

Dissertations on Mycobacterium Tuberculosis ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to Mycobacterium tuberculosis. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •

Application of EPR spectroscopy to study the resting state structure and the mechanism of Mycobacterium tuberculosis catalase-peroxidase (KatG) by Girotto, Stefania, PhD from CITY UNIVERSITY OF NEW YORK, 2004, 157 pages http://wwwlib.umi.com/dissertations/fullcit/3115252

•

Caracterisation de l'hemoglobine HbO de la bacterie Mycobacterium tuberculosis (French text) by Savard, Pierre-Yves, MSc from UNIVERSITE LAVAL (CANADA), 2003, 92 pages http://wwwlib.umi.com/dissertations/fullcit/MQ85565

•

Molecular characterization of Mycobacterium tuberculosis PknB by Drews, Steven Jeffrey, PhD from THE UNIVERSITY OF BRITISH COLUMBIA (CANADA), 2003, 155 pages http://wwwlib.umi.com/dissertations/fullcit/NQ85982

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Novel vaccine strategies against aerosol infection with Mycobacterium tuberculosis in mice by Taylor, Jennifer Lynn, PhD from COLORADO STATE UNIVERSITY, 2003, 206 pages http://wwwlib.umi.com/dissertations/fullcit/3107102

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The discovery of a novel Mycobacterium tuberculosis virulence factor (CFP32) associated with the induction of monocyte interleukin-10 and the subsequent development of an assay to differentiate the subspecies of the Mycobacterium tuberculosis complex by Huard, Richard C., PhD from WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY, 2003, 115 pages http://wwwlib.umi.com/dissertations/fullcit/3099965

•

The Mycobacterium tuberculosis two-component system PhoP-PhoR is involved in virulence and lipid regulation by Walters, Shaun Brian John, PhD from NEW YORK UNIVERSITY, 2003, 152 pages http://wwwlib.umi.com/dissertations/fullcit/3105921

•

Toll-like receptor-dependent inhibition of macrophage interferon-gamma induced responses by Mycobacterium tuberculosis and its 19-kilodalton lipoprotein by Pai, Rish Kochikar, PhD from CASE WESTERN RESERVE UNIVERSITY (HEALTH SCIENCES), 2003, 155 pages http://wwwlib.umi.com/dissertations/fullcit/3107705

Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.

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CHAPTER 5. PATENTS ON MYCOBACTERIUM TUBERCULOSIS 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.8 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 “Mycobacterium tuberculosis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on Mycobacterium tuberculosis, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Mycobacterium Tuberculosis By performing a patent search focusing on Mycobacterium tuberculosis, 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 8Adapted

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

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

Abundant extracellular product vaccines and methods for their production and use Inventor(s): Horwitz; Marcus A. (Los Angeles, CA) Assignee(s): The Regents of the University of California (Oakland, CA) Patent Number: 6,752,993 Date filed: November 23, 1993 Abstract: Vaccines based on majorly abundant extracellular products of pathogens and methods for their use and production are presented. The most prevalent or majorly abundant extracellular products of a target pathogen are selected irrespective of their absolute molecular immunogenicity and used as vaccines to stimulate a protective immune response in mammalian hosts against subsequent infection by the target pathogen. In addition to other infectious agents, the vaccines-so produced can be used to stimulate an effective immune response against intracellular pathogens and in particular Mycobacterium tuberculosis. Excerpt(s): The present invention generally relates to immunotherapeutic agents and vaccines against pathogenic organisms such as bacteria, protozoa, viruses and fungus. More specifically, unlike prior art vaccines and immunotherapeutic agents based upon pathogenic subunits or products which exhibit the greatest or most specific molecular immunogenicity, the present invention uses the most prevalent or majorly abundant immunogenic determinants released by a selected pathogen such as Mycobacterium tuberculosis to stimulate an effective immune response in mammalian hosts. Accordingly, the acquired immunity and immunotherapeutic activity produced through the present invention is directed to those antigenic markers which are displayed most often on infected host cells during the course of a pathogenic infection without particular regard to the relative or absolute immunogenicity of the administered compound. It has long been recognized that parasitic microorganisms possess the ability to infect animals thereby causing disease and often the death of the host. Pathogenic agents have been a leading cause of death throughout history and continue to inflict immense suffering. Though the last hundred years have seen dramatic advances in the prevention and treatment of many infectious diseases, complicated host-parasite interactions still limit the universal effectiveness of therapeutic measures. Difficulties in countering the sophisticated invasive mechanisms displayed by many pathogenic vectors is evidenced by the resurgence of various diseases such as tuberculosis, as well as the appearance of numerous drug resistant strains of bacteria and viruses. Among those pathogenic agents of major epidemiological concern, intracellular bacteria have proven to be particularly intractable in the face of therapeutic or prophylactic measures. Intracellular bacteria, including the genus Mycobacterium and the genus Legionella, complete all or part of their lifecycle within the cells of the infected host organism rather than extracellularly. Around the world, intracellular bacteria are responsible for millions of deaths each year and untold suffering. Tuberculosis, caused by Mycobacterium tuberculosis, is the leading cause of death from infectious disease worldwide, with 10 million new cases and 2.9 million deaths every year. In addition, intracellular bacteria are responsible for millions of cases of leprosy. Other debilitating diseases transmitted by intracellular agents include cutaneous and visceral leishmaniasis, American

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trypanosomiasis (Chagas disease), listeriosis, toxoplasmosis, histoplasmosis, trachoma, psittacosis, Q-fever, and Legionellosis including Legionnaires' disease. At this time, relatively little can be done to prevent debilitating infections in susceptible individuals exposed to these organisms. Web site: http://www.delphion.com/details?pn=US06752993__ •

Antimicrobial compounds Inventor(s): Dick; James D. (Upperco, MD), Kuhajda; Francis P. (Lutherville, MD), Parrish; Nicole M. (Ellicott City, MD), Pasternack; Gary R. (Baltimore, MD), Townsend; Craig A. (Baltimore, MD) Assignee(s): The Johns Hopkins University School of Medicine (Baltimore, MD) Patent Number: 6,713,654 Date filed: August 28, 2000 Abstract: This invention provides methods for treating a mycobacterial infection by administering to an animal a pharmaceutical composition containing a compound having the formula R--SO.sub.n --Z--CO--Y, where R is an alkyl group having 6-20 carbons; Z is a radical selected from --CH.sub.2 --, --O--, and --NH--, two of these radicals coupled together, or --CH.sub.2.dbd.CH.sub.2 --; Y is --NH.sub.2, O--CH.sub.2 -C.sub.6 H.sub.5, --CO--CO--O--CH.sub.3, or O--CH.sub.3; and n is 1 or 2. It has been discovered that these compounds inhibit growth of microbial cells which synthesize.alpha.-substitued,.beta.-hydroxy fatty acids, particularly corynemycolic acid, nocardic acid, and mycolic acid. These compounds may be used to inhibit growth of mycobacterial cells, such as Mycobacterium tuberculosis, drug-resistant M. tuberculosis, M. avium intracellulare, and M. leprae. Excerpt(s): This invention relates to the synthesis and in vivo application of compounds which have antibiotic activity against microbes that synthesize mycolic acid, including Mycobacterium sp., particularly drug resistant Mycobacierium strains, and to the use of these compounds to treat any susceptible pathogenic microorganism or parasite. The emergence of multiply drug resistant (MDR) strains of Mycobacterium tuberculosis and other atypical mycobacteria which infect immunocompromised patients (e.g., AIDS patients) highlights the need for continued antibiotic development. Mycobacterium sp. synthesize a multitude of complex lipids and glycolipids unique to this genus, making these biochemical pathways attractive targets for drug therapy (Bloch, K., "Control mechanisms for fatty acid synthesis in Mycobacterium smegmatis," Adv. Enzymol. 45:184, 1977; Brennan, P. J., and Nikaido, H., "The envelope of mycobacteria," Ann. Rev. Biochem. 64:29-63, 1995). The.beta.-ketoacyl synthase (KS) of particulate Type II fatty acid synthases or the corresonding domain of the polyfunctional Type I fatty acid synthases catalyzes the critical two-carbon homologation during buildup of the growing fatty acid chain. This process typically gives acids of length C.sub.16 to C.sub.18. In chain elongation of normal fatty acids, carried out for example by mycobacteria, CoA and/or acyl-carrier protein (ACP) thioesters of these acids are further reacted with malonyl-CoA to greatly extend their length to 60-90 carbons. These high molecular weight acids are known collectively as mycolic acids. Web site: http://www.delphion.com/details?pn=US06713654__

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Carbohydrate complex extracted from Mycobacterium tuberculosis and process for the preparation thereof Inventor(s): Chung; Chong-Chan (Garden Heights 1st. 101-601, #300, Bumeo 4-dong, Suaeong-gu, Daegu, KR), Chung; Tai-Ho (Cheongun Apt. 7-309, #111-1, Daebong-dong, Jung-gu, Daegu, KR) Assignee(s): none reported Patent Number: 6,274,356 Date filed: December 9, 1999 Abstract: A carbohydrate complex, which is a mixture of low molecular-weight polysaccharides of an arabinomannan structure extracted from Mycobacterium tuberculosis, is highly effective in treating various cancer patients without incurring any adverse side effects. Excerpt(s): The present invention relates to a carbohydrate complex extracted from Mycobacterium tuberculosis, which has an anticancer activity, and to a process for the preparation thereof. It is generally known that the anticancer activity of Mycobacterium tuberculosis is attributable to active agents in the cytoplasmic membrane thereof, particularly the polysaccharide and lipid derivatives. For instance, Azuma et al. succeeded in isolating N-acetylmuramyl-L-alanyl-D-isoglutamin(MDP) which is an active component of M. tuberculosis [Azuma, L. et al., J. Bact., 96, 1885-1887(1968)]. Web site: http://www.delphion.com/details?pn=US06274356__

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DNA molecule encoding for cellular uptake of Mycobacterium tuberculosis and uses thereof Inventor(s): Riley; Lee W. (New York, NY) Assignee(s): Cornell Research Foundation, Inc. (Ithaca, NY) Patent Number: 6,509,151 Date filed: February 22, 1995 Abstract: The present invention relates to a DNA molecule conferring on Mycobacterium tuberculosis an ability to enter mammalian cells and to survive within macrophages. The protein encoded by this gene fragment is useful in vaccines to prevent infection by Mycobacterium tuberculosis, while the antibodies raised against this protein can be employed in passively immunizing those already infected by the organism. Both these proteins and antibodies may be utilized in diagnostic assays to detect Mycobacterium tuberculosis in tissue or bodily fluids. The protein of the present invention can be associated with various other therapeutic materials, for administration to mammals, particularly humans, to achieve uptake of those materials by such cells. Excerpt(s): The present invention relates to a DNA molecule encoding for uptake of Mycobacterium tuberculosis and its use in drugs, vaccines, and diagnostic tests. Tuberculosis is the leading cause of death in the world with an estimated 9 million new cases of tuberculosis and 2.9 million deaths occurring from the disease each year. In the United States, the steadily declining incidents of tuberculosis has been reversed since 1985. This problem is compounded by the increasing incidence of drug-resistant strains of Mycobacterium tuberculosis. Recent outbreaks of tuberculosis have involved settings in which a large number of HIV-infected persons resided in close proximity (e.g., AIDS wards in hospitals, correctional facilities, and hospices). Transmission of

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tuberculosis to health care workers occurred in these outbreaks; 18 to 50% of such workers showed a conversion in their skin tests. See F. Laraque et. al., "Tuberculosis in HIV-Infected Patients," The AIDS Reader (September/October 1992), which is hereby incorporated by reference. Web site: http://www.delphion.com/details?pn=US06509151__ •

EF-Tu mRNA as a marker for viability of bacteria Inventor(s): Klatser; Paul R. (Amsterdam, NL), Oudshoorn; Pieter (St. Michielsgestel, NL) Assignee(s): bioMerieux, B.V. (NL) Patent Number: 6,489,110 Date filed: July 21, 2000 Abstract: The present invention is related to the detection of bacteria, such as Mycobacteria, in human or animal body fluids such as blood, sputum and urine. The present invention provides a method for assessing the viability of bacteria such as Mycobacterium tuberculosis without the need for propagation of the bacteria. The method of the present invention is in particular useful for assessing the viability of Mycobacteria species such as are M. tuberculosis or M. leprae. With the present invention oligonucleotides are provided that can be used as primers and probes for the amplification of bacterial EF-Tu mRNA. The use of the oligonucleotides according to the invention is not limited to any particular amplification technique or any particular modification thereof. It is evident that the oligonucleotides according to the invention find their use in many different nucleic aid amplification techniques and various methods for detecting the presence of (amplified) bacterial EF-Tu mRNA. Excerpt(s): For example, tuberculosis (TB) caused by Mycobacterium tuberculosis is a major public health problem in many countries world-wide with particular significance in developing countries. Tuberculosis control programmes are faced with an increased burden of cases, a shift towards diagnostically more difficult categories of patients such as extrapulmonary and smear-negative cases, and the emergence of multidrug-resistant strains of M. tuberculosis. Improved diagnosis would be a valuable contribution in the struggle to solve this global public health emergency. The method of the present invention is concerned with the amplification of specific nucleic acid sequences. Web site: http://www.delphion.com/details?pn=US06489110__

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Fusion proteins of Mycobacterium tuberculosis antigens and their uses Inventor(s): Alderson; Mark (Bainbridge Island, WA), Campos-Neto; Antonio (Bainbridge Island, WA), Skeiky; Yasir (Seattle, WA) Assignee(s): Corixa Corporation (Seattle, WA) Patent Number: 6,544,522 Date filed: December 30, 1998 Abstract: The present invention relates to fusion proteins of Mycobacterium tuberclosis antigens. In particular, it relates to two fusion proteins, each of which contains three individual M. tuberculosis antigens, and a fusion protein of two M. tuberculosis

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antigens, their coding sequences, and methods for their use in the treatment and prevention of tuberculosis. Excerpt(s): Tuberculosis is a chronic infectious disease caused by infection with M. tuberculosis. It is a major disease in developing countries, as well as an increasing problem in developed areas of the world, with about 8 million new cases and 3 million deaths each year. Although the infection may be asymptomatic for a considerable period of time, the disease is most commonly manifested as an acute inflammation of the lungs, resulting in fever and a nonproductive cough. If untreated, serious complications and death typically result. Although tuberculosis can generally be controlled using extended antibiotic therapy, such treatment is not sufficient to prevent the spread of the disease. Infected individuals may be asymptomatic, but contagious, for some time. In addition, although compliance with the treatment regimen is critical, patient behavior is difficult to monitor. Some patients do not complete the course of treatment, which can lead to ineffective treatment and the development of drug resistance. In order to control the spread of tuberculosis, effective vaccination, and accurate early diagnosis of the disease are of utmost importance. Currently, vaccination with live bacteria is the most efficient method for inducing protective immunity. The most common Mycobacterium employed for this purpose is Bacillus Calmette-Guerin (BCG), an avirulent strain of M. bovis. However, the safety and efficacy of BCG is a source of controversy and some countries, such as the United States, do not vaccinate the general public with this agent. Web site: http://www.delphion.com/details?pn=US06544522__ •

Methods for inducing interleukin-12 and a type1/Th1 T-cell response Inventor(s): Libraty; Daniel H. (Bangkok, TH), Modlin; Robert L. (Sherman Oaks, CA) Assignee(s): The Regents of the University of California (Oakland, CA) Patent Number: 6,517,839 Date filed: July 17, 1998 Abstract: Methods for inducing interleukin-12 production and inducing a type 1/Th1 T cell response in a subject, thereby stimulating cell-mediated immunity for prevention or treatment of pathogen infections or treatment of a interferon (-sensitive tumor, are provided. Compounds effective in the above-described methods include a lipopeptide having an N-terminal ester- or amide-linked fatty acyl group and are administered in an amount effective to induce interleukin-12 and to induce the type 1/Th1 T-cell response. Preferably, the subject is a human patient, and the lipopeptide is an N-terminal moiety of a 19 kDa or a 38 kDa lipoprotein of Mycobacterium tuberculosis. Excerpt(s): The present invention relates generally to the fields of medical microbiology and immunology. More particularly, the invention provides methods for inducing the production of interleukin-12 in peripheral blood mononuclear cells and, thereby, inducing a type 1/Th1 T cell immune response that is central to an effective cellmediated immune response to intracellular pathogens or interferon.gamma.-sensitive tumors. Infection with the intracellular pathogen Mycobacterium tuberculosis (M. tuberculosis) continues to produce great morbidity and mortality throughout the world with 8 million new cases of tuberculosis and 3 million deaths occurring annually. Such creates an urgency to understand mechanisms of cell-mediated immunity (CMI) to the infection (Bloom and Murray, Science 257: 1055-1064, 1992). The spectrum of clinical outcomes after infection with M. tuberculosis is determined largely by the interaction of T-cells and monocyte/macrophages. Two functionally distinct subsets of T-cells

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modulate the outcome of such intracellular infections (Mosmann et al., J. Immunol 136:2348-2357, 1986). In human infectious disease, Type 1 T-cells that produce interleukin-2 (IL-2) and interferon.gamma. (IFN-.gamma.) activate macrophages to kill or inhibit the growth of pathogens, resulting in mild or self-curing disease (Yamamura et al., Science 254:277-279, 1991; Salgame et al., Science 254:279-282, 1991). In contrast, type 2 T-cells which produce interleukins-4, -5, and -10 (IL-4, IL-5, IL-10) augment humoral responses (circulating antibody responses) and inhibit CMI, resulting in fulminant disease. The differentiation of naive T-cells into producing either type 1 or type 2 cytokine profiles is shaped by the cytokine milieu produced by the surrounding monocytes and macrophages. In particular, interleukin-12 (IL-12) is a key bridge between the innate immune response of monocyte/macrophages and the adaptive immune response of type 1 T-cells (Romagnani, S., Immunol Today 13:379-381, 1992). In animal models of infection due to intracellular pathogens, the production of IL-12 is important in the generation of protective, Th1-mediated, immunity (Scott et al., J Exp Med 168:1675-1684, 1988; Heinzel et al.; J Exp Med 169:591989; Liew et al., Eur J Immunol 19:1227-1232, 1989; Sadick et al.,J Exp Med 171:115-127, 1990). For example, in mycobacterial infection, IL-12 production at the site of disease is a prominent characteristic of the resistant phenotype or self-limited disease. In tuberculosis, IL-12 has been found in the pleural fluid of patients with tuberculous pleuritis; and, anti-IL-12 antibodies partially inhibit the proliferative response of the pleural fluid lymphocytes to M. tuberculosis (Zhang et al., J Clin Invest 93:1733-1739, 1994). In leprosy, IL-12 induces the expansion of mycobacteria-reactive T-cells which produce IFN-.gamma., but has little effect on T-cells which produce IL-4 (Sieling et al., J Immunol 153:3639-3647, 1994). Further, in a murine model, exogenous administration of IL-12 increases the resistance of mice to M. tuberculosis infection via the IFN-.gamma. pathway (Flynn et al., J Immunol 155:2515-2524, 1995; Cooper et al., Immunology 84:423-432, 1995). In addition, production of IFN-.gamma. is required for immunity to mycobacterial infection (Flynn et al., J Exp Med 178:2249-2254, 1993; Cooper et al., J Exp Med 178:2243-2247, 1993). Web site: http://www.delphion.com/details?pn=US06517839__ •

Monoclonal antibodies to Mycobacterium tuberculosis and a modified ELISA assay Inventor(s): Casadevall; Arturo (Pelham, NY), Glatman-Freedman; Aharona (Irvington, NY) Assignee(s): Albert Einstein College of Medicine of Yeshiva University (Bronx, NY) Patent Number: 6,545,130 Date filed: June 4, 1997 Abstract: The present invention provides for monoclonal antibodies, the hybridoma cell lines which produce these antibodies, and the use of such monoclonal antibodies in the detection of M. tuberculosis. More specifically, the present invention provides for monoclonal antibodies that react with surface epitopes of M. tuberculosis and the use of these monoclonal antibodies for detecting and diagnosing M. tuberculosis. Also provided by the present invention is a modified ELISA assay for detection of microorganisms, and a modified ELISA assay employing the monoclonal antibodies of the present invention for detecting M. tuberculosis. Excerpt(s): Tuberculosis continues to be a major worldwide health problem and is responsible for most incidences of death by an infectious agent. The worldwide incidence of tuberculosis was estimated by the World Health Organization to be 8.8 million in 1995, with a mortality estimate of 3.0 million persons, and is expected to rise

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to 10.2 million by the year 2000 (Dolin, et al., Bull. WHO. 72: 213-220 (1994)). The tuberculosis problem has been compounded by the development of the AIDS epidemic and the growing number of HIV-related cases of tuberculosis (Dolin, et al., Bull. WHO. 72: 213-220 (1994)). As the incidence of tuberculosis increases, major problems also develop concerning this disease. For example, the lack of a sensitive and rapid laboratory method of diagnosing tuberculosis makes it difficult to differentiate between M. tuberculosis and M. avium-intracellulare, both of which are frequently present in HIV infected patients. Multiple methods of detection of M. tuberculosis employing polyclonal and monoclonal antibodies have been described (Cho, et al., Yonsei Med. J. 31:333-338 (1990); Cho, et al., J. Clin. Microbiol. 30: 3065-3069 (1992); Friedman, et al., Am. Rev. Respir. Dis. 140: 668-671 (1989); Kadival, et al., J. Clin. Microbiol. 23: 901904(1986); Mason, et al., Tubercle Lung Dis. 74:195-199(1993); Papa, et al., Res. Microbiol. 143: 327-331 (1992); Sada, et al., Lancet 2 651-652 (1983); Schoningh, et al., J. Clin. Microbiol. 28: 708-713 (1990); Verstijnen, et al., J. Clin. Microbiol. 29:1372-1375 (1991) Watt, et al., J Infect Dis. 158:681-686 (1988); Wu, et al., Chin. J. Microbiol. Immunol. 22:173-180 (1989); Yanez, et al., Clin. Microbiol. 23: 822-825 (1986)), but none have acquired a widespread role in the diagnosis of tuberculosis as these antibodies crossreact with other mycobacterial strains (Cho, et al., Yonsei Med. J. 31:333-338 (1990); Friedman, et al., Am. Rev. Respir. Dis. 140: 668-671 (1989); Kadival, et al., J. Clin. Microbiol. 23: 901-904 (1986); Wu, et al., Chin. J. Microbiol. Immunol. 22:173-180 (1989); Yanez, et al., J. Clin. Microbiol. 23: 822-825 (1986)). In addition, in order to obtain significant results, a large amount of mycobacteria or mycobacterial antigen is required (Cho, et al., J. Clin. Microbiol. 30: 3065-3069 (1992); Mason, et al., Tubercle Lung Dis. 74:195-199 (1993); Papa, et al., Res. Microbiol. 143: 327-331 (1992); Schoningh, et al., J. Clin. Microbiol. 28: 708-713 (1990); Verstijnen, et al., J. Clin. Microbiol. 29:1372-1375 (1991)). Improvements in antibody-based diagnostic tests for the detection of M. tuberculosis would require specific antibody reagents with high affinity for mycobacterial antigens. Several monoclonal antibodies have been generated against surface components of M. tuberculosis (Cho, et al., Yonsei Med. J. 31:333-338 (1990); Cho, et al., J. Clin. Microbiol. 30: 3065-3069 (1992); Mauch, et al., J. Clin. Microbiol. 26:1691-1694 (1988)) but they are often cross reactive with other strains or cytoplasmic fractions (Cho, et al., Yonsei Med. J. 31:333-338 (1990); Mauch, et al., J. Clin. Microbiol. 26:1691-1694 (1988)). There is thus a need for a monoclonal antibody that selectively binds to M. tuberculosis and does not cross react with other strains of mycobacteria. An additional problem concerns the protocol used for detecting M. tuberculosis. The protocols described thus far for detecting mycobacteria, such as direct ELISA (Mason, et al., Tubercle Lung Dis. 74:195-199 (1993); Schoningh, et al., J. Clin. Microbiol. 28: 708-713 (1990); Verstijnen, et al., J. Clin. Microbiol. 29:1372-1375 (1991)), capture ELISA (Cho, et al., Yonsei Med. J. 31:333-338 (1990); Cho, et al., J. Clin. Microbiol. 30: 3065-3069 (1992); Friedman, et al., Am. Rev. Respir. Dis. 140: 668-671 (1989); Kadival, et al., J. Clin. Microbiol. 23: 901-904 (1986); Rattan, et al., Tubercle Lung Dis. 74: 200-203 (1993); Sada, et al., Lancet 2 651-652 (1983); Watt, et al., J Infect Dis. 158:681-686 (1988); Wu, et al., Chin. J. Microbiol. Immunol. 22:173-180 (1989); Yanez, et al., J. Clin. Microbiol. 23: 822825 (1986)) and DOT ELISA (Cho, et al., J. Clin. Microbiol. 30: 3065-3069 (1992); Papa, et al., Res. Microbiol. 143: 327-331 (1992)), are deficient in many areas. For example, none of the methods listed above allow for visualization of single captured microorganisms. Furthermore, many of these methods require the use of polyclonal immunoglobulins which have the potential disadvantages of lot to lot variation, reliance on animal sources and unwanted cross-reactivities. Accordingly, there is an outstanding need for a method of detecting M. tuberculosis which eliminates the problems existing in current methods of detection.

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Web site: http://www.delphion.com/details?pn=US06545130__ •

Mycobacteria functional screening and/or expression vectors Inventor(s): Berthet; Francois-Xavier (Paris, FR), Gicquel; Brigitte (Paris, FR), Lim; Eng Mong (Paris, FR), Portnoi; Denis (Paris, FR), Timm; Juliano (Paris, FR) Assignee(s): Institut Pasteur (Paris Cedex, FR) Patent Number: 6,248,581 Date filed: June 9, 1997 Abstract: Recombinant screening, cloning and/or expression vector characterized in that it replicates in mycobacteria and contains 1) a mycobacteria functional replicon; 2) a selection marker, 3) a reporter cassette comprising a) a multiple cloning site (polylinker) b) a transcription terminator which is active in mycobacteria and is located upstream of the polylinker, and c) a coding nucleotide sequence derived from a gene coding for an expression, export and/or secretion protein marker, the nucleotide sequence being deprived of its initiation codon and its regulating sequences. This vector is used for identification and expression of exporter polypeptides, such as the Mycobacterium tuberculosis P28 antigen. Excerpt(s): The Mycobacterium genus includes major human pathogens such as M. leprae and M. tuberculosis, the agents responsible for leprosy and tuberculosis, which remain serious public health problems world-wide. M. bovis and M. tuberculosis, the causative agents of tuberculosis, are intracellular facultative bacteria. Despite the major health problems linked to these pathogenic organisms, little is known about their exported and/or secreted proteins. In SDS-PAGE analyses of M. tuberculosis culture filtrate show at least 30 secreted proteins (1,19,38). Some of them have been characterized, their genes cloned and sequenced (7, 35, 37). Others, although they are immunodominant antigens of major importance for inducing protective immunity (2, 21), have not been completely identified. In addition, it is probable that a great number of exported proteins remain attached to the cell membrane and, consequently, are not present in culture supernatants. It has been shown that proteins located at the outer surface of various pathogenic bacteria, such as the 103 kDa Yersina pseudotuberculosis invasin (14) or the 80 kDa Listeria monocytogenes internalin (10) play an important role in interactions with the host cells and, consequently, in pathogenicity as in the induction of protective responses. Thus, a membrane-bound protein could be important for M. tuberculosis infection as well as for the induction of a protective response against this infection. These proteins could certainly be of interest for the preparation of vaccines. The BCG (Bacille CalmetteGuerin), an avirulent strain derived from M. bovis, has been widely used as vaccine against tuberculosis. It is also a very important vector for the construction of live recombinant vaccines, particularly because of its high immunogenicity. Consequently, the study of the molecular biology of mycobacteria is currently of great interest. Web site: http://www.delphion.com/details?pn=US06248581__

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Mycobacterium tuberculosis specific DNA fragment Inventor(s): Kumar; Deepak (Lucknow-1, IN), Srivastava; Brahm Shanker (Lucknow-1, IN), Srivastava; Ranjana (Lucknow-1, IN) Assignee(s): Council of Scientific and Industrial Research (New Delhi, IN) Patent Number: 6,242,585 Date filed: September 18, 1998 Excerpt(s): This invention relates to a Mycobacterium tuberculosis specific DNA fragment containing IS like and repetitive sequences, a method of production of such DNA fragment and the use of such DNA fragment, for example, to rapidly diagnose Mycobacterium tuberculosis infection in clinical samples, and to identify clinical isolates of Mycobacterium tuberculosis. The DNA fragment may be used to determine information about the epidemiology of Mycobacterium tuberculosis infection. Specifically this invention relates to the use of sequence specific DNA fragments to diagnose Mycobacterium tuberculosis and strains of Mycobacterium tuberculosis. A purpose of the study of the epidemiology of tuberculosis is to distinguish the genetic diversity of the causative agent Mycobacterium tuberculosis and to obtain information about strain to strain variability. This can be achieved by molecular epidemiological methods including DNA fingerprinting and restriction fragment length polymorphism (RFLP) analysis. Such approaches, can aid the investigation of point source outbreaks, transmission, pathogenesis and may be employed as a marker of strain typing. Tuberculosis (TB) is a major cause of infectious mortality. According to a recent WHO report, the number of deaths attributed to TB was larger number in 1995 than in any other year in history (Moran, N. 1996. WHO Issues Another Gloomy Report. Nature Medicine 4:377). Tuberculosis remains widespread worldwide and constitutes a major health problem particularly in developing countries. One third of the total world's population (nearly two billion people) is infected with Mycobacterium tuberculosis out of which 5 to 10% develop the disease. TB causes more than 3 million deaths per year and recently WHO has predicted that 30 million people will die of TB in the next ten years (Joint International Union Against Tuberculosis and World Health Organization Study Group. Tubercl 63:157-169, 1982). Tuberculosis is caused by a gram positive acid fact bacterium Mycobacterium tuberculosis or M. bovis, which are the tubercle bacilli of the family of Mycobacteriaceae. M. bovis is a species which causes tuberculosis in cattle and can be transmitted to humans and other animals in which it causes tuberculosis. At present nearly all tuberculosis in humans is caused by Mycobacterium tuberculosis. Infections occasionally result from other species of mycobacteria that are common environmental saprophytes. These species have been collectively termed as MOTT (Mycobacteria other than typical tubercle), environmental or tuberculoid bacilli. The difference between the two infections is that infection with Mycobacterium tuberculosis is always transmitted from host to host. In contrast, human beings infected with other mycobacteria rarely transmit the disease. Hence the essential component of any tuberculosis control program is containment of the disease. Identification of infected individuals, especially those most likely to transmit viable bacilli, comes as a first priority in strategies for tuberculosis control. Early and timely diagnosis of tuberculosis is essential for identifying individuals carrying the bacilli. Therefore a need has arisen for a method of diagnosis of tuberculosis which is rapid, sensitive and specific. Routine diagnostic methods used for identification of Mycobacterium tuberculosis includes acid fast smear test in clinical samples like sputum, tests based on growth of bacilli of specific media and differential biochemical tests. The culture of mycobacteria from clinical samples is the most reliable and provides for definite diagnosis of tuberculosis.

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Although 100% specific, it takes six to eight weeks due to slow growth of organisms and further biochemical testing before identification can be made (Heifests, L B. and Good, R. C. 1994. Current Laboratory Methods for the Diagnosis of Tuberculosis. Tuberculosis Pathogenesis, Protection and Control (ed. B. R. Bloom) ASM Washington D.C., pp. 85110). Web site: http://www.delphion.com/details?pn=US06242585__ •

Nucleic acid and amino acid sequences relating to Mycobacterium tuberculosis and leprae for diagnostics and therapeutics Inventor(s): Mao; Jen-i (Lexington, MA), Smith; Douglas R. (Gloucester, MA) Assignee(s): Genome Therapeutics Corporation (Waltham, MA) Patent Number: 6,583,266 Date filed: September 16, 1994 Abstract: Embodiments of the present invention feature nucleic acid and proteins derived from Mycobacterium tuberculosis and leprae. The proteins and nucleic acid of the present invention have applications in diagnostics and therapeutics. Excerpt(s): The present invention relates to non-naturally occurring nucleic acid and peptides corresponding to nucleic acid and peptides of Mycobacterium tuberculosis and Mycobacterium leprae. The nucleic acid and peptides of the present invention have utility for diagnostics and therapeutics. Mycobacterium tuberculosis is the causative agent of tuberculosis. Tuberculosis is a chronic bacterial infection characterized by the formation of granulomas in infected tissues and by cell mediated hypersensitivity. The usual site of the disease is the lungs but other organs may be involved. In countries where human immuno-deficiency virus (HIV) infection is endemic, tuberculosis is a frequent cause of morbidity in AIDS patients. Tuberculosis has shown a resurgence in recent years worldwide. Mycobacteria contain an array of protein and polysaccharide antigens giving rise to a cell mediated hypersensitivity. The hypersensitivity is often used to diagnose tuberculosis and to monitor the disease pathogenesis. See: Harrison's Principles of Internal Medicine, Twelfth Edition, McGraw-Hill, Inc., (1991), pp. 637-645. Mycobacterium leprae is the causative agent of Hanson's disease or leprosy. Leprosy is a chronic infection of superficial tissues, especially the skin and peripheral nerves. Mycobacterium leprae multiplies slowly, and has not been grown in tissue culture or artificial media. Mycobacterium leprae does not elicit strong immunological responses in infected individuals. However, a serodiagnostic test for the detection of antibody to Mycobacterium leprae antigen is used to aid in the diagnosis. See Harrison, supra, pp. 645-648. Web site: http://www.delphion.com/details?pn=US06583266__

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Nucleic acid encoding M. tuberculosis algu protein Inventor(s): Lam; Kelvin T. (Belmont, MA) Assignee(s): Anadys Pharmaceuticals, Inc. (Waltham, MA) Patent Number: 6,355,469 Date filed: January 16, 1998

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Abstract: The invention relates to Mycobacterium tuberculosis RNA polymerase algU sigma subunit protein, DNA encoding, and methods of detecting inhibitors of the RNA polymerase. Excerpt(s): Mycobacteria are gram-positive bacilli, nonmotile rod-shaped organisms that do not form spores. The composition of the cell wall includes a very high concentration of lipids complexed to a variety of peptides and polysaccharides. The unusual structure of the cell wall distinguishes mycobacteria from most other bacteria and is detectable by its resistance to acid-alcohol staining. The disease caused by M. tuberculosis is a progressive, deadly illness that tends to develop slowly and follows a chronic course (Plorde, 1994). It is presently estimated that one-third of the world's population is infected with M. tuberculosis, 30 million of whom have active disease (Plorde, 1994). An additional 8 million people develop the disease annually (Plorde, 1994). Most infections are caused by inhalation of droplet nuclei carrying the mycobacterium. A single cough can generate 3000 infected droplet nuclei and even 10 bacilli may be sufficient to cause a pulmonary infection. In addition to the primary infection, reactivation of the disease can occur in older people and in immunocompromised patients. When intracellular pathogens, such as Mycobacterium tuberculosis, are ingested by macrophages the bacteria are under environmental stress. The genes required for survival following uptake by macrophages can provide insight into mycobacterial pathogenesis, and provide novel targets for developing antibacterial agents. The ability to adapt to the intracellular stress requires regulation of complex gene expression and this regulation may be mediated in part by one or more alternative sigma factors. Therefore stress response alternative sigma factors (sigE family) from M. tuberculosis are potential novel targets for antibacterial therapeutics. Web site: http://www.delphion.com/details?pn=US06355469__ •

Polynucleotide tuberculosis vaccine Inventor(s): Content; Jean (Rhode-Saint-Genese, BE), Huygen; Kris (Brussels, BE), Liu; Margaret A. (Rosemont, PA), Montgomery; Donna (Chalfont, PA), Ulmer; Jeffrey (Chalfont, PA) Assignee(s): Merck & Co., Inc. (Rahway, NJ) Patent Number: 6,384,018 Date filed: January 22, 1998 Abstract: Genes encoding Mycobacterium tuberculosis (M.tb) proteins were cloned into eukaryotic expression vectors to express the encoded proteins in mammalian muscle cells in vivo. Animals were immunized by injection of these DNA constructs, termed polynucleotide vaccines or PNV, into their muscles. Immune antisera was produced against M.tb antigens. Specific T-cell responses were detected in spleen cells of vaccinated mice and the profile of cytokine secretion in response to antigen 85 was indicative of a T.sub.h 1 type of helper T-cell response (i.e., high IL-2 and IFN-.gamma.). Protective efficacy of an M.tb DNA vaccine was demonstrated in mice after challenge with M.bovis BCG, as measured by a reduction in mycobacterial multiplication in the spleens and lungs of M.tb DNA-vaccinated mice compared to control DNA-vaccinated mice or primary infection in naive mice. Excerpt(s): A major obstacle to the development of vaccines against viruses and bacteria, particularly those with multiple serotypes or a high rate of mutation, against which elicitation of neutralizing antibodies and/or protective cell-mediated immune responses

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is desirable, is the diversity of the external proteins among different isolates or strains. Since cytotoxic T-lymphocytes (CTLs) in both mice and humans are capable of recognizing epitopes derived from conserved internal viral proteins [J. W. Yewdell et al., Proc. Natl. Acad. Sci. (USA) 82, 1785 (1985); A. R. M. Townsend, et al., Cell 44, 959 (1986); A. J. McMichael et al., J. Gen. Virol. 67, 719 (1986); J. Bastin et al., J. Exp. Med. 165, 1508 (1987); A. R. M. Townsend and H. Bodmer, Annu. Rev. Immunol. 7, 601 (1989)], and are thought to be important in the immune response against viruses [Y.-L. Lin and B.A. Askonas, J. Exp. Med. 154, 225 (1981); I. Gardner et al., Eur. J. Immunol. 4, 68 (1974); K. L. Yap and G. L. Ada, Nature 273, 238 (1978); A. J. McMichael et al., New Engl. J. Med. 309, 13 (1983); P. M. Taylor and B. A. Askonas, Immunol. 58, 417 (1986)], efforts have been directed towards the development of CTL vaccines capable of providing heterologous protection against different viral strains. It is known that CTLs kill virallyor bacterially-infected cells when their T cell receptors recognize foreign peptides associated with MHC class I and/or class II molecules. These peptides can be derived from endogenously synthesized foreign proteins, regardless of the protein's location or function within the pathogen. By recognition of epitopes from conserved proteins, CTLs may provide heterologous protection. In the case of intracellular bacteria, proteins secreted by or released from the bacteria are processed and presented by MHC class I and II molecules, thereby generating T-cell responses that may play a role in reducing or eliminating infection. Most efforts to generate CTL responses have either used replicating vectors to produce the protein antigen within the cell [J. R. Bennink et al., ibid. 311, 578 (1984); J. R. Bennink and J. W. Yewdell, Top. Microbiol. Immunol. 163, 153 (1990); C. K. Stover et al., Nature 351, 456 (1991); A. Aldovini and R. A. Young, Nature 351, 479 (1991); R. Schafer et al., J. Immunol. 149, 53 (1992); C. S. Hahn et al., Proc. Natl. Acad. Sci. (USA) 89, 2679 (1992)], or they have focused upon the introduction of peptides into the cytosol [F. R. Carbone and M. J. Bevan, J. Exp. Med. 169, 603 (1989); K. Deres et al., Nature 342, 561 (1989); H. Takahashi et al., ibid. 344, 873 (1990); D. S. Collins et al., J. Immunol. 148, 3336 (1992); M. J. Newman et al., ibid. 148, 2357 (1992)]. Both of these approaches have limitations that may reduce their utility as vaccines. Retroviral vectors have restrictions on the size and structure of polypeptides that can be expressed as fusion proteins while maintaining the ability of the recombinant virus to replicate [A. D. Miller, Top. Microbiol. Immunol. 158, 1 (1992)], and the effectiveness of vectors such as vaccinia for subsequent immunizations may be compromised by immune responses against vaccinia [E. L. Cooney et al., Lancet 337, 567 (1991)]. Also, viral vectors and modified pathogens have inherent risks that may hinder their use in humans [R. R. Redfield et al., New Engl. J. Med. 316, 673 (1987); L. Mascola et al., Arch. Intern. Med. 149, 1569 (1989)]. Furthermore, the selection of peptide epitopes to be presented is dependent upon the structure of an individual's MHC antigens and, therefore, peptide vaccines may have limited effectiveness due to the diversity of MHC haplotypes in outbred populations. Web site: http://www.delphion.com/details?pn=US06384018__

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Sodium salt of 3-(4-cinnamyl-1-piperazinyl)-imino-methyl rifamycin SV Inventor(s): Dimova; Velitchka Ilieva (Mladoct 1, B1.66A, Vh.B, 1784 Sofia, BG), Evstatieva; Anka Veltcheva (Hadji Dimitar B1.27A, 1510 Sofia, BG), Konstantinova; Roumiana Gueorguieva (Stara planina Strasse 17, 1504 Sofia, BG), Ninov; Kiril Asenov (Soultan tepe Str. 18, 1505 Sofia, BG) Assignee(s): none reported Patent Number: 6,476,036 Date filed: July 20, 2001 Abstract: Sodium salt of 3-(4-cinnamyl-1-piperazinyl)-iminomethyl rifamycin SV was synthesized. The compound shows high activity against Gram-positive and Gramnegative microorganims, Mycobacterium tuberculosis (including atypical and rifampicin resistant) and may be used in the medical practice. The sodium salt has formula (II). The process for preparation of the sodium salt consists of reacting equimolar quantities of 3-(4-cinnamyl-1-piperazinyl)-iminomethyl rifamycin SV and sodium ascorbate with addition of 30% methanol solution of sodium methylate, followed by filtration and removement of the solvent by distillation under reduced pressure. The compound can also be obtained from the sodium salt of 3-formil rifamycin SV, which is reacting with N.sup.1 -amino-N.sup.4 -cinnamypiperazin in medium of inert solvent at room temperature. Excerpt(s): Sodium salt of 3-(4-cinnamyl-1-piperazinyl)-iminomethyl rifamycin SV was synthesized. The process for preparation of the sodium salt consists of reacting equimolar quantities of 3-(4-cinnamyl-1-piperazinyl)-iminomethyl rifamycin SV and sodium ascorbate with addition of 30% methanol solution of sodium methylate, followed by filtration and removement of the solvent by distillation under reduced pressure. The compound can also be obtained from the sodium salt of 3-formil rifamycin SV, which is reacting with N.sup.1 -amino-N.sup.4 -cinnamypiperazine in medium of inert solvent at room temperature. Web site: http://www.delphion.com/details?pn=US06476036__

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Target-dependent reactions using structure-bridging oligonucleotides Inventor(s): Anderson; Todd A. (Madison, WI), Brow; Mary Ann D. (Madison, WI), Dahlberg; James E. (Madison, WI), Dong; Fang (Madison, WI), Fors; Lance (Madison, WI), Lyamichev; Victor I. (Madison, WI), Neri; Bruce P. (Madison, WI), Prudent; James R. (Madison, WI) Assignee(s): Third Wave Technologies, Inc. (Madison, WI) Patent Number: 6,709,815 Date filed: July 18, 2000 Abstract: The present invention relates to methods and compns. for treating nucleic acids, and in particular, methods and compns. for the detection and characterization of nucleic acid sequences and sequence changes. The invention provides methods for examg. the conformations assumed by single strands of nucleic acid, forming the basis of novel methods of detection of specific nucleic acid sequences. The present invention contemplates use of novel detection methods for, among other uses, clinical diagnostic purposes, including but not limited to the detection and identification of pathogenic

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organisms. Examples are presented for the analysis of Mycobacterium tuberculosis and hepatitis C virus genes. Excerpt(s): The present invention relates to methods and compositions for analyzing nucleic acids, and in particular, methods and compositions for detection and characterization of nucleic acid sequences and sequence changes. The detection and characterization of specific nucleic acid sequences and sequence changes have been utilized to detect the presence of viral or bacterial nucleic acid sequences indicative of an infection, the presence of variants or alleles of mammalian genes associated with disease and cancers, and the identification of the source of nucleic acids found in forensic samples, as well as in paternity determinations. As nucleic acid sequence data for genes from humans and pathogenic organisms accumulates, the demand for fast, costeffective, and easy-to-use tests for as yet unknown, as well as known, mutations within specific sequences is rapidly increasing. A handful of methods have been devised to scan nucleic acid segments for mutations. One option is to determine the entire gene sequence of each test sample (e.g., a clinical sample suspected of containing bacterial strain). For sequences under approximately 600 nucleotides, this may be accomplished using amplified material (e.g., PCR reaction products). This avoids the time and expense associated with cloning the segment of interest. However, specialized equipment and highly trained personnel are required for DNA sequencing, and the method is too laborintense and expensive to be practical and effective in the clinical setting. Web site: http://www.delphion.com/details?pn=US06709815__

Patent Applications on Mycobacterium Tuberculosis As of December 2000, U.S. patent applications are open to public viewing.9 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 Mycobacterium tuberculosis: •

32-kDa protein derived from Mycobacterium tuberculosis and related peptides Inventor(s): Content, Jean; (Rhode St Genese, BE), De Bruyn, Jacqueline; (Beersel, BE), De Wit, Lucas; (Puurs, BE), Van Vooren, Jean-Paul; (St-Pieters Leeuw, BE) Correspondence: Fish & Richardson PC; 225 Franklin ST; Boston; MA; 02110; US Patent Application Number: 20030225249 Date filed: December 23, 2002 Abstract: The invention relates to recombinant polypeptides and peptides and particularly to the polypeptide containing in its polypeptidic chain the following amino acid sequence: the one extending from the extremity constituted by nucleotide at position (1) to the extremity constituted by nucleotide at position (194) represented in FIG. 4a and FIG. 4b. The polypeptides and peptides of the invention can be used for the diagnostic of tuberculosis, and can also be part of the active principle in the preparation of vaccine against tuberculosis. Excerpt(s): The invention relates to recombinant polypeptides and peptides, which can be used for the diagnosis of tuberculosis. The invention also relates to a process for preparing the above-said polypeptides and peptides, which are in a state of biological

9

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

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purity such that they can be used as part of the active principle in the preparation of vaccines against tuberculosis. It also relates to nucleic acids coding for said polypeptides and peptides. Furthermore, the invention relates to the in vitro diagnostic methods and kits using the above-said polypeptides and peptides and to the vaccines containing the above-said polypeptides and peptides as active principle against tuberculosis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

A METHOD FOR PREPARING MASSIVELY RmlC PROTEIN AND PURIFIED RmlC PROTEIN OF MYCOBACTERIUM TUBERCULOSIS BY IT Inventor(s): Lee, Tae-Yoon; (Taegu-shi, KR) Correspondence: Merchant & Gould PC; P.O. Box 2903; Minneapolis; MN; 55402-0903; US Patent Application Number: 20030166234 Date filed: March 22, 2002 Abstract: This invention relates to a mass preparation method of RmlC protein and the purified RmlC protein by the said method. RmlC is a gene product of rmlC, which is one of the biosynthesis genes of rhamnose that is an important element that consists cell wall of Mycobacterium tuberculosis. To be more specific, this invention improves the following disadvantage of recombinant RmlC protein of Mycobacterium tuberculosis previously reported that contains unnecessary 15 amino acids into the natural RmlC protein. This invention relates to a recombinant plasmid, a recombinant E. coli that is transformed by the plasmid, preparation method of Mycobacterium tuberculosis RmlC recombinant protein using the recombinant E. coli, purification method of recombinant RmlC protein, and the RmlC protein purified by the said method. Excerpt(s): This invention relates to a mass preparation method of RmlC protein, a gene product of rmlC that is one of the genes synthesizing rhamnose, which is an important element that constitutes cell wall of Mycobacterium tuberculosis. To be more specific, this invention relates to an improvement of disadvantages such as expression efficiency reduction of RmlC protein for the development of anti-tuberculosis drug(s) because of the fusion of 15 unnecessary amino acids into Mycobacterium tuberculosis RmlC recombinant protein as reported previously (Stern R. J. et al. Microbiology 145:663671(1999)), problems of crystal formation because of the fusion of unnecessary amino acids when crystal of RmlC protein is formed, and extension of required time because of the fusion of unnecessary amino acids when the structure of RmlC protein is determined by X-ray crystallography. This method contains a recombinant plasmid that expresses RmlC protein itself without unnecessary amino acids and a method that can produce RmlC protein of Mycobacterium tuberculosis in large quantities that contains enzymatic activity of the corresponding RmlC protein, a recombinant E. coli transformed by the plasmid, a preparation method of Mycobacterium tuberculosis RmlC recombinant protein using E. coli, a purification method of recombinant RmlC protein prepared by said method, and the RmlC protein purified by said method. Approximately 1.7 billion people, 32% of the world population, are infected by tuberculosis. There are 8 million new patients every year and about 34% of them, 2.7 million, died from this serious disease. In Korea, it is estimated that there are approximately 0.7 million tuberculosis patients, 0.14 million new patients every year, and 4,000 people died from the disease. Therefore, tuberculosis remains as a serious health problem. Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis and currently the prevalence is increasing worldwide as a complication, of

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acquired immunodeficiency syndrome(AIDS). Also, many of the recent Mycobacterium tuberculosis has multiple-drug resistance that makes tuberculosis treatment more difficult. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Abundant extracellular products and methods for their production and use Inventor(s): Horwitz, Marcus A.; (Los Angeles, CA) Correspondence: Attn: Louis C. Cullman; Oppenheimer Wolff & Donnelly Llp; Suite 700; 840 Newport Center Drive; Newport Beach; CA; 92660; US Patent Application Number: 20030152584 Date filed: May 15, 2002 Abstract: Vaccines based on one or more combinations of majorly abundant extracellular products of pathogens and methods for their use and production are presented. The most prevalent or majorly abundant extracellular products of a target pathogen are selected irrespective of their absolute molecular immunogenicity and used as vaccines to stimulate a protective immune response in mammalian hosts against subsequent infection by the target pathogen. The majorly abundant extracellular products may be characterized and distinguished by their respective N-terminal amino acid or DNA sequences. As the vaccines may comprise different combinations of the extracellular products, subunits thereof, or encoding nucleic acids, a broad range of effective immunotherapeutic compositions are provided by the present invention. In addition to other infectious agents, the vaccines so produced can be used to stimulate an effective immune response against intracellular pathogens and in particular Mycobacterium tuberculosis. Excerpt(s): This application is a continuation-in-part of co-pending U.S. patent application Ser. No. 08/447,398 filed on May 23, 1995, which is a continuation-in-part of co-pending U.S. patent application Ser. No. 08/289,667 filed on Aug. 12, 1994, which is a continuation-in-part of co-pending U.S. patent application Ser. No. 08/156,358 filed on Nov. 23, 1993, all incorporated herein by reference. The present invention generally relates to immuno-therapeutic agents and vaccines against pathogenic organisms such as bacteria, protozoa, viruses and fungus. More specifically, unlike prior art vaccines and immunotherapeutic agents based upon pathogenic subunits or products which exhibit the greatest or most specific molecular immunogenicity, the present invention uses the most prevalent or majorly abundant immunogenic determinants released by a selected pathogen such as Mycobacterium tuberculosis to stimulate an effective immune response in mammalian hosts. Accordingly, the acquired immunity and immunotherapeutic activity produced through the present invention is directed to those antigenic markers which are displayed most often on infected host cells during the course of a pathogenic infection without particular regard to the relative or absolute immunogenicity of the administered compound. It has long been recognized that parasitic micro-organisms possess the ability to infect animals thereby causing disease and often the death of the host. Pathogenic agents have been a leading cause of death through-out history and continue to inflict immense suffering. Though the last hundred years have seen dramatic advances in the prevention and treatment of many infectious diseases, complicated host-parasite interactions still limit the universal effectiveness of therapeutic measures. Difficulties in countering the sophisticated invasive mechanisms displayed by many pathogenic vectors is evidenced by the resurgence of various

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diseases such as tuberculosis, as well as the appearance of numerous drug resistant strains of bacteria and viruses. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Agar medium for the growth of Mycobacterium tuberculosis Inventor(s): Heifets, Leonid; (Denver, CO), Sanchez, Tracy; (Lafayette, CO) Correspondence: Sheridan Ross PC; 1560 Broadway; Suite 1200; Denver; CO; 80202 Patent Application Number: 20040101926 Date filed: June 16, 2003 Abstract: A novel agar medium for the isolation, sub-cultivation, and indirect or direct drug-susceptibility testing of Mycobacterium tuberculosis is disclosed. Also disclosed are methods of isolating and growing Mycobacterium tuberculosis and methods of drug-resistance screening using the agar medium of the invention. Excerpt(s): This application claims the benefit of priority under 35 U.S.C.sctn. 119(e) from U.S. Provisional Application Serial No. 60/190,701, filed Mar. 20, 2000, and entitled "New Agar Medium For Mycobacterium tuberculosis". The entire disclosure of U.S. Provisional Application Serial No. 60/190,701 is incorporated herein by reference. This invention relates to a novel agar medium for the isolation, sub-cultivation, and indirect or direct drug-susceptibility testing of Mycobacterium tuberculosis. The invention also relates to methods of isolating and growing Mycobacterium tuberculosis and to methods of drug-resistance screening using the agar medium of the invention. At first glance, it seems that nothing is new in the cultivation of Mycobacterium tuberculosis. The first attempts of M. tuberculosis cultivation on agar medium go back to the report by Fannie and Walter Hesse in 1881. In 1882, Robert Koch used blood serum coagulated on glass slides for M. tuberculosis cultivation. Apparently, he was not too much concerned about the biosafety of such a procedure. He later improved this method, which was called the "plate technique", by adding peptone, some salts and glycerol. Also, in 1882, Richard Petri invented the petri dish to be used instead of a glass slide. These attempts at cultivation on a transparent type of media were interrupted in 1903 with introduction of the first egg-based media by Dorset (Dorset, Science. 17:374, 1903), followed by a variety of egg-based media recipes (American Trudeau Society, Handbook of Tuberculosis Laboratory Methods, Washington, D.C., 1962; IUAT, Bull Int Union Tuberc Lung Dis. 24:78, 1954; Jensen, Abteilung Originale. 125:222-239, 1932; Ogawa et al., Kekkaku. 24:13-29, 1949; Petragnani, Bollettino dell'Istituto sieroterapico Milanese. 5: 173-185, 1926; Petroff, J. Exp. Med. 21:38-42, 1915; Stonebrink, Acta Tuberc. Scand. 35:67-80, 1958). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Attenuated Mycobacterium tuberculosis vaccines Inventor(s): Bardarov, Stoyan; (Bronx, NY), Hsu, Tsungda; (Bronx, NY), Jacobs, William R.; (Pelham, NY), Sambandamurthy, Vasan; (Worcester, MA) Correspondence: Elie H. Gendloff; Craig J. Arnold; Alan D. Miller; Amster, Rothstein & Ebenstein; 90 Park Avenue; New York; NY; 10016; US Patent Application Number: 20040001866 Date filed: January 24, 2003 Abstract: Non-naturally occurring mycobacteria in the Mycobacterium tuberculosis complex are provided. These mycobacteria have a deletion of an RD1 region or a region controlling production of a vitamin, and exhibit attenuated virulence in a mammal when compared to the mycobacteria without the deletion. Also provided are nonnaturally occurring mycobacteria that have a deletion of a region controlling production of lysine, and mycobacteria comprising two attenuating deletions. Vaccines comprising these mycobacteria are also provided, as are methods of protecting mammals from virulent mycobacteria using the vaccines. Also provided are methods of preparing these vaccines which include the step of deleting an RD1 region or a region controlling production of a vitamin from a mycobacterium in the M. tuberculosis complex. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/358,152, filed Feb. 19, 2002. That application is incorporated by reference herewith in its entirety. The present invention generally relates to live bacterial vaccines. More specifically, the invention is related to novel Mycobacterium sp. compositions, and the use of those compositions to protect mammals against disease caused by virulent Mycobacterium sp. Abiko, Y. in Metabolic Pathways. D. M. Greenburg, Ed. (Academic Press, New York, 1975). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Biological materials and uses thereof Inventor(s): Coates, Anthony Robert Milnes; (Tooting London, GB) Correspondence: Sughrue Mion, Pllc; 2100 Pennsylvania Avenue, N.W.; Suite 800; Washington; DC; 20037; US Patent Application Number: 20040132163 Date filed: January 26, 2004 Abstract: The invention relates to pharmaceutical compositions of an approx 60kDa polypeptide (or its encoding nucleic acid molecules) or functionally equivalent molecules or fragments thereof from Mycobacterium tuberculosis or related prokaryotes in the treatment of non-cancerous pathological conditions such as autoimmune and allergic disorders. Excerpt(s): The present invention relates to the use of an approximately 60 kDa polypeptide (or its encoding nucleic acid molecule) or functionally equivalent molecules or fragments thereof from Mycobacterium tuberculosis or related prokaryotes in the prevention and/or treatment of non-cancerous conditions, such as autoimmune disorders, osteoporosis, allergic disorders or conditions of immunoactivation, particularly asthma, and/or conditions typified by a T helper lymphocyte 2 (Th2)-type immune response and/or conditions associated with eosinophilia and methods of stimulating the production of immune response mediators, e.g. cytokines, in vitro or in

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vivo. Autoimmunity reflects the loss of tolerance to "self" resulting in inappropriate destruction of normal cells or tissue. In many conditions, autoantibodies are found, but may reflect an effect rather than cause of a disease. In some diseases however autoantibodies are the first, major, or only detectable abnormality. One class of molecules which is implicated in this respect are the chaperonins which are highly immunogenic. Chaperonins belong to a group of proteins called molecular chaperones which bind non-native proteins and assist them, in an ATP-dependent catalytic process, to fold into the correct three-dimensional form required for a functional protein. Chaperonins are believed to stimulate the immune system at many levels simultaneously, including monocytes, macrophages, fibroblast-like cells, perhaps other types of cells, and T cells. The immune defences in mammals may be divided into the "innate" and "adaptive" defences. Those which are already in place, such as phagocytes, natural killer cells and complement are considered innate. On challenge, adaptive immunity is activated in the form of B and T lymphocytes. Chaperonins are known to act directly on the innate defence mechanisms, particularly on phagocytes. They also stimulate a powerful adaptive immune response, namely the production of antibody and the stimulation of T lymphocytes which in some cases may be protective. Notably they induce cytokine secretion which is thought to be important for host defences. In some cases however it is believed that the presence of chaperonins may be damaging to the host. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Compositions and methods for the prevention, treatment and detection of tuberculosis and other diseases Inventor(s): Leishman, Kathryn; (Los Angeles, CA) Correspondence: Heller Ehrman White & Mcauliffe Llp; 1666 K Street,nw; Suite 300; Washington; DC; 20006; US Patent Application Number: 20030108927 Date filed: October 7, 2002 Abstract: Methods and compositions are provided for the prevention and treatment of infectious diseases such as syphilis, tuberculosis, pneumonia, other bacterial infections, AIDS, and other viral infections. Many of the compositions are active against carbon monoxide dehydrogenase ("CODH"), and include substances such as antigens, antibodies specific for CODH, and other inhibitors of CODH such as nickel and molybdenum metal chelators. The methods and compositions are particularly suited for treatment of diseases from previously under recognized anaerobic or facultative anaerobic pathogens such as Mycobacterium tuberculosis and Mycobacterium pneumonia. Excerpt(s): This application is a continuation-in-part of U.S. Ser. No. 10/018,243, filed Dec. 18, 2001, which is a continuation of international application no. PCT/US00/16679, filed Jun. 19, 2000, which receives priority from provisional applications 60/206,518 filed May 22, 2000 and 60/194,766 filed Apr. 3, 2000. All prior applications are incorporated by reference in their entireties. This invention relates to compositions and methods for detecting, preventing and treating infectious diseases such as Mycobacterium tuberculosis ("M. TB"), M. pneumonia ("M. TP"), and to new classes of antibiotics effective against anaerobic and facultative anaerobic microorganisms. Treatment and prophylaxis of infectious diseases have been advanced tremendously by the discovery of antibiotics and vaccines. The discovery and implementation of antibiotics to kill

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bacteria has greatly increased human life span and the discovery of the role of the immune system in warding off and reversing viral disease has been exploited to great benefit by vaccination programs against those diseases. Despite those great successes, however, new modalities of action for antibiotics against the bacteria are needed in view of the development of resistance to those same antibiotics. At the same time, mankind's creativity and understanding of the molecular biology behind disease is challenged anew by the AIDS crisis. Despite almost two decades of intensive research there is still no cure for AIDS, though it appears that effective treatment for various infections, including HIV, that 30% , afflict AIDS patients prolongs their lives. Thus, modem society is faced with two major challenges: the prevention, treatment and detection of intractable disease such as tuberculosis, syphilis, and AIDS and the development of antibiotics that utilize new molecular modalities against bacteria that resist the old treatments. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Compositions and methods for treatment of infectious and inflammatory diseases Inventor(s): Ho, John L.; (New York, NY) Correspondence: Michael L. Goldman, ESQ.; Nixon & Peabody Llp; Clinton Square; P.O. Box 31051; Rochester; NY; 14603-1051; US Patent Application Number: 20030199012 Date filed: January 31, 2003 Abstract: The present invention relates to a nucleic acid construct having a nucleic acid molecule that encodes a factor suppressing an immune response to Mycobacterium tuberculosis in a host subject; an isolated antibody against the protein or polypeptide encoded by the nucleic acid molecule; and uses for the protein and its antibody, including in a method for detection of Mycobacterium tuberculosis in a sample of tissue or body fluids; a method of vaccinating a mammal against infection by Mycobacterium tuberculosis; a vaccine for preventing infection and disease of mammals by Mycobacterium tuberculosis and for actively immunizing mammals against Mycobacterium tuberculosis; and methods of treating inflammatory disease in mammals. Excerpt(s): This application claims the benefit of U.S. Provisional Patent Application Serial No. 60/353,985, filed Feb. 1, 2002. The present invention relates to compositions and methods for the detection, treatment, and prevention of Mycobacterium tuberculosis infection. Control of Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis (Th), is immune cell mediated as shown by humans without a functioning interferon gamma receptor (IFN-.lambda.R) or interleukin-12 receptor (IL12R) manifesting with disseminated mycobacteria disease (Dorman et al., "InterferonGamma and Interleukin-12 Pathway Defects and Human Disease," Cytokine Growth Factor Rev. 11(4):321-33 (2000); Jouanguy et al., "IL-12 and IFN-Gamma in Host Defense Against Mycobacteria and Salmonella in Mice and Men,"Curr. Opin. Immunol. 11(3):346-51 (1999); Altare et al., "Inherited Interleukin 12 Deficiency in a Child with Bacille Calmette-Guerin and Salmonella Enteritidis Disseminated Infection," J. Clin. Invest. 102(12):2035-40 (1998); Sakai et al., "Missense Mutation of the Interleukin-12 Receptor Beta 1 Chain-Encoding Gene is Associated with Impaired Immunity Against Mycobacterium avium Complex Infection," Blood 97(9):2688-94 (2001)). Moreover, immunosuppression by drugs, cancer, HIV-1 or immune senescence is associated with reactivation Tb, highlighting the fact that Mtb avoids immune elimination to establish

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life-long infection (Rook et al., "Advances in the Immunopathogenesis of Pulmonary Tuberculosis," Curr. Opin. Pulm. Med. 7(3):1 16-23 (2001); Flynn et al., "Immunology of Tuberculosis," Annu. Rev. Immunol. 19:93-129 (2001); Ho et al., "Defenses of the Lung Against Tuberculosis," in The Lung: Scientific Foundations, Crystal et al., eds., 2nd Edition, Chapter 183, pp. 2381-94 (1997); Vanham et al., "Examining a Paradox in the Pathogenesis of Human Pulmonary Tuberculosis: Immune Activation and Suppression/Anergy," Tuber. Lung Dis. 78(3-4):145-58 (1997); Ellner, "Regulation of the Human Immune Response During Tuberculosis," J. Lab. Clin. Med. 130(5):469-75 (1997)). This accounts for one in three persons worldwide having latent Mtb infection and a 5-10% lifetime risk of progression to active disease, translating to.about.8 million annual active Tb cases and.about.3 million annual deaths (Bishai, "The Mycobacterium tuberculosis Genomic Sequence: Anatomy of a Master Adaptor," Trends Microbiol. 6(12):464-5 (1998)). Genes present in Mtb but absent in non-pathogenic mycobacteria are proposed as virulence factors. However, which Mtb specific genes mediate rapid progression to disease or transit to latent infection, and how these genes function, remain poorly defined. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

CYCLOPROPYL CONTAINING DERIVATIVES THEREOF

OXAZOLIDINONE

ANTIBIOTICS

AND

Inventor(s): Fukuda, Yasumichi; (Oyama, JP) Correspondence: Mcdermott Will & Emery; 600 13th Street, N.W.; Washington; DC; 20005-3096; US Patent Application Number: 20030225107 Date filed: November 27, 2002 Abstract: This invention relates to new oxazolidinones having a cyclopropyl moiety, which are effective against aerobic and anerobic pathogens such as multi-resistant staphylococci, streptococci and enterococci, Bacteroides spp., Clostridia spp. species, as well as acid-fast organisms such as Mycobacterium tuberculosis and other mycobacterial species.The compounds are represented by structural formula I: 1its enantiomer, diastereomer, or pharmaceutically acceptable salt or ester thereof. Excerpt(s): This application claims priority from U.S. Provisional Application Serial No. 60/333,741, filed Nov. 29, 2001. Oxazolidinones represent the first new class of antibacterials to be developed since the quinolones. The oxazolidinones are synthetic antibacterial compounds that are orally or intravenously active against problematic multidrug resistant Gram positive organisms and are not cross-resistant with other antibiotics. See Riedl et al, Recent Developments with Oxazolidinone Antibiotics, Exp. Opin. Ther. Patents (1999) 9(5), Ford et al., Oxazolidinones: New Antibacterial Agents, Trends in Microbiology 196 Vol. 5, No. 5, May 1997 and WO 96/35691. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Desaturase antigen of Mycobacterium tuberculosis Inventor(s): Gicquel, Brigitte; (Paris, FR), Jackson, Mary; (Paris, FR) Correspondence: Finnegan, Henderson, Farabow, Garrett & Dunner; Llp; 1300 I Street, NW; Washington; DC; 20005; US Patent Application Number: 20040142332 Date filed: February 20, 2003 Abstract: The use of genetic methodology based on the fusion of the proteins with the alcaline phosphatase (Lim et al., 1995) has allowed the isolation of a new exported protein of M. tuberculosis. In the present article, first of all the isolation of a gene encoding this exported protein called DES is described as well as its characterization and its destribution among the different microbacterial species. It is notably shown that the protein has in its primary sequence amino acids only found at the level of active sites of enzymes of class II diiron-oxo proteins family. Among the proteins of this family, DES protein of M. tuberculosis does not present significative homologies with stearoyl ACP desaturases. Secondly, the antigenic feature of this protein has been studied. For this, DES protein of M. tuberculosis has been overexpressed in E. coli under recombinant and purified protein from from this bacterium. The reactivity of tuberculous patients sera infected by M. tuberculosis or M. bovis against DES protein in Western blot experimentations has been tested. 100% of the tested patients did recognize the protein. The intensity of the antibody response against DES protein measured by ELISA of tuberculous patients sera compared with the one relating to sera patients suffering from other pathologies show that there is a significative difference between the intensity of the antibody responses of these two categories of patients. Accordingly, DES protein is a potentially interesting tool for the tuberculosis serodiagnostic. Excerpt(s): Tuberculosis and leprosy, caused by the bacilli from the Mycobacterium tuberculosis complex and M. leprae respectively are the two major mycobacterial diseases. Pathogenic mycobacteria have the ability to survive within host phagocytic cells. From the interactions between the host and the bacteria results the pathology of the tuberculosis infection through the damages the host immune response causes on tissues (Andersen & Brennan, 1994). Alternatively, the protection of the host is also dependent on its interactions with mycobacteria. Identification of the bacterial antigens involved in these interactions with the immune system is essential for the understanding of the pathogenic mechanisms of mycobacteria and the host immunological response in relation to the evolution of the disease. It is also of great importance for the improvement of the strategies for mycobacterial disease control through vaccination and immunodiagnosis. Through the years, various strategies have been followed for identifying mycobacterial antigens. Biochemical tools for fractionating and analysing bacterial proteins permitted the isolation of antigenic proteins selected on their capacity to elicit B or T cell responses (Romain et al., 1993; Sorensen et al., 1995). The recent development of molecular genetic methods for mycobacteria (Jacobs et al., 1991; Snapper et al., 1990; Hatful, 1993; Young et al., 1985) allowed the construction of DNA expression libraries of both M. tuberculosis and M. leprae in the.lambda.gt11 vector and their expression in E. coli The screening of these recombinant libraries using murine polyclonal or monoclonal antibodies and patient sera led to the identification of numerous antigens (Braibant et al., 1994; Hermans et al., 1995; Thole & van der Zee, 1990). However, most of them turned out to belong to the group of highly conserved heat shock proteins (Thole & van der Zee, 1990; Young et al., 1990). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Detection of rpoB sequences of Mycobacterium tuberculosis Inventor(s): Brentano, Steven T.; (Santee, CA), Cleuziat, Philippe; (L'Isle D'Abeau, FR), Delgado, Francisco D.; (San Diego, CA), Jucker, Markus T.; (Poway, CA) Correspondence: Gen Probe Incorporated; 10210 Genetic Center Drive; San Diego; CA; 92121 Patent Application Number: 20030108921 Date filed: September 18, 2002 Abstract: A method of detecting rpoB sequences of Mycobacterium tuberculosis present in a biological sample that includes steps of amplifying the M. tuberculosis rpoB sequence in vitro in a nucleic acid amplification mixture that includes specific disclosed primer sequences, and detecting the amplified sequences using multiple probes that provide sequence information by their specific hybridization to portions of the amplified nucleic acid. Compositions for amplifying and detecting in vitro the rpoB sequences of M. tuberculosis in a sample are disclosed. Excerpt(s): This application claims the benefit of U.S. provisional application No. 60/323,485, filed Sep. 18, 2001, under 35 U.S.C. 119(e). This invention relates to in vitro diagnostic detection of pathogenic bacteria, and specifically relates to compositions and assays for detecting nucleic acid sequences associated with rifampin resistance of Mycobacterium Tuberculosis by using in vitro nucleic acid amplification of the rpoB gene and detection of amplified products. Rifampin (RIF), an antibiotic synthesized from rifamycin B, is a key component of drug therapy against Mycobacterium tuberculosis. Rifampin has a unique site of action on the beta subunit of prokaryotic RNA polymerase. In Escherichia coli, missense mutations and short deletions in the central region of the RNA polymerase subunit gene (rpoB) result in strains resistant to rifampin (Lisityn et al., 1984, Mol. Gen. Genet. 196 :173-174). Similarly, in M. tuberculosis a wide variety of mutations in the rpoB gene have been identified that confer rifampin resistance (Telenti et al., 1993, Lancet 341: 647-650). More than 90% of rifampin-resistant M. tuberculosis isolates are also resistant to isoniazid, and, therefore, rifampin resistance is a valuable surrogate marker for multiple drug resistance. Thus, there is a need for tests that can detect rapidly the genetic basis for rifampin resistance for diagnosis that leads to appropriate treatment of infected individuals. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Diagnosis kit for mycobacterium species indentification and drug-resistance detection and manufacturing method thereof Inventor(s): Kim, Hyung-Jung; (Gyonggi-do, KR), Kim, Jeong Mi; (Seoul, KR), Kim, Na Young; (Seoul, KR), Park, Mi Sun; (Busan, KR), Yoon, Sung Wook; (Seoul, KR) Correspondence: Frank Chau; F Chau & Associates; Suite 501; 1900 Hempstead Turnpike; East Meadow; NY; 11554; US Patent Application Number: 20040038233 Date filed: July 7, 2003 Abstract: The present invention relates to diagnosis kit for Mycobacterium species identification and drug-resistance detection and manufacturing method thereof, which can discriminate a Mycobacterium Tuberculosis rpoB gene point mutation relating to the Mycobacterium species identification and drug-resistance swiftly, exactly and in

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large quantities using an oligonucleotide chip. The diagnosis kit for Mycobacterium species identification and drug-resistance detection in accordance with the present invention consists of an oligonucleotide chip including a Mycobacterium tuberculosis complex probe, a Mycobacterium species identification probe and a drug-resistance detection probe of a Mycobacterium tuberculosis rpoB gene, and a fluorescent material containing a biotin-binding protein so as to detect hybridization of amplified products of a specimen marked as biotine and the corresponding probe. Excerpt(s): The present invention relates to a diagnosis kit for Mycobacterium species identification and drug-resistance detection and a manufacturing method thereof, and more specifically, to a diagnosis kit for Mycobacterium species identification and drugresistance detection in which point mutations of Mycobacterial rpoB gene related to the drug-resistance can be discriminated speedily and accurately in large quantity by using an oligonucleotide chip, and a manufacturing method thereof. About two million people die from tuberculosis worldwide each year. The increase in immigration, the spread of HIV/AIDS, and the emergence of drug-resistance strains are enhancing the mortality of tuberculosis. AIDS patients and newborns with weak immune system can develop tuberculosis from not only Mycobacterium tuberculosis infection but also MOTT (Mycobacterium other than tuberculosis) infection, particularly, Mycobacterium aviumintracellulare (MAI), Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium kansasaii, Mycobacterium xenopi, Mycobacterium marinum, Mycobacterium scrofulaceum, and Mycobacterium szulgai. Tuberculosis is normally treated by chemotherapy with various anti-tuberculosis drugs. Since there are numerous different strains of Mycobacteria with diverse drug-susceptibility, detection and identification of the causative bacterium is important for the effective treatment. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Halogenated antituberculosis agents Inventor(s): Kauffman, Joel M.; (Wayne, PA), Kobarfard, Farzad; (Philadelphia, PA) Correspondence: Ratner & Prestia; P.O. Box 7228; Wilmington; DE; 19803; US Patent Application Number: 20030114531 Date filed: September 9, 2002 Abstract: Halogenated derivatives of two synthetic anti-tuberculosis agents, thioacetazone and p-aminosalicylic acid, have been synthesized. In general, the halogenated compound has the structure of Structure I: 1wherein X.sub.1 is a halogen and X.sub.2 is a second halogen or hydrogen, and Y is sulfur or oxygen; or,has the structure of Structure IV: 2wherein X.sub.1 is a halogen and X.sub.2 is a second halogen or hydrogen. Alternatively, the halogenated compounds may be pharmaceutically acceptable salts of these compounds. These halogenated derivatives possess antimycobacterial activity and are particularly useful for the treatment of Mycobacterium tuberculosis infections. In particular, fluorinated analogs of thioacetazone and p-aminosalicylic acid have been synthesized for use as anti-tuberculosis therapeutic agents either alone or in combination with other conventional anti-tuberculosis therapeutic agents. Excerpt(s): This invention relates generally to the field of therapeutic agents that have anti-mycobacterial activity. More particularly, this invention relates to halogenated compounds that have anti-Mycobacterium tuberculosis activity, therapeutic agents for treating tuberculosis and methods of treating tuberculosis. Tuberculosis is the oldest documented infectious disease, and it remains an important global health problem. An

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estimated 1 billion people worldwide are infected with Mycobacterium tuberculosis; 8 to 10 million new tuberculosis cases occur each year, and the number of new cases is estimated to increase to 12 million in the year 2005. Inadequacy of diagnosis and prevention in addition to inefficient treatment programs account for uncontrolled infection in developing countries. Therapies exist to treat tuberculosis, however tuberculosis is not entirely cured by present drug treatments. Current drugs can minimize relapse rates with optimal treatment. With the best available chemotherapy, tubercle bacilli are slowly disposed of or killed. The widespread use of some drugs, such as isoniazid, has resulted in the development of resistant strains such that current drugs fail to eradicate some Mycobacterial infections. Therefore new drugs with antimycobacterial action are essential to successfully treat tuberculosis infections. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Human T cell response to MHC-binding motif clusters Inventor(s): Groot, Anne De; (Providence, RI) Correspondence: Mintz Levin; One Financial Center; Boston; MA; 02111; US Patent Application Number: 20020192233 Date filed: November 9, 2001 Abstract: The invention provides Mycobacterium tuberculosis (Mtb) vaccine candidate peptides. The invention also provides a method for identifying Mtb vaccine candidate peptides as well as vaccines comprising these Mtb candidate peptides. Excerpt(s): This application is a continuation of U.S. Ser. No. 09/813,333, filed Mar. 20, 2001, which claims priority to U.S. Ser. No. 60/190,834, filed Mar. 20, 2000, both of which are incorporated herein by reference in their entireties. This invention relates generally to vaccines and to computer-based algorithms used to predict epitopes. The reemergence of tuberculosis as a public health issue, particularly Mycobacterium tuberculosis (Mtb) superinfection of Human Immunodeficiency Virus (HIV)- infected individuals, has prompted the need for improvements in vaccination. Recognition of and response to Mycobacterium tuberculosis protein antigens by CD4+ T cells requires the intracellular processing of these antigens, and the subsequent presentation of the derived peptides by class II major histocompatability complex (MHC) molecules at the surface of antigen presenting cells (APC). To identify these T-cell epitopes, the standard approach has been to synthesize overlapping peptides spanning the entire sequence of a given protein antigen. These peptides are then tested for their capacity to stimulate T cell proliferative responses in vitro, using cells from Mtb immune individuals. Although this overlapping peptide method is thorough, it is both cost- and labor-intensive. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Hybrids of M. tuberculosis antigens Inventor(s): Andersen, Peter; (Bronshoj, DK), Olsen, Anja Weinreich; (Soborg, DK), Rasmussen, Peter Birk; (Frederiksberg, DK), Skjot, Rikke Louise Vinther; (Hedehusene, DK) Correspondence: Thomas J. Kowalski; C/o Frommer Lawrence & Haug Llp; 745 Fifth Avenue; New York; NY; 10151; US Patent Application Number: 20020176867 Date filed: March 13, 2001 Abstract: The present invention discloses fusion proteins of the immunodominant antigens ESAT-6 and Ag85B from Mycobacterium tuberculosis or homologues thereof, and a tuberculosis vaccine based on the fusion proteins, which vaccine induces efficient immunological memory. Excerpt(s): This application is a continuation-in-part of U.S. Ser. No. 09/246,191, filed Dec. 30, 1998, which claims priority from U.S. provisional application No. 60/070,488, filed Jan. 5, 1998. Reference is also made to: the concurrently-filed US application of Andersen et al., Ser. No. ______(attorney docket 670001-2002.4); U.S. application Ser. No. 09/289,388 filed Apr. 12, 1999, which is a continuation of U.S. application Ser. No. 08/465,640 filed Jun. 5, 1995, now U.S. Pat. No. 5,955,077, issued Sep. 21, 1999, which is a continuation-in-part of U.S. Ser. No. 08/123,182 filed Sep. 20, 1993, now abandoned, and a continuation-in-part of PCT/DK94/00273, filed Jul. 1, 1994, published as WO95/01441, and claiming priority from Danish application 0798/93, filed Jul. 2, 1993; U.S. application Ser. No. 09/050,739 filed Mar. 30, 1998, which is claims priority from U.S. provisional application Ser. No. 60/044,624 filed Apr. 18, 1997; Andersen et al., application Ser. No. 09/791,171, filed Feb. 20, 2001, as a divisional of U.S. application Ser. No. 09/050,739; and commonly-owned U.S. Patent No. 6,120,776. Each of these patents, patent applications and patent publications, as well as all documents cited in the text of this application, and references cited in the documents referred to in this application (including references cited in the aforementioned patents, patent applications and patent publications or during their prosecution) are hereby incorporated herein by reference. The present application discloses new fusion proteins of the immunodominant antigens ESAT-6 and Ag85B from Mycobacterium tuberculosis or homologues thereof, and a tuberculosis subunit vaccine comprising at least one fusion protein. The vaccine induced efficient immunological memory. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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IS6110 based molecular detection of Mycobacterium tuberculosis Inventor(s): Dattagupta, Nanibhushan; (San Diego, CA), Hwang, I-Shiou; (San Diego, CA) Correspondence: Laurie A. Axford; Morrison & Foerster Llp; Suite 500; 3811 Valley Centre Drive; San Diego; CA; 92130; US Patent Application Number: 20030219757 Date filed: May 24, 2002 Abstract: This invention relates generally to Mycobacterium tuberculosis complex (TBC) detection. More specifically, the present invention provides for novel IS6110 probes for a direct, specific and sensitive diagnostic test of tuberculosis (TB). These

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probes hybridize with the IS6110 DNA sequence that is believed to be present only in the Mycobacterium tuberculosis complex (TBC). Arrays comprising the novel IS6110 probes immobilized on a support for hybridization analysis and methods for TBC detection using the probes or arrays of immobilized probes are also provided. Excerpt(s): This invention relates generally to Mycobacterium tuberculosis complex (TBC) detection. More specifically, the present invention provides for novel IS6110 probes for a specific and sensitive diagnostic test of tuberculosis (TB). These probes hybridize with the IS6110 DNA sequence that is believed to be present only in the Mycobacterium tuberculosis complex (TBC). Arrays comprising the novel IS6110 probes immobilized on a support for hybridization analysis and methods for TBC detection using the probes are also provided. Tuberculosis (TB) is one of the most deadly and common infectious diseases and claims three million lives a year worldwide. Although the disease is found mostly in developing countries, a growing number of cases are diagnosed in industrialized countries. The causative agent of TB-Mycobacterium tuberculosis (Mtb)--is a slow-growing pathogen and is among the most recalcitrant in terms of clinical treatment. It is one of the Mycobacterium species in the TBC, which is a term used to refer to the species of Mycobacterium associated with TB. The other such species are M. bovis, M. bovis-BCG, M. africanum, and M. microti. In addition, a deadly partnership is forged between Mtb and Human Immunodeficiency Virus (HIV). An increased susceptibility to TB is associated with early stages of HIV infection, and TB in turn accelerates the progression to Acquired Immunodeficiency Syndrome (AIDS). The increased incidence of TB, especially in patients suffering with AIDS, makes early detection of Mtb crucial among these patients to provide for prompt treatment and cost-effective management to control the disease(s). One reliable method of TB diagnosis is based on culturing M tuberculosis from the clinical specimen and identifying it morphologically and biochemically. This usually takes anywhere from three to six weeks, during which time a patient may become seriously ill and infect other individuals. Therefore, a rapid test capable of reliably detecting the presence of M. tuberculosis is vital for early detection and treatment. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for detecting a Mycobacterium tuberculosis specific intein and use in diagnosis of tuberculosis Inventor(s): Daffe, Mamadou; (Toulouse, FR), Laneelle, Marie-Antoinette; (VigouletAuzil, FR), Lefevre, Fabrice; (Nimes, FR), Masson, Jean-Michel; (Toulouse, FR), Saves, Isabelle; (Saint Loup Cammas, FR) Correspondence: Young & Thompson; 745 South 23rd Street 2nd Floor; Arlington; VA; 22202 Patent Application Number: 20040137511 Date filed: January 24, 2003 Abstract: The invention concerns a method for detecting and/or quantifying Mycobacterium tuberculosis in a sample, characterised in that it consists in detecting in said sample the presence of an intein inserted at a site whereof the location is Mycobacterium tuberculosis specific using a reagent specific to said location, and optionally in quantifying the detected signal. Excerpt(s): The present invention relates to the detection of Mycobacterium tuberculosis for the purpose of diagnosing tuberculosis in a patient. The detection

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method of the invention is based on searching, in a biological sample from a patient, for an intein specific for Mycobacterium tuberculosis. The invention also relates to a kit for carrying out said method. Mycobacterium tuberculosis is a strict pathogen of humans also capable of infecting some animal species which live alongside them. It constitutes the agent responsible for human tuberculosis. Infection, mainly aerial, most commonly manifests itself through a pulmonary infection. Tuberculosis is one of the infections which causes most deaths, and it has been reported that the number of deaths increases each year by 10% (Bloom and Murray, Science (1992), 257, 1055-64). Tuberculosis poses a public health problem since not only have a large number of children in developing countries already been infected, or will be before reaching an adult age, but tuberculosis is also one of the opportunistic infections developed by immunodepressed individuals such as individuals suffering from Aids. Moreover, many strains of Mycobacterium tuberculosis exhibit resistance to various antibiotics (Shankar et al., Lancet (1990), 335, 423-42), which makes treatment all the more difficult. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for identifying Mycobacterium tuberculosis and mycobacteria other than tuberculosis, together with detecting resistance to an antituberculosis drug of mycobateria obtained by mutation of rpoB gene Inventor(s): Bai, Gill-Han; (Seongnam-shi, KR), Bang, Hye Eun; (Seoul, KR), Cho, SangNae; (Seoul, KR), Kim, Sang-Jae; (Seoul, KR), Lee, Hyeyoung; (Seoul, KR) Correspondence: Powell Goldstein Frazer & Murphy Llc; PO Box 97223; Washington; DC; 20090-7223; US Patent Application Number: 20030108881 Date filed: January 30, 2002 Abstract: The present invention provides a method for identifying Mycobacterium tuberculosis and non-tuberculosis Mycobacterium (MOTT), and for the determination of drug susceptibility of M. tuberculosis based on detection of mutations in the rpoB gene. Excerpt(s): This application claims priority to the foreign application KR 2001-43450 filed Jul. 19, 2001. The present invention relates to a method for identifying Mycobacterium tuberculosis (hereinafter, referred to as `M. tuberculosis`) and Mycobacterium Other Than Tuberculosis (hereinafter, referred to as `MOTT`), and for the determination of resistance of M. tuberculosis to an antituberculosis drug obtained by the mutation of the rpoB gene. Tuberculosis is a chronic wasting disease caused by M. tuberculosis. Worldwide, it ranks the first in mortality and morbidity among infectious diseases (Global Tuberculosis Programme. Global Tuberculosis Control, WHO Report 1997. World Health Organization, 1997). Carriers of M. tuberculosis presently number about 1.9 billion, a third of the world population, and about 8-10 million of these carriers develop into new tuberculosis patients per year, and about 3 million of patients die of tuberculosis per year (Dolin P. J., Raviglion M. C., Kochi, A. (1994) Global tuberculosis incidence and mortality during 1990-2000. Bull World Health Organization. 72(2): 213-220; Kochi, A. (1992) The global tuberculosis situation and the new control strategy of the World Health Organization. Tubercle. SCI. 72:1-6; Styblo K. Epidemiology of Tuberculosis the Hague, Royal Netherland Tuberculosis Association (1991), p. 83 in: Minister of Health and Welfare, The Korean National Tuberculosis Association. Measures for Tuberculosis Control in 2000s, p5, 1997). Also, about a half of the population in Korea are carriers of M. tuberculosis, and about 150,000 persons

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develop into new tuberculosis patients per year, and about 14,000 patients per year die of tuberculosis (Sreevatsan S. Stockbauer K E, Pan X, Kreiswirth B N, Mogha S L, Jacobs W R Jr, Telenti A, Musser J M. (1997) Ethambutol resistance in M. tuberculosis: critical role of embB mutations. Antimicrob Agents Chemother 41:1677-1681). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for isolating a polynucleotide of interest from the genome of a mycobacterium using a BAC-based DNA library: application to the detection of mycobacteria Inventor(s): Billault, Alain; (Roissy-en-Brie, FR), Buchrieser-Brosch, Roland; (Paris, FR), Cole, Stewart; (Clamart, FR), Gordon, Stephen; (Paris, FR) Correspondence: Finnegan, Henderson, Farabow,; Garrett And Dunner, L.L.P.; 1300 I Street, N.W.; Washington; DC; 20005-3315; US Patent Application Number: 20030198974 Date filed: September 30, 2002 Abstract: A method for isolating a polynucleotide of interest that is present in the genome of a first mycobacterium strain and/or is expressed by the first mycobacterium strain, where the polynucleotide of interest is also absent or altered in the genome of a second mycobacterium strain and/or is not expressed in the second mycobacterium. The method includes (a) contacting the genomic DNA of the first mycobacterium strain under hybridizing conditions with the DNA of a least one clone that belongs to a bacterial artificial chromosome (BAC) genomic DNA library of the second mycobacterium strain, and (b) isolating the polynucleotide of interest that does not form a hybrid with the DNA of the second mycobacterium strain. This invention further pertains to a Mycobacterium tuberculosis strain H37Rv genomic DNA library, as well as a Mycobacterium bovis BCG strain Pasteur genomic DNA library, and the recombinant BAC vectors that belong to those genomic DNA libraries. This invention also relates to mycobacterial nucleic acids, and methods and kits for using these nucleic acids to detect mycobacteria in a biological sample. Excerpt(s): The present invention pertains to a method for isolating a polynucleotide of interest that is present in the genome of a mycobacterium strain and/or is expressed by said mycobacterium strain and that is absent or altered in the genome of a different mycobacterium strain and/or is not expressed in said different mycobacterium strain, said method comprising the use of at least one clone belonging to a genomic DNA library of a given mycobaterium strain, said DNA library being cloned in a bacterial artificial chromosome (BAC). The invention concerns also polynucleotides identified by the above method, as well as detection methods for mycobacteria, particularly Mycobacterium tuberculosis, and kits using said polynucleotides as primers or probes. Finally, the invention deals with BAC-based mycobacterium DNA libraries used in the method according to the invention and particularly BAC-based Mycobacterium tuberculosis and Mycobacterium bovis BCG DNA libraries. Radical measures are required to prevent the grim predictions of the World Health Organisation for the evolution of the global tuberculosis epidemic in the next century becoming a tragic reality. The powerful combination of genomics and bioinformatics is providing a wealth of information about the etiologic agent, Mycobacterium tuberculosis, that will facilitate the conception and development of new therapies. The start point for genome sequencing was the integrated map of the 4.4 Mb circular chromosome of the widelyused, virulent reference strain, M. tuberculosis H37Rv and appropriate cosmids were

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subjected to systematic shotgun sequence analysis at the Sanger Centre. Cosmid clones (Balasubramanian et al., 1996; Pavelka et al., 1996) have played a crucial role in the M. tuberculosis H37Rv genome sequencing project. However, problems such as underrepresentation of certain regions of the chromosome, unstable inserts and the relatively small insert size complicated the production of a comprehensive set of canonical cosmids representing the entire genome. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for treatment of bacterial infections with once or twice-weekly administered rifalazil Inventor(s): Montgomery, Alan B.; (Bellevue, WA), Porubek, David J.; (Seattle, WA), Rose, Lynn M.; (Seattle, WA) Correspondence: Hana Verny; Peters, Verny, Jones & Schmitt Llp; Suite 6; 385 Sherman Avenue; Palo Alto; CA; 94306; US Patent Application Number: 20030203903 Date filed: September 14, 2002 Abstract: A method for treatment of bacterial infections with rifalazil administered onceweekly, or twice-weekly. A method for treatment of tuberculosis caused by Mycobacterium tuberculosis, infections caused by Mycobacterium avium complex, infections caused by Chlamydia pneumoniae and infections caused by Helicobacter pylori by administering to a patient suffering from the bacterial infection 1-100 mg of rifalazil once or twice a week. In this dose regimen, the treatment is fast, efficacious and eliminates undesirable secondary symptoms observed with daily doses of 1-50 mg of rifalazil. Excerpt(s): This application is based on and claims priority of Provisional Application Serial No. 60/112,921 filed on Dec. 18, 1998. The current invention concerns a method for treatment of bacterial infections with rifalazil administered once-weekly or twiceweekly. In particular, the invention concerns a method for treatment of tuberculosis caused by Mycobacterium tuberculosis, infections caused by Mycobacterium avium complex, infections caused by Chlamydia pneumoniae and infections caused by Helicobacter pylori by administering to a patient suffering from the bacterial infection rifalazil once or twice a week. In this dose regimen, the treatment is fast, efficacious and eliminates undesirable secondary symptoms observed with daily doses of 1-50 mg of rifalazil. Bacterial infection caused by mycobacterium species and similar infections caused by Chlamydia pneumoniae or H. pylori cause serious health problems in the United States and worldwide. For example, tuberculosis, caused by Mycobacterium tuberculosis is one of the most serious infectious diseases outside of developed countries, with over one billion people infected worldwide. The worldwide infection rate results in eight million active tuberculosis cases annually and over two million deaths per year. In the United States, 26,000 new cases of active tuberculosis were reported in 1994. The number of active cases in the United States is high because of the increase in patients with AIDS and the increase in immigration from developing countries. Moreover, there is reported an increase in multidrug resistance tuberculosis and disseminated Mycobacterium avium complex infections. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Methods of diagnosing multidrug resistant tuberculosis Inventor(s): Barry, Clifton E. III; (Bethesda, MD), Bekker, Linda-Gail; (New York, NY), DeBarber, Andrea E.; (Rockville, MD), Mdluli, Khisimuzi; (Seattle, WA) Correspondence: Townsend And Townsend And Crew, Llp; Two Embarcadero Center; Eighth Floor; San Francisco; CA; 94111-3834; US Patent Application Number: 20030013090 Date filed: June 22, 2001 Abstract: The invention relates to the discovery that a putative gene of Mycobacterium tuberculosis with no previously identified function is responsible for the ability of the bacterium to activate thioamide drugs. Since M. tuberculosis has a low rate of synonymous mutations, all mutations in this gene, identified as Rv3854c and now termed "EtaA," are expected to inhibit the ability of a bacterium with the mutation to activate a thioamide or thiocarbonyl drug. Thus, detecting a bacterium with a mutation in this gene indicates that the bacterium is resistant to treatment with thioamides. Excerpt(s): This application claims priority from U.S. Provisional Application Ser. No. 60/214,187, filed Jun. 26, 2000, the contents of which are incorporated by reference for all purposes. The World Health Organization ("WHO") estimates that as much as onethird of the world's population is infected with tuberculosis. In 1998, the latest year for which estimates are available, Mycobacterium tuberculosis ("MTb") infected 7.25 million people and resulted in 2.9 million fatalities (Farmer, P. et al., Int J Tuberc Lung Dis 2:869 (1998)). Underlying these statistics is an emerging epidemic of multiple drugresistant ("MDR") tuberculosis that severely undermines control efforts and is transmitted indiscriminately across national borders (Viskum, K. et al., Int J Tuberc Lung Dis 1:299 (1997); Bass, J. B. et al., Am J Respir Crit Care Med 149:1359 (1994)). Resistance to any of the front-line drugs generally bodes poorly for the patient, who then is committed to a regimen of less active "second-line" therapies. Where multidrug resistance is suspected, the WHO recommends that three or more drugs be administered at the same time, to decrease the chance that the organism will be able to develop resistance to all of the agents. One of the most efficacious of the second-line drugs is the thioamide ethionamide (ETA) (Farmer, P. et al., supra). Like the front-line drug, isoniazid (INH), ETA is specific for mycobacteria and is thought to exert a toxic effect on mycolic acid constituents of the cell wall of the bacillus (Rist, N. Adv Tuberc Res 10:69 (1960); Banerjee, A. et al., Science 263:227 (1994)). Current tuberculosis therapies include a large number of "prodrugs" that must be metabolically activated to manifest their toxicity upon specific cellular targets (Barry, C. B., III et al., Biochem Pharm 59:221 (2000)). The best characterized example of this is the activation of INH by the catalaseperoxidase KatG, generating a reactive form that then inactivates enzymes involved in mycolic acid biosynthesis (Slayden, R. A. et al., Microbes and Infection (2000) (in press); Heym, B. et al., Tubercle Lung Dis 79:191 (1999)). The majority of clinically observed INH resistance is associated with the loss of this activating ability by the bacillus (Musser, J. M., Clin Microbiol Rev 8:496 (1995)), but such strains typically retain their sensitivity toward ETA, suggesting that ETA activation requires a different enzyme than KatG (Rist, N., Adv. Tub. Res. 10, 69 (1960)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Mucosal microparticle conjugate vaccine Inventor(s): Sjoholm, Ingvar; (Uppsala, SE), Wikingsson, Lena Degling; (Spanga, SE) Correspondence: Burns, Doane, Swecker & Mathis, L.L.P.; P.O. Box 1404; Alexandria; VA; 22313-1404; US Patent Application Number: 20030211122 Date filed: June 12, 2003 Abstract: Mucosal, particularly oral, microparticle conjugate vaccines against certain pathogenic microorganisms, especially intracellular pathogenic microorganisms, are disclosed. An immunizing component of such a vaccine comprises protectiongenerating antigens derived from a certain pathogenic microorganism, such as Mycobacterium tuberculosis or Salmonella enteritidis, conjugated, possibly via a linker, to biodegradable microparticles, particularly starch microparticles, such as cross-linked starch microparticles, e.g. polyacryl starch microparticles. Further, a method of inducing protective immunity against a certain pathogenic microorganism in a mammal, and the use of protection-generating antigens derived from a certain pathogenic microorganism conjugated, possibly via a linker to biodegradable microparticles for the production of a mucosal microparticle conjugate vaccine are described. Excerpt(s): The present invention relates to microparticle conjugate vaccines for mucosal, e.g. oral, administration to a mammal, including man. The vaccines are directed against a certain pathogenic microorganism, particularly an intracellular microorganism, such as Mycobacterium tuberculosis or Salmonella enteritidis. The invention also relates to a method of inducing protective immunity against such a microorganism, and to the use of protection-generating antigens derived from such a microorganism conjugated to biodegradable microparticles, for the production of the vaccines. Generally, vaccines today are formulated for parenteral administration. Only a few vaccines are used orally and then for specific purposes. Thus, oral cholera vaccines are intended to produce antibodies against the B-subunit CTB of the cholera toxin, causing diarrhea of the infected person, by disrupting the salt and water balance over the gut wall. The antibodies are supposed to inhibit the binding of the toxin via the CTB unit to a specific receptor (the GM1 receptor) in the epithelial wall. Moreover, some vaccines containing attenuated polio virus, with disputed efficacy, are approved to be used in some countries. However, no carrier system for oral use with isolated antigens has yet been approved for use in humans. There are some obvious advantages with oral vaccines. They are easier to use than parenteral ones, as the administration does not require professional personnel, like nurses, and an oral administration avoids the stress caused by an injection, particularly in children. In addition, the manufacture of an oral product is easier and thereby cheaper than for a sterile, parenteral product. More important though, are the potentially improved effects of an oral vaccination over a parenteral one in newborns, where the immune system in the mucosal and gut regions develop earlier than in other parts of the body, where the parenteral vaccines are active. Also for elderly people the mucosal response is probably better after oral vaccination. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Mutant mycobacteria for use in therapy Inventor(s): Boettger, Eric; (Zurich, CH), Colston, Jo; (London, GB), Colston, Kay; (Surrey, GB), Sander, Peter; (Zurich, CH), Springer, Burkhard; (Zurich, CH) Correspondence: Nixon & Vanderhye, PC; 1100 N Glebe Road; 8th Floor; Arlington; VA; 22201-4714; US Patent Application Number: 20040057966 Date filed: October 15, 2003 Abstract: This invention relates to recA mutant mycobacteria, particularly mutants of mycobacterial species which are members of the Mycobacterium tuberculosis complex, such as M. bovis BCG and M. tuberculosis. These mutant mycobacteria are useful as immunotherapteutic agents and vaccines for the treatment of a range of disorders, including tuberculosis. Excerpt(s): This invention relates to Mycobacterium mutants, particularly mutants of mycobacterial species which are members of the Mycobacterium tuberculosis complex, such as M. bovis BCG and M. tuberculosis which are useful as immunotherapeutic agents, vaccines, or carriers for use in generating new vaccines. Such agents are useful in the treatment of a range of disorders, including tuberculosis. Infection with M. tuberculosis is a major cause of human morbidity and mortality. Despite many efforts in mycobacterial genetics little is known about its virulence factors and mechanisms of pathogenicity. Mycobacterium bovis BCG is a member of the M. tuberculosis complex which is used as live vaccine against M. tuberculosis infection and has been administered to more than a billion people world-wide (Cohn, D. L. (1997) Am. J. Med. Sci. 6: 372-376, Cohn, M. L. et al (1954) Am. Rev. Tuberc. 70: 641-664). BCG has also been used as a non-specific immunotherapeutic agent in cancer treatment (Nseyo, U. O., and Lamm, D. L. (1997) Semin. Surg. Oncol. 13: 342-349; Patard, J. J. et al (1998). Urol. Res. 26: 155-159). Non-virulent strains of M. tuberculosis have also developed for use as vaccines. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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MYCOBACTERIAL RPOB SEQUENCES Inventor(s): DREUKOW, JORG; (HOLLISTER, CA), GINGERAS, THOMAS; (SANTA CLARA, CA) Correspondence: Morgan Lewis & Bockius Llp; 1111 Pennsylvania Avenue, N.W.; Washington; DC; 20004; US Patent Application Number: 20020187467 Date filed: April 2, 1999 Abstract: This invention provides polynucleotide probes, sequences and methods for speciating and phenotyping organisms, for example, using probes based on the Mycobacterium tuberculosis rpoB gene. The groups or species to which an organism belongs may be determined by comparing hybridization patterns of target nucleic acid from the organism to hybridization patterns in a database. Excerpt(s): This application derives priority from U.S. Ser. No. 60/080,616, filed Apr. 3, 1999, and incorporated by reference. Applications U.S. Ser. No. 08/797,812, filed Feb. 7, 1997, U.S. Ser. Nos. 60/011,339, filed Feb. 08, 1996; 60/012,631, filed Mar. 01, 1996; 08/629,031, filed Apr. 08, 1996; and 60/017,765, filed May 15, 1996 are directed to related

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subject matter. These applications are specifically incorporated by reference in their entirety for all purposes. This invention is directed to polymorphisms in rpoB genes of mycobacteria and use of the same in the identification and characterization of microorganisms. Multidrug resistance and human immunodeficiency virus (HIV-1) infections are factors which have had a profound impact on the tuberculosis problem. An increase in the frequency of Mycobacterium tuberculosis strains resistant to one or more anti-mycobacterial agents has been reported, Block, et al., (1994) JAMA 271:665671. Immunocompromised HIV-1 infected patients not infected with M. tuberculosis are frequently infected with M. avium complex (MAC) or M. avium-M. intracellulare (MAI) complex. These mycobacteria species are often resistant to the drugs used to treat M. tuberculosis. These factors have re-emphasized the importance for the accurate determination of drug sensitivities and mycobacteria species identification. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Mycobacterium tuberculosis DNA sequences encoding immunostimulatory peptides and methods for using same Inventor(s): Nano, Francis E.; (Victoria, CA) Correspondence: Klarquist Sparkman, Llp; One World Trade Center, Suite 1600; 121 SW Salmon Street; Portland; OR; 97204; US Patent Application Number: 20030049263 Date filed: November 28, 2001 Abstract: Nucleotide sequences isolated from Mycobacterium tuberculosis are disclosed. These sequences encode immunostimulatory peptides. Also disclosed are vaccine preparations formulated using these peptides. Excerpt(s): This application is a continuation-in-part of co-pending U.S. application No. 08/990,823, filed Dec. 15, 1997, which is incorporated herein by reference. The 08/990,823 application claims priority from PCT application No. U.S. 96/10375, filed Jun. 14, 1996, which claims priority from U.S. Provisional application No.60/000,254, filed Jun. 15, 1995, all of which are incorporated herein by reference. Over the past few years the editors of the Morbidity and Mortality Weekly Report have chronicled the unexpected rise in tuberculosis cases. It has been estimated that one billion people are infected with M. tuberculosis worldwide, with 7.5 million active cases of tuberculosis. Even in the United States, tuberculosis continues to be a major problem especially among the homeless, Native Americans, African-Americans, immigrants, and the elderly. HIV-infected individuals represent the newest group to be affected by tuberculosis. Of the 88 million new cases of tuberculosis expected in this decade, approximately 10% will be attributable to HIV infection. The emergence of multi-drug resistant strains of M. tuberculosis has complicated matters further and even raises the possibility of a new tuberculosis epidemic. In the U.S. about 14% of M. tuberculosis isolates are resistant to at least one drug, and approximately 3% are resistant to at least two drugs. M. tuberculosis strains have even been isolated that are resistant to all seven drugs in the repertoire of drugs commonly used to combat tuberculosis. Resistant strains make treatment of tuberculosis extremely difficult: for example, infection with M. tuberculosis strains resistant to isoniazid and rifampin leads to mortality rates of approximately 90% among HIV-infected individuals. The mean time to death after diagnosis in this population is 4-16 weeks. One study reported that, of nine immunocompetent health care workers and prison guards infected with drug-resistant

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M. tuberculosis, five died. The expected mortality rate for infection with drug-sensitive M. tuberculosis is 0%. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Mycobacterium tuberculosis superoxide dismutase Inventor(s): Lee, Fang-Jen S.; (Taipei, TW), Wu, Chung-Hsiun H.; (Taipei, TW) Correspondence: Fish & Richardson PC; 225 Franklin ST; Boston; MA; 02110; US Patent Application Number: 20030219443 Date filed: January 17, 2003 Abstract: The invention relates to Mycobacterium tuberculosis superoxide dismutase antibodies, methods of using them for detection of M. tuberculosis, methods of testing for an inhibitor of an M. tuberculosis superoxide dismutase, and methods of detecting tuberculosis infection. Excerpt(s): This application claims priority from U.S. Provisional Application Serial No. 60/108,309, filed Nov. 13, 1998, now abandoned. Superoxide dismutase catalyzes the conversion of superoxide radicals (O.sub.2.sup.-) into molecular oxygen (O.sub.2) and hydrogen peroxide (H.sub.2O.sub.2). The conversion of superoxide radicals is generally beneficial to a cell, since such molecules can react with the cell's genomic DNA to induce mutations. Superoxide dismutases (SOD) have been classified based on the inorganic atoms they require for activity. Three SOD families have been identified: those requiring manganese (MnSOD), those requiring iron (FeSOD), and those requiring copper and zinc (Cu, ZnSOD). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Novel peroxiredoxin defense system from Mycobacterium tuberculosis Inventor(s): Bryk, Ruslana; (New York, NY), Lima, Christopher D.; (New York, NY), Nathan, Carl F.; (Larchmont, NY) Correspondence: Michael L. Goldman, ESQ.; Nixon Peabody Llp; Clinton Square; P.O. Box 31051; Rochester; NY; 14603-1051; US Patent Application Number: 20030190325 Date filed: January 15, 2003 Abstract: The present invention relates to methods of preventing and treating tuberculosis in a subject infected with Mycobacterium tuberculosis. The method involves inhibiting AhpD in the subject under conditions effective to make the pathogen susceptible to antimicrobial reactive nitrogen intermediates or reactive oxygen intermediates. The present invention also relates to methods of preventing and treating tuberculosis in a subject infected with Mycobacterium tuberculosis involving inhibiting dihydrolipoamide dehydrogenase or dihydrolipoamide succinyltransferase in Mycobacterium tuberculosis in the subject under conditions effective to make the pathogen susceptible to antimicrobial reactive nitrogen intermediates or reactive oxygen intermediates. Also disclosed are methods for identifying candidate compounds suitable for treatment or prevention of tuberculosis. Methods of producing an AhpD crystal suitable for X-ray diffraction as well as methods for designing a compound suitable for

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treatment or prevention of tuberculosis and compounds suitable for treatment or prevention of tuberculosis are also disclosed. Excerpt(s): This application claims the benefit of U.S. patent application Ser. No. 60/348,844, filed Jan. 16, 2002, which is hereby incorporated by reference in its entirety. The present invention relates to prevention and treatment of tuberculosis in a subject infected with Mycobacterium tuberculosis by inhibiting AhpD, dihydrolipoamide dehydrogenase, and/or dihydrolipoamide succinyltransferase to impart susceptibility to antimicrobial reactive nitrogen intermediates or reactive oxygen intermediates. A method of producing an AhpD crystal suitable for X-ray diffraction and a compound suitable for treatment or prevention of tuberculosis in a subject are also disclosed. Mycobacterium tuberculosis infects about one-third of the human population, persists for decades, and causes disease in a small fraction of those infected. Despite the low disease rate, Mycobacterium tuberculosis is the single leading cause of death from bacterial infection and accounts for an extraordinary proportion of the chronic infectious morbidity and mortality of humankind. Mycobacterium tuberculosis provokes inflammation that leads human macrophages to express the high output isoform of nitric oxide synthase (iNOS or NOS2). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Oligonucleotides for detecting tubercle bacillus and method therefor Inventor(s): Ishiguro, Takahiko; (Kanagawa, JP), Maruyama, Takahiro; (Kanagawa, JP), Masuda, Noriyoshi; (Tokyo, JP), Matsuba, Takao; (Kanagawa, JP), Tsuchiya, Shigeo; (Tokyo, JP) Correspondence: Oblon, Spivak, Mcclelland, Maier & Neustadt, P.C.; 1940 Duke Street; Alexandria; VA; 22314; US Patent Application Number: 20040087782 Date filed: March 24, 2003 Abstract: An oligonucleotide, capable of specific cleavage and amplification of a pab gene which codes for pab, an antigenic protein of Mycobacterium tuberculosis, or an RNA derived therefrom, as well as being useful in high sensitive detection and identification thereof, is provided. Further, a combination of oligonucleotides, useful in specific amplification, high sensitive detection and identification of an RNA derived from Mycobacterium tuberculosis pab gene as well as a process for detecting Mycobacterium tuberculosis by using said combination, are provided. Excerpt(s): The present invention relates to oligonucleotides and a method for detecting Mycobacterium tuberculosis in clinical examination. The oligonucleotides provided in the present invention are useful as reagents for genetic diagnosis which involves procedures such as cleavage, amplification and detection of RNA or DNA, and as reagents for inhibiting reverse transcription or translation of RNA. In particular, the sequences of the oligonucleotides provided in the present invention are useful for reagents or the like for quantitative determination and detection of Mycobacterium tuberculosis. Notwithstanding the significant reduction of the occurrence of tuberculosis, it is becoming a serious subject of discussion since its morbidity in the older people has recently increased and, also, it may result in a mass infection among young people who have not experienced tuberculous infection before. The usual examination methods for Mycobacterium tuberculosis were based on smear test or culture test. However, since the growth of Mycobacterium tuberculosis is slow, it takes

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more than 4 weeks to obtain results. Recently, genetic detection kits for detecting tubercule bacillus are commercially available. Included therein is a kit which performs a DNA amplification, in which the detection is carried out by amplifying a genomic DNA coding for 16S rRNA with PCR, followed by hybridization with a specific DNA probe, and a kit which performs the detection by EIA, in which a gene coding for the protein antigen b (hereafter, referred to as "pab"), an antigenic protein of Mycobacterium tuberculosis, having a known sequence (Inf. and Immun. 57, 2481-2488, 1989), is amplified with a ligase chain reaction (LCR method). For details, see U.S. Pat. No.5,631,130. Although these detection methods are automated or semi-automated, as their detection time requires in the order of 4 to 6 hours, they are not suitable in a case where urgent treatment is required. Further, since a DNA amplification process cannot distinguish living bacteria from dead bacteria, it is not suitable in a case, for example, where observation of the effect of an antibiotic is being carried out. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Polynucleotide functionally coding for the LHP protein from Mycobacterium tuberculosis, its biologically active derivative fragments, as well as methods using the same Inventor(s): Anderson, Peter; (Bronshoj, DK), Berthet, Francois-Xavier; (Paris, FR), Gicquel, Brigitte; (Paris, FR), Rasmussen, Peter Birk; (Bergsgade, DK) Correspondence: Oblon Spivak Mcclelland Maier & Neustadt PC; Fourth Floor; 1755 Jefferson Davis Highway; Arlington; VA; 22202; US Patent Application Number: 20030092899 Date filed: May 8, 2002 Abstract: The present invention is directed to a polynucleotide carrying an open reading frame coding for an antigenic polypeptide from Mycobacterium tuberculosis, named lhp, which is placed under the control of its own regulation signals which are functional in mycobacteria, specially in mycobacteria belonging to the Mycobacterium tuberculosis complex and also in fast growing mycobacteria such as Mycobacterium smegmatis. The invention is also directed to the polypeptide LHP encoded by lhp and most preferably to suitable antigenic portions of LHP as well as to oligomeric polypeptides containing more than one unit of LHP or an antigenic portion of LHP. The invention concerns also immunogenic and vaccine compositions containing a polypeptide or an oligomeric polypeptide such as defined above, as well as antibodies directed specifically against such polypeptides that are useful as diagnostic reagents. In another embodiment, the present invention is directed to a polynucleotide carrying the natural regulation signals of lhp which is useful in order to express heterologous proteins in mycobacteria. Finally, the present invention is directed to oligonucleotides comprising at least 12 consecutive nucleotides from the regulation sequence of lhp which are useful as reagents for detecting the presence of Mycobacterium tuberculosis in a biological sample. Excerpt(s): This application is a filed May 8, 2002, allowed, which claims priority from Provisional Application, U.S. Application Serial No. 60/052,631 filed Jul. 16, 1997. The entire disclosure of this application is incorporated herein-by-reference. The present invention is directed to a polynucleotide comprising an open reading frame coding for a polypeptide from Mycobacterium tuberculosis, named LHP capable of inducing an immune response in a host. lhp is placed under the control of its own regulation signals which are functional in mycobacteria, especially in mycobacteria belonging to the

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Mycobacterium tuberculosis complex and also in fast growing mycobacteria such as Mycobacterium smegmatis and also in E. coli. The Mycobacterium tuberculosis complex has its usual meaning, i.e. the complex of mycobacteria causing tuberculosis which are Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium microti and the vaccine strain M. bovis BCG. The invention is also directed to the polypeptide LHP encoded by lhp and most preferably to suitable antigenic portions of LHP as well as to oligomeric polypeptides containing more than one unit of LHP or an antigenic portion of LHP. The invention concerns also immunogenic and vaccine compositions containing a polypeptide or an oligomeric polypeptide such as defined above or live recombinant attenuated mycobacteria transformed with a polynucleotide according to the present invention. The invention also concerns antibodies directed specifically against such polypeptides that are useful as diagnostic reagents. In another embodiment, the present invention is directed to a polynucleotide carrying the natural regulation signals of lhp which is useful in order to express heterologous proteins in mycobacteria as well as functionally active regulatory polynucleotides derived from said regulatory region. Finally, the present invention is directed to oligonucleotides comprising at least 12 consecutive nucleotides which are useful as reagents for detecting the presence of Mycobacterium tuberculosis in a biological sample. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Rapid lateral flow assay for determining exposure to Mycobacterium tuberculosis and other mycobacteria Inventor(s): Simonson, Lloyd G.; (Spring Grove, IL) Correspondence: Banner & Witcoff, LTD.; Ten South Wacker Drive; Suite 3000; Chicago; IL; 60606; US Patent Application Number: 20030143652 Date filed: January 30, 2002 Abstract: An assay method and kit is disclosed for detecting the presence of at least one predesignated, target antibody to a mycobacterium in a sample selected from one or more patient bodily fluids. The method comprises the following steps: (a) contacting the sample of one or more patient bodily fluids with at least one mycobacterium antigen on a lateral-flow assay membrane to bind to the target antibody in the sample; (b) previously, simultaneously or subsequently to step (a), binding the at least one mycobacterium antigen with a conjugated label producing a detectable signal; and (c) detecting the signal whereby the presence of the target antibody is determined in the sample by the intensity or presence of the signal. The method can further comprise the step of evaluating immunization status of the patient from whom the sample came by comparing the signal or lack thereof with immunizations previously received by the patient and in comparison to a known standard control. In a preferred embodiment, the mycobacterium antigen specifically binds to Mycobacterium tuberculosis specific antibodies. Preferably, the immunoassay of the present invention comprises a lateralflow assay comprising a membrane, a conjugated label pad, and at least one mycobacterium antigen bound to the membrane. In a preferred embodiment, the at least one mycobacterium antigen is selected from the group consisting of 38 kDa and 16 kDa antigens. Excerpt(s): The present invention relates to a rapid test method and assay for determining the presence of antibodies in a patient to disease-related antigens, e.g.,

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antibodies to Mycobacterium tuberculosis, and other mycobacterial antigens. Antibodies are naturally produced biomolecules that react specifically with usually foreign biomolecules called antigens. Disease-related microbial infections, e.g., Mycobacterium tuberculosis, which causes tuberculosis (TB), are usually characterized by the production of antibodies to the specific disease-related antigens. Antibodies are also produced with other diseases and afflictions, e.g., autoimmune diseases, wherein there is often a destructive antibody response to the host. In the case of autoimmune diseases, the host supplies the disease-related antigen, a host tissue. In this case, the corresponding host antibody synthesis may have been initiated by either a foreign substance or by a host tissue not normally encountered by the host's immune system. Subsequent antibody production may proceed in the absence of the foreign substance, due to similar structural nature of the host tissue. Herein the term "disease-related antigen" includes microbial antigens and antigens associated with the host antibody response in autoimmune diseases. Infectious diseases are widespread in the world. Military personnel, including Navy and Marine personnel, are at particular risk because of their global deployment. According to the World Health Organization, the infectious disease tuberculosis caused by Mycobacterium tuberculosis (MTB) kills about three million people every year. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Secreted proteins and uses thereof Inventor(s): Fraser, Christopher C.; (Lexington, MA) Correspondence: Fish & Richardson PC; 225 Franklin ST; Boston; MA; 02110; US Patent Application Number: 20030170784 Date filed: March 26, 2002 Abstract: The invention provides isolated nucleic acid molecules, designated TANGO 228 nucleic acid molecules, which encode secreted proteins with homology to the rat MCA-32 protein, isolated nucleic acid molecules, designated TANGO 240 nucleic acid molecules, which encode secreted proteins with homology to the Mycobacterium tuberculosis hypothetical protein Rv0712, and isolated nucleic acid molecules, designated TANGO 243 nucleic acid molecules, which encode proteins with homology to human PLAP (phospholipase A2-activating protein).The invention also provides antisense nucleic acid molecules, expression vectors containing the nucleic acid molecules of the invention, host cells into which the expression vectors have been introduced, and non-human transgenic animals in which a nucleic acid molecule of the invention has been introduced or disrupted. The invention still further provides isolated polypeptides, fusion polypeptides, antigenic peptides and antibodies. Diagnostic, screening and therapeutic methods utilizing compositions of the invention are also provided. Excerpt(s): Many secreted proteins, for example, cytokines and cytokine receptors, play a vital role in the regulation of cell growth, cell differentiation, and a variety of specific cellular responses. A number of medically useful proteins, including erythropoietin, granulocyte-macrophage colony stimulating factor, human growth hormone, and various interleukins, are secreted proteins. Thus, an important goal in the design and development of new therapies is the identification and characterization of secreted and transmembrane proteins and the genes which encode them. Many secreted proteins are receptors which bind a ligand and transduce an intracellular signal, leading to a variety of cellular responses. The identification and characterization of such a receptor enables

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one to identify both the ligands which bind to the receptor and the intracellular molecules and signal transduction pathways associated with the receptor, permitting one to identify or design modulators of receptor activity, e.g., receptor agonists or antagonists and modulators of signal transduction. The present invention is based, at least in part, on the discovery of cDNA molecules which encode the TANGO 228, 240, and 243 proteins, all of which are either wholly secreted or transmembrane proteins. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Structure of isocitrate lyase enzyme from Mycobacterium tuberculosis and inhibitory agents to combat persistent infection Inventor(s): Honer Zu Bentrup, Kerstin A.; (New Orleans, LA), Jacobs, William R. JR.; (Bronx, NY), McKinney, John D.; (New York, NY), Russell, David G.; (Ithaca, NY), Sacchettini, James C.; (College Station, TX), Sharma, Sujata; (Pearland, TX), Sharma, Vivek; (Pearland, TX) Correspondence: Scott Reese, PH.D.; Howrey, Simon, Arnold & White, L.L.P.; 750 Bering Drive; Houston; TX; 77057-2198; US Patent Application Number: 20030018166 Date filed: August 3, 2001 Abstract: The invention provides methods and compositions for use in identifying inhibitors of biochemical pathways important for persistent infection, allowing the identification and/or design of improved therapeutics for treating persistent infections by pathogenic microbes. Particularly disclosed is the importance of the glyoxylate shunt to the persistent phase of various infectious agents, including Mycobacteria, such as M. tuberculosis, and the identification of preferred targets for drug development, including the enzymes isocitrate lyase (ICL) and malate synthase. Crystals and three-dimensional structures of M. tuberculosis ICL, without ligand and in complex with two inhibitors are also disclosed, for exemplary use in the design of inhibitors and therapeutic agents. Excerpt(s): The present invention generally relates to the fields of pathogenic microbes and to therapeutic agents for treating persistent infections, including infection by M. tuberculosis. Through rigorous definition of an important pathway for persistent infection, the invention provides preferred targets for drug development from the glyoxylate shunt pathway, such as the isocitrate lyase and malate synthase enzymes. Exemplary embodiments of the invention concern crystals and three-dimensional structures of M. tuberculosis isocitrate lyase in complex with inhibitors, for particular use in the design of inhibitors and therapeutic agents. Although modem medicine has provided many weapons to combat disease, infection by pathogenic microbes still poses a significant threat to human life. In recent times, an increasing number of microbes have developed resistance to many commonly used antimicrobial agents, thereby contributing to a new spread of disease. Mycobacteria are examples of microbial pathogens that exhibit persistent infection. Mycobacterium tuberculosis, the causative agent of the tuberculosis (TB) disease, exhibits a penetrance in the human population that is rivaled by few other pathogens. Tuberculosis remains the largest cause of death in the world from a single infectious disease and causes many fatalities in developing countries. The success of M. tuberculosis is dependent on its ability to persist and maintain chronic infection in humans (Parrish et al., 1998). During chronic tuberculosis, the bacteria exist in diverse metabolic states that are not targeted by conventional antimycobacterials (Mitchison, 1980). Lengthy regimens of anti-TB drugs are necessary and are currently the only way to even approach killing of the persistent bacteria.

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Treatment of Mycobacterium tuberculosis with antisense polynucleotides Inventor(s): Harth, Gunter; (Los Angeles, CA), Horwitz, Marcus A.; (Los Angeles, CA), Zamecnik, Paul C.; (Boston, MA) Correspondence: Gates & Cooper Llp; Howard Hughes Center; 6701 Center Drive West, Suite 1050; Los Angeles; CA; 90045; US Patent Application Number: 20040033972 Date filed: August 29, 2002 Abstract: Methods of inhibiting the proliferation of Mycobacterium tuberculosis comprising contacting Mycobacterium tuberculosis with an effective amount of a polynucleotide complementary to an mRNA transcript expressed by Mycobacterium tuberculosis are provided. Typical methods of the invention utilize phosphorothioate modified antisense polynucleotides (PS-ODNs) against the mRNA of M.tuberculosis genes such as glutamine synthetase, aroA,ask, groES, and the genes of the Antigen 85 complex. Excerpt(s): This application claims the benefit of U.S. provisional patent application No. 60/171,929, filed Dec. 22, 1999, the entire contents of which are incorporated herein by reference. The present invention relates to the use of antisense polynucleotides as prophylactic and therapeutic agents in the treatment of Mycobacterium tuberculosis infection. TB is acquired by the respiratory route; actively infected individuals spread this infection efficiently by coughing or sneezing "droplet nuclei" which contain viable bacilli. Overcrowded living conditions and shared air spaces are especially conducive to the spread of TB, underlying the increase in instances that have been observed in the U.S. in prison inmates and among the homeless in larger cities. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Vaccine and drug delivery by topical application of vectors and vector extracts Inventor(s): Shi, Zhongkai; (Birmingham, AL), Tang, De-chu C.; (Birmingham, AL), van Kampen, Kent Rigby; (Hoover, AL) Correspondence: Frommer Lawrence & Haug; 745 Fifth Avenue- 10th FL.; New York; NY; 10151; US Patent Application Number: 20040009936 Date filed: January 16, 2003 Abstract: Disclosed and claimed are methods of non-invasive immunization and drug delivery in an animal and/or methods of inducing a systemic immune or therapeutic response in an animal following topical application of non-replicative vectors, products therefrom and uses for the methods and products therefrom. Also disclosed and claimed are methods of non-invasive immunization and drug delivery in an animal and/or a method of inducing a systemic immune response or systemic therapeutic response to a gene product comprising contacting skin of the animal with cell-free extracts in an amount effective to induce the response, wherein the extracts are prepared by filtration of disrupted cells, wherein the cell comprises and expresses a nucleic acid molecule. Preferably, the cell is temporarily disrupted by sonication, remaining intact

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and viable after the sonication. Also, methods are disclosed and claimed for enhancing the immunogenicity and efficacy of an epicutaneous vaccine for inducing a systemic immune response to an antigen, in an animal comprising contacting skin of the animal with vaccines admixed with heat-shock protein 27, in an amount effective to induce the response. The methods include contacting skin of the animal with a vector in an amount effective to induce the systemic immune or therapeutic response. The vector can include and express an exogenous nucleic acid molecule encoding an epitope or gene product of interest. The systemic immune response can be to or from the epitope or gene product. The nucleic acid molecule can encode an epitope or antigen of interest and/or a nucleic acid molecule that stimulates and/or modulates an immunological response and/or stimulates and/or modulates expression, e.g., transcription and/or translation, such as transcription and/or translation of an endogenous and/or exogenous nucleic acid molecule; e.g., one or more of influenza hemagglutinin, influenza nuclear protein, influenza M2, tetanus toxin C-fragment, anthrax protective antigen, anthrax lethal factor, anthrax germination factors, rabies glycoprotein, HBV surface antigen, HIV gp120, HIV gp160, human carcinoembryonic antigen, malaria CSP, malaria SSP, malaria MSP, malaria pfg, botulinum toxin A, and Mycobacterium tuberculosis HSP; and/or a therapeutic, an immunomodulatory gene, such as co- stimulatory gene and/or a cytokine gene. The immune response can be induced by the vector expressing the nucleic acid molecule in the animal's cells including epidermal cells. The immune response can also be induced by antigens expressed from the nucleic acid molecule within the vector. The immune response can be against a pathogen or a neoplasm. A prophylactic vaccine or a therapeutic vaccine or an immunological composition can include the vector. The animal can be a vertebrate, e.g., a mammal, such as human, a cow, a horse, a dog, a cat, a goat, a sheep or a pig; or fowl such as turkey, chicken or duck. The vector can be one or more of a viral vector, including viral coat, e.g., with some or all viral genes deleted therefrom, bacterial, protozoan, transposon, retrotransposon, and DNA vector, e.g., a recombinant vector; for instance, an adenovirus, such as an adenovirus defective in its E1 and/or E3 and/or E4 region(s) and/or all adenoviral genes. Excerpt(s): This application is a continuation-in-part of U.S. patent application Ser. No. 10/116,963, filed Apr. 5, 2002, which is a continuation-in-part of U.S. patent application Ser. No. 10/052,323, filed Jan. 18, 2002, which is a continuation-in-part of U.S. patent application Ser. No. 09/563,826, filed May 3, 2000 (issued Feb. 19, 2002 as Patent No. 6,348,450), which claims priority from U.S. Provisional Application No. 60/132,216, filed May 3, 1999, and is also a continuation-in-part of U.S. patent application Ser. No. 09/533,149, filed Mar. 23, 2000, which in turn is a continuation of U.S. patent application Ser. No. 09/402,527, filed on Aug. 13, 2000. Each of these applications and each of the documents cited in each of these applications ("application cited documents"), and each document referenced or cited in the application cited documents, either in the text or during the prosecution of those applications, as well as all arguments in support of patentability advanced during such prosecution, are hereby incorporated herein by reference. Various documents are also cited in this text ("application cited documents"). Each of the application cited documents, and each document cited or referenced in the application cited documents, is hereby incorporated herein by reference. The present invention relates generally to the fields of immunology and vaccine technology. The present invention also relates to techniques of skin-targeted non-invasive delivery of to elicit immune responses and uses thereof. The invention further relates to methods of non-invasive immunization in an animal and/or methods of inducing an immunological, e.g., systemic immune response or a therapeutic, e.g., a systemic therapeutic response, in an animal, products therefrom and uses for the methods and

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products therefrom. The invention yet further relates to such methods comprising contacting skin of the animal with a vector in an amount effective to induce the response, e.g., systemic immune response, in the animal. Even further, the invention relates to such methods wherein the vector comprises and expresses an exogenous nucleic acid molecule encoding an epitope or gene product of interest, e.g., an antigen or therapeutic. Still further, the invention relates to such methods wherein the response, e.g., systemic immune or therapeutic response, can be to or from the epitope or gene product. Even further still, the invention relates to such methods wherein the vector is non-replicative. The invention yet further relates to such methods wherein the response is induced by contacting the skin of an animal with cell-free extracts in an amount effective to induce the response, wherein the extracts are prepared by filtration of disrupted cells chosen from the group consisting of bacterium, fungus, cultured animal cells, and cultured plant cells, wherein the cell comprises and expresses a nucleic acid molecule encoding the gene product. 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 Mycobacterium tuberculosis, 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 “Mycobacterium tuberculosis” (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 Mycobacterium tuberculosis. You can also use this procedure to view pending patent applications concerning Mycobacterium tuberculosis. 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 6. BOOKS ON MYCOBACTERIUM TUBERCULOSIS Overview This chapter provides bibliographic book references relating to Mycobacterium tuberculosis. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on Mycobacterium tuberculosis 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 “Mycobacterium tuberculosis” (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 Mycobacterium tuberculosis: •

Tuberculosis Contact: Rosen Publishing Group, Incorporated, 29 E 21st St, New York, NY, 10010, (212) 777-3017. Summary: This monograph discusses the history of tuberculosis (TB) from ancient times to the modern day and discusses how it was perceived and explained by different societies at different times in history. It covers the characteristics of the disease and the bacteria, Mycobacterium tuberculosis, and how scientists began to understand this disease. It discusses the search for TB treatment, diagnostic methods, and its resurgence including the emergence of multiple drug resistant (MDR) strains of TB.

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•


Anti-Tuberculosis Drug Resistance in the World: Report No. 2: Prevalence and Trends Contact: WHO Stop Tuberculosis Strategy and Operations Unit, World Health Organization, Communicable Diseases, Stop Tuberculosis Department, Stop Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: This report gives the results of the Global Project on Anti-Tuberculosis Drug Resistance Surveillance (DRS), conducted between 1996 and 1999, three years after the initial survey of 35 geographical settings, with the aim of collecting worldwide information on drug resistance of Mycobacterium tuberculosis. The report includes the following data: (1) information collected in the period 1996-1999 on the prevalence of drug resistance from 58 geographical settings; (2) trends on drug resistance from 28 geographical settings; (3) data from 17 geographical settings on the levels of drug resistance according to place of birth; (4) individual patient data from 11 geographical settings to assess determinants of drug resistance; (5) and ecological data from all 72 geographical settings that participated in the Global Project since 1994. The report discusses the project’s background and methodology and provides statistical results and a discussion of the findings. The findings describe the magnitude of anti-tuberculosis drug resistance; the relationship between drug resistance and TB control indicators; the impact of migration on drug resistance; and the impact of age, HIV, and prior TB treatment on the magnitude of drug resistance. Data confirm that prior anti-tuberculosis therapy is a strong predictor of drug resistance. The report also includes copies of the forms used in data collection and individual country profiles.

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 “Mycobacterium tuberculosis” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “Mycobacterium tuberculosis” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “Mycobacterium tuberculosis” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

Rapid susceptibility testing of mycobacterium avium complex and Mycobacterium tuberculosis isolated from AIDS patients final report for the period 01 June 1992 - 31 May 1994 (SuDoc NAS 1.26:196268) by Arvind M. Dhople; ISBN: B00010MA02; http://www.amazon.com/exec/obidos/ASIN/B00010MA02/icongroupinterna

Chapters on Mycobacterium Tuberculosis In order to find chapters that specifically relate to Mycobacterium tuberculosis, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and Mycobacterium tuberculosis 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

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search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “Mycobacterium tuberculosis” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on Mycobacterium tuberculosis: •

Reemergence of Mycobacterium Tuberculosis Infection as a Major Occupational Risk for Health Professionals 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. 296-308. 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 the reemergence of Mycobacterium tuberculosis (TB) infections as a major occupational risk 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 authors discuss the etiology, transmission, and progression of this infectious disease, current risk factors, management of infected patients, and effectiveness of established infection control guidelines. The authors conclude with a discussion of the implications of TB for dentistry, including infection control concerns and guidelines. 2 figures. 5 tables. 38 references.

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CHAPTER 7. PERIODICALS AND NEWS ON MYCOBACTERIUM TUBERCULOSIS Overview In this chapter, we suggest a number of news sources and present various periodicals that cover Mycobacterium tuberculosis.

News Services and Press Releases One of the simplest ways of tracking press releases on Mycobacterium tuberculosis 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 “Mycobacterium tuberculosis” (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 Mycobacterium tuberculosis. 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 “Mycobacterium tuberculosis” (or synonyms). The following was recently listed in this archive for Mycobacterium tuberculosis: •

Mutant Mycobacterium tuberculosis may lead to better TB vaccine Source: Reuters Medical News Date: September 12, 2002

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•

Sequencing of Mycobacterium tuberculosis genome complete Source: Reuters Medical News Date: June 11, 1998

•

Genome Of Mycobacterium tuberculosis Sequenced Source: Reuters Medical News Date: December 19, 1997 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 “Mycobacterium tuberculosis” (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 “Mycobacterium tuberculosis” (or synonyms). If you know the name of a company that is relevant to Mycobacterium tuberculosis, 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/.

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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 “Mycobacterium tuberculosis” (or synonyms).

Academic Periodicals covering Mycobacterium Tuberculosis Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to Mycobacterium tuberculosis. In addition to these sources, you can search for articles covering Mycobacterium tuberculosis 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 8. 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 Mycobacterium tuberculosis. 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 non-profit 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).

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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. 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 Mycobacterium tuberculosis 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 “Mycobacterium tuberculosis” (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

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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 Mycobacterium tuberculosis: •

Thalidomide http://www.rarediseases.org/nord/search/nodd_full?code=23

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.

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APPENDICES

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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 Institute10: •

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/

10

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

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•

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

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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

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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.11 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:12 •

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

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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

11

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). 12 See http://www.nlm.nih.gov/databases/databases.html.

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•

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 NLM Gateway13 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.14 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “Mycobacterium tuberculosis” (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 25823 190 379 670 39 27101

HSTAT15 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.16 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.17 Simply search by “Mycobacterium tuberculosis” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

13

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

14

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). 15 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 16 17

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 Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.

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Coffee Break: Tutorials for Biologists18 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.19 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.20 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/.

18 Adapted 19

from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.

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. 20 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.

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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 Mycobacterium tuberculosis 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 Mycobacterium tuberculosis. 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 Mycobacterium tuberculosis. 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 “Mycobacterium tuberculosis”:

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AIDS http://www.nlm.nih.gov/medlineplus/aids.html AIDS and Infections http://www.nlm.nih.gov/medlineplus/aidsandinfections.html Bacterial Infections http://www.nlm.nih.gov/medlineplus/bacterialinfections.html Occupational Health for Healthcare Providers http://www.nlm.nih.gov/medlineplus/occupationalhealthforhealthcareproviders. html Tuberculosis http://www.nlm.nih.gov/medlineplus/tuberculosis.html 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 Mycobacterium tuberculosis. 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: •

Diagnosis: Rapid Diagnostic Tests for Tuberculosis Contact: New York City Department of Health and Mental Hygiene, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013-0061, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This information sheet discusses new rapid diagnostic tests that can detect Mycobacterium tuberculosis in 3-5 hours compared to traditional methods that require 1-8 weeks. The two new tests the Gen-Probe Amplified Mycobacterium Tuberculosis Direct (MTD) test and the Roche Amplicor Mycobacterium tuberculosis (MTB) test are both based on nucleic acid amplification assays. The information sheet discusses the use and interpretation of rapid diagnostic tests, their limitations, and laboratories that offer rapid diagnostic testing. 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

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located at http://www.guideline.gov/ by using the keyword “Mycobacterium tuberculosis” (or synonyms). The following was recently posted: •

Guidelines for using the QuantiFERON®-TB Mycobacterium tuberculosis infection

test

for

diagnosing

latent

Source: Centers for Disease Control and Prevention - Federal Government Agency [U.S.]; 2003 January 31; 4 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3618&nbr=2844&a mp;string=mycobacterium+AND+tuberculosis 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 Mycobacterium tuberculosis. 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: •


•

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

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to Mycobacterium tuberculosis. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with Mycobacterium tuberculosis.

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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 Mycobacterium tuberculosis. 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 “Mycobacterium tuberculosis” (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 “Mycobacterium tuberculosis”. 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 “Mycobacterium tuberculosis” (or synonyms) into the “For 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 “Mycobacterium tuberculosis” (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.21

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

21

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)22: •

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/

22

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

Finding Medical Libraries

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•

Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml

•

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

•

Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html

•

Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

•

Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp

•

Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/

•

Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm

•

Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html

•

Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/

•

Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm

•

Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/

•

Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/

•

Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/

•

Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm

•

Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html

•

Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

•

Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

•

Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

•

Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

•

Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/

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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

•

Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

•

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

•

Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

•

Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html

•

Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

•

Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

•

Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

•

Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

•

Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

•

Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

•

Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

•

Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

•

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

•

Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

•

Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

•

National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

•

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/

•

National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

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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

•

New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

•

New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

•

New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

•

New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

•

New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

•

New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

•

New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

•

New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

•

Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

•

Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

•

Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

•

Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

•

Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

•

Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

•

Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

•

Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

•

Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

•

Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

•

Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/

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•

South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

•

Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

•

Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

•

Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

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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

•

MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

•

Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

•

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

•

On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

•

Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

•

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).

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

233

MYCOBACTERIUM TUBERCULOSIS DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 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] Aberrant: Wandering or deviating from the usual or normal course. [EU] Abscess: A localized, circumscribed collection of pus. [NIH] Acanthocephala: A phylum of parasitic worms, closely related to tapeworms and containing two genera: Moniliformis, which sometimes infects man, and Macracanthorhynchus, which infects swine. [NIH] Acatalasia: A rare autosomal recessive disorder resulting from the absence of catalase activity. Though usually asymptomatic, a syndrome of oral ulcerations and gangrene may be present. [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] 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] Acute leukemia: A rapidly progressing cancer of the blood-forming tissue (bone marrow). [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] Acyl: Chemical signal used by bacteria to communicate. [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

234


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] Adduct: Complex formed when a carcinogen combines with DNA or a protein. [NIH] Adenine: A purine base and a fundamental unit of adenine nucleotides. [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] Adenosine Kinase: An enzyme that catalyzes the formation of ADP plus AMP from adenosine plus ATP. It can serve as a salvage mechanism for returning adenosine to nucleic acids. EC 2.7.1.20. [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] Adenylate Cyclase: An enzyme of the lyase class that catalyzes the formation of cyclic AMP and pyrophosphate from ATP. EC 4.6.1.1. [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] 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 Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [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]

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] 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

Dictionary 235

emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]

Agarose: A polysaccharide complex, free of nitrogen and prepared from agar-agar which is produced by certain seaweeds (red algae). It dissolves in warm water to form a viscid solution. [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] 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] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Alcohol Dehydrogenase: An enzyme that catalyzes reversibly the final step of alcoholic fermentation by reducing an aldehyde to an alcohol. In the case of ethanol, acetaldehyde is reduced to ethanol in the presence of NADH and hydrogen. The enzyme is a zinc protein which acts on primary and secondary alcohols or hemiacetals. EC 1.1.1.1. [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] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [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] 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] 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] Ambroxol: A metabolite of bromhexine that stimulates mucociliary action and clears the air passages in the respiratory tract. It is usually administered as the hydrochloride. [NIH]

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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] 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] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [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] 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] Analytes: A component of a test sample the presence of which has to be demonstrated. The term "analyte" includes where appropriate formed from the analyte during the analyses. [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] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anergic: 1. Characterized by abnormal inactivity; inactive. 2. Marked by asthenia or lack of energy. 3. Pertaining to anergy. [EU] Anergy: Absence of immune response to particular substances. [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]

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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] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]

Anthrax: An acute bacterial infection caused by ingestion of bacillus organisms. Carnivores may become infected from ingestion of infected carcasses. It is transmitted to humans by contact with infected animals or contaminated animal products. The most common form in humans is cutaneous anthrax. [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]

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] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [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] Antilymphocyte Serum: Serum containing gamma-globulins which are antibodies for lymphocyte antigens. It is used both as a test for histocompatibility and therapeutically in transplantation. [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] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are

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highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] 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] Antitoxin: A purified antiserum from animals (usually horses) immunized by injections of a toxin or toxoid, administered as a passive immunizing agent to neutralize a specific bacterial toxin, e.g., botulinus, tetanus or diphtheria. [EU] Antituberculosis: Refers to a drug used to treat tuberculosis. [NIH] Antiviral: Destroying viruses or suppressing their replication. [EU] Aplastic anemia: A condition in which the bone marrow is unable to produce blood cells. [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] Aqueous: Having to do with water. [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] Aspartic: The naturally occurring substance is L-aspartic acid. One of the acidic-amino-acids is obtained by the hydrolysis of proteins. [NIH] Aspartic Endopeptidases: A sub-subclass of endopeptidases that depend on an aspartic acid residue for their activity. EC 3.4.23. [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] Asthenia: Clinical sign or symptom manifested as debility, or lack or loss of strength and energy. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH]

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Atrial: Pertaining to an atrium. [EU] Atrioventricular: Pertaining to an atrium of the heart and to a ventricle. [EU] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Attenuated: Strain with weakened or reduced virulence. [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] Autoantibodies: Antibodies that react with self-antigens (autoantigens) of the organism that produced them. [NIH] Autoantigens: Endogenous tissue constituents that have the ability to interact with autoantibodies and cause an immune response. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autopsy: Postmortem examination of the body. [NIH] Avidity: The strength of the interaction of an antiserum with a multivalent antigen. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [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] 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 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 Vaccines: Suspensions of attenuated or killed bacteria administered for the prevention or treatment of infectious bacterial disease. [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] Bacteriophage lambda: A temperate inducible phage and type species of the genus lambdalike Phages, in the family Siphoviridae. Its natural host is E. coli K12. Its virion contains linear double-stranded DNA, except for 12 complementary bases at the 5'-termini of the

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polynucleotide chains. The DNA circularizes on infection. [NIH] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] 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]

Beta-Thromboglobulin: A platelet-specific protein which is released when platelets aggregate. Elevated plasma levels have been reported after deep venous thrombosis, preeclampsia, myocardial infarction with mural thrombosis, and myeloproliferative disorders. Measurement of beta-thromboglobulin in biological fluids by radioimmunoassay is used for the diagnosis and assessment of progress of thromboembolic disorders. [NIH] Bezafibrate: Antilipemic agent that lowers cholesterol and triglycerides. It decreases low density lipoproteins and increases high density lipoproteins. [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] 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] 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 Transport: The movement of materials (including biochemical substances and drugs) across cell membranes and epithelial layers, usually by passive diffusion. [NIH] Biomolecular: A scientific field at the interface between advanced computing and biotechnology. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] 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 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]

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Biotransformation: The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alteration may be either nonsynthetic (oxidation-reduction, hydrolysis) or synthetic (glucuronide formation, sulfate conjugation, acetylation, methylation). This also includes metabolic detoxication and clearance. [NIH] Bladder: The organ that stores urine. [NIH] Blast phase: The phase of chronic myelogenous leukemia in which the number of immature, abnormal white blood cells in the bone marrow and blood is extremely high. Also called blast crisis. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [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 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 Fluids: Liquid components of living organisms. [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 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 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] 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] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchiectasis: Persistent abnormal dilatation 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]

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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] 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] Canonical: A particular nucleotide sequence in which each position represents the base more often found when many actual sequences of a given class of genetic elements are compared. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [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] Carcinoembryonic Antigen: A glycoprotein that is secreted into the luminal surface of the epithelia in the gastrointestinal tract. It is found in the feces and pancreaticobiliary secretions and is used to monitor the respone to colon cancer treatment. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenic: Producing carcinoma. [EU] Cardiac: Having to do with the heart. [NIH] Cardiovascular: Having to do with the heart and blood vessels. [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-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] Catalase: An oxidoreductase that catalyzes the conversion of hydrogen peroxide to water and oxygen. It is present in many animal cells. A deficiency of this enzyme results in acatalasia. EC 1.11.1.6. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Cathepsins: A group of lysosomal proteinases or endopeptidases found in aqueous extracts of a variety of animal tissue. They function optimally within an acidic pH range. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH]

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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 Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [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 Physiology: Characteristics and physiological processes of cells from cell division to cell death. [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] Cellular adhesion: The close adherence (bonding) to adjoining cell surfaces. [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] 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] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] 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] 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] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH]

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Chaperonin 10: Members of the chaperonin heat-shock protein family. Chaperonin 10 purified from bacteria, plastids, or mitochondria occurs as an oligomer of seven identical subunits arranged in a single ring. [NIH] Chaperonin 60: Members of the chaperonin heat-shock protein family. Chaperonin 60 purified from bacteria, plastids, or mitochondria is an oligomeric protein with a distinctive structure of fourteen subunits, arranged in two rings of seven subunits each. [NIH] Chaperonins: A class of sequence-related molecular chaperones found in bacteria, mitochondria, and plastids. Chaperonins are abundant constitutive proteins that increase in amount after stresses such as heat shock, bacterial infection of macrophages, and an increase in the cellular content of unfolded proteins. Bacterial chaperonins are major immunogens in human bacterial infections because of their accumulation during the stress of infection. Two members of this class of chaperones are chaperonin 10 and chaperonin 60. [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] Chemotherapeutic agent: A drug used to treat cancer. [NIH] Chemotherapy: Treatment with anticancer drugs. [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] Cholera Toxin: The enterotoxin from Vibrio cholerae. It is a protein that consists of two major components, the heavy (H) or A peptide and the light (L) or B peptide or choleragenoid. The B peptide anchors the protein to intestinal epithelial cells, while the A peptide, enters the cytoplasm, and activates adenylate cyclase, and production of cAMP. Increased levels of cAMP are thought to modulate release of fluid and electrolytes from intestinal crypt cells. [NIH] Cholera Vaccines: Vaccines or candidate vaccines used to prevent infection with vibrio cholerae. The original cholera vaccine consisted of killed bacteria, but other kinds of vaccines now exist. [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] 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]

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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 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 phase: Refers to the early stages of chronic myelogenous leukemia or chronic lymphocytic leukemia. The number of mature and immature abnormal white blood cells in the bone marrow and blood is higher than normal, but lower than in the accelerated or blast phase. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] 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] Clear cell carcinoma: A rare type of tumor of the female genital tract in which the inside of the cells looks clear when viewed under a microscope. [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] Cluster Analysis: A set of statistical methods used to group variables or observations into strongly inter-related subgroups. In epidemiology, it may be used to analyze a closely grouped series of events or cases of disease or other health-related phenomenon with welldefined distribution patterns in relation to time or place or both. [NIH] Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [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] Coliphages: Viruses whose host is Escherichia coli. [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] 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] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable compounds at once. [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 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,

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megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementation: The production of a wild-type phenotype when two different mutations are combined in a diploid or a heterokaryon and tested in trans-configuration. [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 axial 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 CAT scan, computed tomography (CT scan), or computerized tomography. [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] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Conjugated: Acting or operating as if joined; simultaneous. [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] Consciousness: Sense of awareness of self and of the environment. [NIH] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] 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] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]

Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [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] Cor: The muscular organ that maintains the circulation of the blood. c. adiposum a heart that has undergone fatty degeneration or that has an accumulation of fat around it; called

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also fat or fatty, heart. c. arteriosum the left side of the heart, so called because it contains oxygenated (arterial) blood. c. biloculare a congenital anomaly characterized by failure of formation of the atrial and ventricular septums, the heart having only two chambers, a single atrium and a single ventricle, and a common atrioventricular valve. c. bovinum (L. 'ox heart') a greatly enlarged heart due to a hypertrophied left ventricle; called also c. taurinum and bucardia. c. dextrum (L. 'right heart') the right atrium and ventricle. c. hirsutum, c. villosum. c. mobile (obs.) an abnormally movable heart. c. pendulum a heart so movable that it seems to be hanging by the great blood vessels. c. pseudotriloculare biatriatum a congenital cardiac anomaly in which the heart functions as a three-chambered heart because of tricuspid atresia, the right ventricle being extremely small or rudimentary and the right atrium greatly dilated. Blood passes from the right to the left atrium and thence disease due to pulmonary hypertension secondary to disease of the lung, or its blood vessels, with hypertrophy of the right ventricle. [EU] Cor pulmonale: Heart disease that results from resistance to the passage of blood through the lungs; it often leads to right heart failure. [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 Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Corpus: The body of the uterus. [NIH] Cosmids: Plasmids containing at least one cos (cohesive-end site) of phage lambda. They are used as cloning vehicles for the study of aberrant eukaryotic structural genes and also as genetic vectors for introducing the nucleic acid of transforming viruses into cultured cells. [NIH]

Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Cross-Sectional Studies: Studies in which the presence or absence of disease or other health-related variables are determined in each member of the study population or in a representative sample at one particular time. This contrasts with longitudinal studies which are followed over a period of time. [NIH] Culture Media: Any liquid or solid preparation made specifically for the growth, storage, or transport of microorganisms or other types of cells. The variety of media that exist allow for the culturing of specific microorganisms and cell types, such as differential media, selective media, test media, and defined media. Solid media consist of liquid media that have been solidified with an agent such as agar or gelatin. [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] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cysteine Endopeptidases: Endopeptidases which have a cysteine involved in the catalytic

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process. This group of enzymes is inactivated by sulfhydryl reagents. EC 3.4.22. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]

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 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] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [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] Cytoplasmic Vesicles: Membrane-limited structures derived from the plasma membrane or various intracellular membranes which function in storage, transport or metabolism. [NIH] 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] Decontamination: The removal of contaminating material, such as radioactive materials, biological materials, or chemical warfare agents, from a person or object. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] 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] 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]

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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] Deoxyribonucleic: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] DES: Diethylstilbestrol. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who used DES. DES may also increase the risk of breast cancer in women who used DES. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Detergents: Purifying or cleansing agents, usually salts of long-chain aliphatic bases or acids, that exert cleansing (oil-dissolving) and antimicrobial effects through a surface action that depends on possessing both hydrophilic and hydrophobic properties. [NIH] Detoxification: Treatment designed to free an addict from his drug habit. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Developed Countries: Countries that have reached a level of economic achievement through an increase of production, per capita income and consumption, and utilization of natural and human resources. [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] 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] Diastolic: Of or pertaining to the diastole. [EU] Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Dihydrotestosterone: Anabolic agent. [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

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needs the larger (B fragment) for entry into cells. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Disinfection: Rendering pathogens harmless through the use of heat, antiseptics, antibacterial agents, etc. [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] 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 its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [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]

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Duct: A tube through which body fluids pass. [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] 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] 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] Elastic: Susceptible of resisting and recovering from stretching, compression or distortion applied by a force. [EU] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] 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]

Electroplating: Coating with a metal or alloy by electrolysis. [NIH] Emaciation: Clinical manifestation of excessive leanness usually caused by disease or a lack of nutrition. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Emollient: Softening or soothing; called also malactic. [EU] 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] 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] Endocardium: The innermost layer of the heart, comprised of endothelial cells. [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

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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] 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-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxins: Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. [NIH] Enteropeptidase: A specialized proteolytic enzyme secreted by intestinal cells. It converts trypsinogen into its active form trypsin by removing the N-terminal peptide. EC 3.4.21.9. [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] Eosinophil: A polymorphonuclear leucocyte with large eosinophilic granules in its cytoplasm, which plays a role in hypersensitivity reactions. [NIH] Eosinophilia: Abnormal increase in eosinophils in the blood, tissues or organs. [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] Epidemiologic Studies: Studies designed to examine associations, commonly, hypothesized causal relations. They are usually concerned with identifying or measuring the effects of risk factors or exposures. The common types of analytic study are case-control studies, cohort studies, and cross-sectional studies. [NIH] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] 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] 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]

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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]

Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythropoietin: Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. [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] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [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] 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] 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] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extrapyramidal: Outside of the pyramidal tracts. [EU] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [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] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Farnesyl: Enzyme which adds 15 carbon atoms to the Ras precursor protein. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatal Outcome: Death resulting from the presence of a disease in an individual, as shown by

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a single case report or a limited number of patients. This should be differentiated from death, the physiological cessation of life and from mortality, an epidemiological or statistical concept. [NIH] 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] 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] Fertilizers: Substances or mixtures that are added to the soil to supply nutrients or to make available nutrients already present in the soil, in order to increase plant growth and productivity. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [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] 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] Filtration: The passage of a liquid through a filter, accomplished by gravity, pressure, or vacuum (suction). [EU] Fistula: Abnormal communication most commonly seen between two internal organs, or between an internal organ and the surface of the body. [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] 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] 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]

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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] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free 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] 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] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [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] 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 through the rectum (flatus) or the mouth (burp). [NIH] Gastric: Having to do with the stomach. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gels: Colloids with a solid continuous phase and liquid as the dispersed phase; gels may be unstable when, due to temperature or other cause, the solid phase liquifies; the resulting colloid is called a sol. [NIH] Gemfibrozil: A lipid-regulating agent that lowers elevated serum lipids primarily by decreasing serum triglycerides with a variable reduction in total cholesterol. These decreases occur primarily in the VLDL fraction and less frequently in the LDL fraction. Gemfibrozil increases HDL subfractions HDL2 and HDL3 as well as apolipoproteins A-I and A-II. Its mechanism of action has not been definitely established. [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

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action. [NIH] Gene Expression Profiling: The determination of the pattern of genes expressed i.e., transcribed, under specific circumstances or in a specific cell. [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] Generator: Any system incorporating a fixed parent radionuclide from which is produced a daughter radionuclide which is to be removed by elution or by any other method and used in a radiopharmaceutical. [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] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event. [NIH] Genetic Techniques: Chromosomal, biochemical, intracellular, and other methods used in the study of genetics. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetic Vectors: Any DNA molecule capable of autonomous replication within a host cell and into which other DNA sequences can be inserted and thus amplified. Many are derived from plasmids, bacteriophages or viruses. They are used for transporting foreign genes into recipient cells. Genetic vectors possess a functional replicator site and contain genetic markers to facilitate their selective recognition. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genitourinary system: The parts of the body that play a role in reproduction, getting rid of waste products in the form of urine, or both. [NIH] 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] 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] 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]

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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]

Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [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] 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]

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] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycoside: Any compound that contains a carbohydrate molecule (sugar), particularly any such natural product in plants, convertible, by hydrolytic cleavage, into sugar and a nonsugar component (aglycone), and named specifically for the sugar contained, as glucoside (glucose), pentoside (pentose), fructoside (fructose) etc. [EU] Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction. [NIH] Gonadal: Pertaining to a gonad. [EU] 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] 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]

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Gram-Positive Rods: A large group of rod-shaped bacteria that retains the crystal violet stain when treated by Gram's method. [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 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] 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] 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]

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] Hair follicles: Shafts or openings on the surface of the skin through which hair grows. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haplotypes: The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the major histocompatibility complex. [NIH] 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] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heat-Shock Proteins: Proteins which are synthesized in eukaryotic organisms and bacteria in response to hyperthermia and other environmental stresses. They increase thermal tolerance and perform functions essential to cell survival under these conditions. [NIH] Heat-Shock Proteins 90: A class of molecular chaperones whose members act in the mechanism of signal transduction by steroid receptors. [NIH] Helminths: Commonly known as parasitic worms, this group includes the acanthocephala, nematoda, and platyhelminths. Some authors consider certain species of leeches that can become temporarily parasitic as helminths. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemiparesis: The weakness or paralysis affecting one side of the body. [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.

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The cleaned blood then flows through another set of tubes back into the body. [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] 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]

Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatocyte: A liver cell. [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] 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]

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] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [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] Homeless Persons: Persons who have no permanent residence. The concept excludes nomadic peoples. [NIH] Homodimer: Protein-binding "activation domains" always combine with identical proteins. [NIH]

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] Homotypic: Adhesion between neutrophils. [NIH]

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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] Hospices: Facilities or services which are especially devoted to providing palliative and supportive care to the patient with a terminal illness and to the patient's family. [NIH] Human growth hormone: A protein hormone, secreted by the anterior lobe of the pituitary, which promotes growth of the whole body by stimulating protein synthesis. The human gene has already been cloned and successfully expressed in bacteria. [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] Hybridoma: A hybrid cell resulting from the fusion of a specific antibody-producing spleen cell with a myeloma cell. [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 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] Hydrolases: Any member of the class of enzymes that catalyze the cleavage of the substrate and the addition of water to the resulting molecules, e.g., esterases, glycosidases (glycoside hydrolases), lipases, nucleotidases, peptidases (peptide hydrolases), and phosphatases (phosphoric monoester hydrolases). EC 3. [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] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hypercalcemia: Abnormally high level of calcium in the blood. [NIH] Hyperreflexia: Exaggeration of reflexes. [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] Hyperthermia: A type of treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anticancer drugs. [NIH]

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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] 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] Idiopathic: Describes a disease of unknown cause. [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] Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] 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] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunocompromised: Having a weakened immune system caused by certain diseases or treatments. [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]

Immunodiffusion: Technique involving the diffusion of antigen or antibody through a semisolid medium, usually agar or agarose gel, with the result being a precipitin reaction. [NIH]

Immunoelectrophoresis: A technique that combines protein electrophoresis and double immunodiffusion. In this procedure proteins are first separated by gel electrophoresis (usually agarose), then made visible by immunodiffusion of specific antibodies. A distinct elliptical precipitin arc results for each protein detectable by the antisera. [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] Immunosuppression: Deliberate prevention or diminution of the host's immune response. It may be nonspecific as in the administration of immunosuppressive agents (drugs or radiation) or by lymphocyte depletion or may be specific as in desensitization or the simultaneous administration of antigen and immunosuppressive drugs. [NIH]

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Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of suppressor T-cell populations or by inhibiting the activation of helper cells. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of interleukins and other cytokines are emerging. [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] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] 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] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] 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] 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] 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] 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] 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

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severe, often generalized, myalgia. [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] Initiator: A chemically reactive substance which may cause cell changes if ingested, inhaled or absorbed into the body; the substance may thus initiate a carcinogenic process. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [EU] 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] Instillation: . [EU] 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-10: Factor that is a coregulator of mast cell growth. It is produced by T-cells and B-cells and shows extensive homology with the Epstein-Barr virus BCRFI gene. [NIH] Interleukin-12: A heterodimeric cytokine that stimulates the production of interferon gamma from T-cells and natural killer cells, and also induces differentiation of Th1 helper cells. It is an initiator of cell-mediated 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-8: A cytokine that activates neutrophils and attracts neutrophils and Tlymphocytes. It is released by several cell types including monocytes, macrophages, Tlymphocytes, fibroblasts, endothelial cells, and keratinocytes by an inflammatory stimulus.

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IL-8 is a member of the beta-thromboglobulin superfamily and structurally related to platelet factor 4. [NIH] Interleukins: Soluble factors which stimulate growth-related activities of leukocytes as well as other cell types. They enhance cell proliferation and differentiation, DNA synthesis, secretion of other biologically active molecules and responses to immune and inflammatory stimuli. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] International Agencies: International organizations which provide health-related or other cooperative services. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [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] Intracellular: Inside a cell. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intraperitoneal: IP. Within the peritoneal cavity (the area that contains the abdominal organs). [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [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]

Invertebrates: Animals that have no spinal column. [NIH] Involuntary: Reaction occurring without intention or volition. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [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] 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] Isocitrate Lyase: A key enzyme in the glyoxylate cycle. It catalyzes the conversion of isocitrate to succinate and glyoxylate. EC 4.1.3.1. [NIH] Isoenzyme: Different forms of an enzyme, usually occurring in different tissues. The isoenzymes of a particular enzyme catalyze the same reaction but they differ in some of their properties. [NIH] Isoniazid: Antibacterial agent used primarily as a tuberculostatic. It remains the treatment of choice for tuberculosis. [NIH] Isonicotinic: A drug used in the treatment of tuberculosis. [NIH] Isoprenoid: Molecule that might anchor G protein to the cell membrane as it is hydrophobic. [NIH]

Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA

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fragments are up to 50 kilobases long. [NIH] Keratinocytes: Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. [NIH] Killer Cells: Lymphocyte-like effector cells which mediate antibody-dependent cell cytotoxicity. They kill antibody-coated target cells which they bind with their Fc receptors. [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] Laryngeal: Having to do with the larynx. [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] Laxative: An agent that acts to promote evacuation of the bowel; a cathartic or purgative. [EU]

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] 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] Leprosy: A chronic granulomatous infection caused by Mycobacterium leprae. The granulomatous lesions are manifested in the skin, the mucous membranes, and the peripheral nerves. Two polar or principal types are lepromatous and tuberculoid. [NIH] Lesion: An area of abnormal tissue change. [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]

Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Levofloxacin: A substance used to treat bacterial infections. It belongs to the family of drugs called quinolone antibiotics. [NIH] Ligands: A RNA simulation method developed by the MIT. [NIH]

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Ligase: An enzyme that repairs single stranded discontinuities in double-stranded DNA molecules in the cell. Purified DNA ligase is used in gene cloning to join DNA molecules together. [NIH] Ligase Chain Reaction: A DNA amplification technique based upon the ligation of oligonucleotide probes. The probes are designed to exactly match two adjacent sequences of a specific target DNA. The chain reaction is repeated in three steps in the presence of excess probe: (1) heat denaturation of double-stranded DNA, (2) annealing of probes to target DNA, and (3) joining of the probes by thermostable DNA ligase. After the reaction is repeated for 20-30 cycles the production of ligated probe is measured. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [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] Lipopolysaccharides: Substance consisting of polysaccaride and lipid. [NIH] 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] Liposarcoma: A rare cancer of the fat cells. [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] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [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] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [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] Luciferase: Any one of several enzymes that catalyze the bioluminescent reaction in certain marine crustaceans, fish, bacteria, and insects. The enzyme is a flavoprotein; it oxidizes luciferins to an electronically excited compound that emits energy in the form of light. The color of light emitted varies with the organism. The firefly enzyme is a valuable reagent for

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measurement of ATP concentration. (Dorland, 27th ed) EC 1.13.12.-. [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]

Lymphadenitis: Inflammation of the lymph nodes. [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] 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] Lymphocyte Depletion: Immunosuppression by reduction of circulating lymphocytes or by T-cell depletion of bone marrow. The former may be accomplished in vivo by thoracic duct drainage or administration of antilymphocyte serum. The latter is performed ex vivo on bone marrow before its transplantation. [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] Lysine: An essential amino acid. It is often added to animal feed. [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] 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] 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] 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

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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] Malate Synthase: An important enzyme in the glyoxylic acid cycle which reversibly catalyzes the synthesis of L-malate from acetyl-CoA and glyoxylate. EC 4.1.3.2. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

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] Maximum Tolerated Dose: The highest dose level eliciting signs of toxicity without having major effects on survival relative to the test in which it is used. [NIH] Median survival time: The point in time from either diagnosis or treatment at which half of the patients with a given disease are found to be, or expected to be, still alive. In a clinical trial, median survival time is one way to measure how effective a treatment is. [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] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Melanin: The substance that gives the skin its color. [NIH] Membrane: A very thin layer of tissue that covers a surface. [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]

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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] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Health: The state wherein the person is well adjusted. [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] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metalloendopeptidases: Endopeptidases which use a metal, normally zinc, in the catalytic mechanism. This group of enzymes is inactivated by metal chelators. EC 3.4.24. [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] Methanol: A colorless, flammable liquid used in the manufacture of formaldehyde and acetic acid, in chemical synthesis, antifreeze, and as a solvent. Ingestion of methanol is toxic and may cause blindness. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] Methyltransferase: A drug-metabolizing enzyme. [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] Mice Minute Virus: The type species of parvovirus prevalent in mouse colonies and found as a contaminant of many transplanted tumors or leukemias. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [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] Microspheres: Small uniformly-sized spherical particles frequently radioisotopes or various reagents acting as tags or markers. [NIH]

labeled

with

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Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mitogen-Activated Protein Kinase Kinases: A serine-threonine protein kinase family whose members are components in protein kinase cascades activated by diverse stimuli. These MAPK kinases phosphorylate mitogen-activated protein kinases and are themselves phosphorylated by MAP kinase kinase kinases. JNK kinases (also known as SAPK kinases) are a subfamily. EC 2.7.10.- [NIH] Mitogen-Activated Protein Kinases: A superfamily of protein-serine-threonine kinases that are activated by diverse stimuli via protein kinase cascades. They are the final components of the cascades, activated by phosphorylation by mitogen-activated protein kinase kinases which in turn are activated by mitogen-activated protein kinase kinase kinases (MAP kinase kinase kinases). Families of these mitogen-activated protein kinases (MAPKs) include extracellular signal-regulated kinases (ERKs), stress-activated protein kinases (SAPKs) (also known as c-jun terminal kinases (JNKs)), and p38-mitogen-activated protein kinases. EC 2,7,1.- [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] 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] Molecular Chaperones: A family of cellular proteins that mediate the correct assembly or disassembly of other polypeptides, and in some cases their assembly into oligomeric structures, but which are not components of those final structures. It is believed that chaperone proteins assist polypeptides to self-assemble by inhibiting alternative assembly pathways that produce nonfunctional structures. Some classes of molecular chaperones are the nucleoplasmins, the chaperonins, the heat-shock proteins 70, and the heat-shock proteins 90. [NIH] 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.

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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 fibroblasts during tissue injury. [NIH] Mononuclear: A cell with one nucleus. [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] 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] 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] 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] 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] Multivalent: Pertaining to a group of 5 or more homologous or partly homologous chromosomes during the zygotene stage of prophase to first metaphasis in meiosis. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Mutate: To change the genetic material of a cell. Then changes (mutations) can be harmful, beneficial, or have no effect. [NIH] Myalgia: Pain in a muscle or muscles. [EU] Mycobacterial disease: Any disease caused by Mycobacterium other than M. tuberculosis, M. bovis, and M. avium. [NIH] Mycobacteriophages: Viruses whose host is one or more Mycobacterium species. They include both temperate and virulent types. [NIH] Mycobacteriosis: Any disease caused by Mycobacterium other than M. tuberculosis, M. bovis, and M. avium. [NIH] 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

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occasionally in sheep and cattle. It should be distinguished from the M. avium complex, which infects primarily humans. [NIH] Mycobacterium avium Complex: A complex that includes several strains of M. avium. M. intracellulare is not easily distinguished from M. avium and therefore is included in the complex. These organisms are most frequently found in pulmonary secretions from persons with a tuberculous-like mycobacteriosis. Strains of this complex have also been associated with childhood lymphadenitis and AIDS. M. avium alone causes tuberculosis in a variety of birds and other animals, including pigs. [NIH] Myeloma: Cancer that arises in plasma cells, a type of white blood cell. [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] Nasal Mucosa: The mucous membrane lining the nasal cavity. [NIH] Natural killer cells: NK cells. A type of white blood cell that contains granules with enzymes that can kill tumor cells or microbial cells. Also called large granular lymphocytes (LGL). [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] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Nematoda: A class of unsegmented helminths with fundamental bilateral symmetry and secondary triradiate symmetry of the oral and esophageal structures. Many species are parasites. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Nephrectomy: Surgery to remove a kidney. Radical nephrectomy removes the kidney, the adrenal gland, nearby lymph nodes, and other surrounding tissue. Simple nephrectomy removes only the kidney. Partial nephrectomy removes the tumor but not the entire kidney. [NIH]

Nephritis: Inflammation of the kidney; a focal or diffuse proliferative or destructive process which may involve the glomerulus, tubule, or interstitial renal tissue. [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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Neurologic: Having to do with nerves or the nervous system. [NIH] 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] 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] Neurotoxic: Poisonous or destructive to nerve tissue. [EU] 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] Neutrophil: A type of white blood cell. [NIH] Niche: The ultimate unit of the habitat, i. e. the specific spot occupied by an individual organism; by extension, the more or less specialized relationships existing between an organism, individual or synusia(e), and its environment. [NIH] Nickel: A trace element with the atomic symbol Ni, atomic number 28, and atomic weight 58.69. It is a cofactor of the enzyme urease. [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] 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] 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] 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 Amplification Techniques: Laboratory techniques that involve the in-vitro

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synthesis of many copies of DNA or RNA from one orginal template. [NIH] Nucleotidases: A class of enzymes that catalyze the conversion of a nucleotide and water to a nucleoside and orthophosphate. EC 3.1.3.-. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Occupational Exposure: The exposure to potentially harmful chemical, physical, or biological agents that occurs as a result of one's occupation. [NIH] Oligonucleotide Probes: Synthetic or natural oligonucleotides used in hybridization studies in order to identify and study specific nucleic acid fragments, e.g., DNA segments near or within a specific gene locus or gene. The probe hybridizes with a specific mRNA, if present. Conventional techniques used for testing for the hybridization product include dot blot assays, Southern blot assays, and DNA:RNA hybrid-specific antibody tests. Conventional labels for the probe include the radioisotope labels 32P and 125I and the chemical label biotin. [NIH] Oligopeptides: Peptides composed of between two and twelve amino acids. [NIH] On-line: A sexually-reproducing population derived from a common parentage. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Open Reading Frames: Reading frames where successive nucleotide triplets can be read as codons specifying amino acids and where the sequence of these triplets is not interrupted by stop codons. [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] Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Ori region: The point or region (origin) at which DNA replication begins in a bacterium or virus. Plasmids used in rec DNA research always contain an ori region, which gives very efficient initiation of replication. [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] 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] Ovalbumin: An albumin obtained from the white of eggs. It is a member of the serpin superfamily. [NIH] Oxazolidinones: Derivatives of oxazolidin-2-one. They represent an important class of synthetic antibiotic agents. [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

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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]

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] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Pachymeningitis: Inflammation of the dura mater of the brain, the spinal cord or the optic nerve. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] P-Aminosalicylic Acid: An antitubercular agent often administered in association with isoniazid. The sodium salt of the drug is better tolerated than the free acid. [NIH] Panax ginseng: A Chinese herb (Panax schinseng) having 5-foliolate leaves and umbels of small greenish flowers succeeded by scarlet berries. [NIH] 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] Paralysis: Loss of ability to move all or part of the body. [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] 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] Particle: A tiny mass of material. [EU] Parvovirus: A genus of the family Parvoviridae, subfamily Parvovirinae, infecting a variety of vertebrates including humans. Parvoviruses are responsible for a number of important diseases but also can be non-pathogenic in certain hosts. The type species is mice minute virus. [NIH] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Paternity: Establishing the father relationship of a man and a child. [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

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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] 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]

Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide Hydrolases: A subclass of enzymes from the hydrolase class that catalyze the hydrolysis of peptide bonds. Exopeptidases and endopeptidases make up the sub-subclasses for this group. EC 3.4. [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] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Nerves: The nerves outside of the brain and spinal cord, including the autonomic, cranial, and spinal nerves. Peripheral nerves contain non-neuronal cells and connective tissue as well as axons. The connective tissue layers include, from the outside to the inside, the epineurium, the perineurium, and the endoneurium. [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] Peroxidase: A hemeprotein from leukocytes. Deficiency of this enzyme leads to a hereditary disorder coupled with disseminated moniliasis. It catalyzes the conversion of a donor and peroxide to an oxidized donor and water. EC 1.11.1.7. [NIH] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH] Phagosomes: Membrane-bound cytoplasmic vesicles formed by invagination of phagocytized material. They fuse with lysosomes to form phagolysosomes in which the hydrolytic enzymes of the lysosome digest the phagocytized material. [NIH] Pharmacodynamic: Is concerned with the response of living tissues to chemical stimuli, that is, the action of drugs on the living organism in the absence of disease. [NIH]

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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] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [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] Phosphoric Monoester Hydrolases: A group of hydrolases which catalyze the hydrolysis of monophosphoric esters with the production of one mole of orthophosphate. EC 3.1.3. [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylating: 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] Phylogeny: The relationships of groups of organisms as reflected by their evolutionary history. [NIH] Physicochemical: Pertaining to physics and chemistry. [EU] 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] Pigments: Any normal or abnormal coloring matter in plants, animals, or micro-organisms. [NIH]

Pilot study: The initial study examining a new method or treatment. [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] 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] 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]

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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] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [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] Platelet Factor 4: A high-molecular-weight proteoglycan-platelet factor complex which is released from blood platelets by thrombin. It acts as a mediator in the heparin-neutralizing capacity of the blood and plays a role in platelet aggregation. At high ionic strength (I=0.75), the complex dissociates into the active component (molecular weight 29,000) and the proteoglycan carrier (chondroitin 4-sulfate, molecular weight 350,000). The molecule exists in the form of a dimer consisting of 8 moles of platelet factor 4 and 2 moles of proteoglycan. [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]

Platyhelminths: A phylum of acoelomate, bilaterally symmetrical flatworms, without a definite anus. It includes three classes: Cestoda, Turbellaria, and Trematoda. [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] Pneumonia: Inflammation of the lungs. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [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] Polymorphic: Occurring in several or many forms; appearing in different forms at different

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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] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [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] Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Practicability: A non-standard characteristic of an analytical procedure. It is dependent on the scope of the method and is determined by requirements such as sample throughout and costs. [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] 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] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Presumptive: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] 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] 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] 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] 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] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH]

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Prophylaxis: An attempt to prevent disease. [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] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] 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] Protein-Serine-Threonine Kinases: A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors. EC 2.7.10. [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] Proteome: The protein complement of an organism coded for by its genome. [NIH] 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] 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] 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]

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Psittacosis: A lung disease caused by a Chlamydia bacterium; occurs in domestic fowls, ducks, pigeons, turkeys and many wild birds and is contracted by man by contact with these birds; the human symptoms are headache, nausea, epistaxis and fever and usually with added symptoms. [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] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]

Pulmonary: Relating to the lungs. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] 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]

Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Purulent: Consisting of or containing pus; associated with the formation of or caused by pus. [EU] Pyrazinamide: A pyrazine that is used therapeutically as an antitubercular agent. [NIH] 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] 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] Rabies: A highly fatal viral infection of the nervous system which affects all warm-blooded animal species. It is one of the most important of the zoonoses because of the inevitably fatal outcome for the infected human. [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] Radioactive: Giving off radiation. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiopharmaceutical: Any medicinal product which, when ready for use, contains one or more radionuclides (radioactive isotopes) included for a medicinal purpose. [NIH]

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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] Reactivation: The restoration of activity to something that has been inactivated. [EU] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] 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, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. [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] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [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] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [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] Replication Origin: The point or region (origin) at which DNA replication begins in a bacterium or virus. Plasmids used in rec DNA research always contain an ori region, which gives very efficient initiation of replication. [NIH] Replicon: In order to be replicated, DNA molecules must contain an origin of duplication and in bacteria and viruses there is usually only one per genome. Such molecules are called replicons. [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 the operon to transcribe messenger RNA. [NIH] Research Support: Financial support of research activities. [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] Respirators: These enable the wearer to breathe in atmospheres polluted by dust, poisonous vapors, smoke, etc., and are therefore used in certain industries or in warfare; they consist essentially of a mask, a metal frame with outlet and inlet valves, and a socket. [NIH] Resuscitation: The restoration to life or consciousness of one apparently dead; it includes

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such measures as artificial respiration and cardiac massage. [EU] 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] Retreatment: The therapy of the same disease in a patient, with the same agent or procedure repeated after initial treatment, or with an additional or alternate measure or follow-up. It does not include therapy which requires more than one administration of a therapeutic agent or regimen. Retreatment is often used with reference to a different modality when the original one was inadequate, harmful, or unsuccessful. [NIH] Reversion: A return to the original condition, e. g. the reappearance of the normal or wild type in previously mutated cells, tissues, or organisms. [NIH] Rhamnose: A methylpentose whose L- isomer is found naturally in many plant glycosides and some gram-negative bacterial lipopolysaccharides. [NIH] Rhinitis: Inflammation of the mucous membrane of the nose. [NIH] Ribonuclease: RNA-digesting enzyme. [NIH] Ribonucleic acid: RNA. One of the two nucleic acids found in all cells. The other is deoxyribonucleic acid (DNA). Ribonucleic acid transfers genetic information from DNA to proteins produced by the cell. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [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] Rickettsiae: One of a group of obligate intracellular parasitic microorganisms, once regarded as intermediate in their properties between bacteria and viruses but now classified as bacteria in the order Rickettsiales, which includes 17 genera and 3 families: Rickettsiace. [NIH]

Rifamycins: A group of antibiotics characterized by a chromophoric naphthohydroquinone group spanned by an aliphatic bridge not previously found in other known antibiotics. They have been isolated from fermentation broths of Streptomyces mediterranei. [NIH] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rod: A reception for vision, located in the retina. [NIH] Salicylate: Non-steroidal anti-inflammatory drugs. [NIH] Salicylic: A tuberculosis drug. [NIH] Saline: A solution of salt and water. [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,

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and parotid glands. [NIH] Sclera: The tough white outer coat of the eyeball, covering approximately the posterior fivesixths of its surface, and continuous anteriorly with the cornea and posteriorly with the external sheath of the optic nerve. [EU] Screening: Checking for disease when there are no symptoms. [NIH] Sebaceous: Gland that secretes sebum. [NIH] Second Messenger Systems: Systems in which an intracellular signal is generated in response to an intercellular primary messenger such as a hormone or neurotransmitter. They are intermediate signals in cellular processes such as metabolism, secretion, contraction, phototransduction, and cell growth. Examples of second messenger systems are the adenyl cyclase-cyclic AMP system, the phosphatidylinositol diphosphate-inositol triphosphate system, and the cyclic GMP system. [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] Sedimentation: The act of causing the deposit of sediment, especially by the use of a centrifugal machine. [EU] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] 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] Sepsis: The presence of bacteria in the bloodstream. [NIH] 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] 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] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Sequester: A portion of dead bone which has become detached from the healthy bone tissue, as occurs in necrosis. [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, pyrimidines, and other amino acids. [NIH] Serine Endopeptidases: Any member of the group of endopeptidases containing at the active site a serine residue involved in catalysis. EC 3.4.21. [NIH] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [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

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in atrophic rhinitis of pigs. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [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]

Shunt: A surgically created diversion of fluid (e.g., blood or cerebrospinal fluid) from one area of the body to another area of the body. [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] Sigma Factor: A protein which is a subunit of RNA polymerase. It effects initiation of specific RNA chains from DNA. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Silicon: A trace element that constitutes about 27.6% of the earth's crust in the form of silicon dioxide. It does not occur free in nature. Silicon has the atomic symbol Si, atomic number 14, and atomic weight 28.09. [NIH] Silicon Dioxide: Silica. Transparent, tasteless crystals found in nature as agate, amethyst, chalcedony, cristobalite, flint, sand, quartz, and tridymite. The compound is insoluble in water or acids except hydrofluoric acid. [NIH] Skin test: A test for an immune response to a compound by placing it on or under the skin. [NIH]

Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smallpox: A generalized virus infection with a vesicular rash. [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] 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] 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] 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

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types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [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] Sperm: The fecundating fluid of the male. [NIH] Spheroplasts: Cells, usually bacteria or yeast, which have partially lost their cell wall, lost their characteristic shape and become round. [NIH] 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] Spinal Nerves: The 31 paired peripheral nerves formed by the union of the dorsal and ventral spinal roots from each spinal cord segment. The spinal nerve plexuses and the spinal roots are also included. [NIH] Spirochete: Lyme disease. [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] Spores: The reproductive elements of lower organisms, such as protozoa, fungi, and cryptogamic plants. [NIH] Sputa: The material expelled from the respiratory passages by coughing or clearing the throat. [NIH] Sputum: The material expelled from the respiratory passages by coughing or clearing the throat. [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] Sterile: Unable to produce children. [NIH] Sterilization: The destroying of all forms of life, especially microorganisms, by heat, chemical, or other means. [NIH] 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] 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] 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]

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Streptomycin: O-2-Deoxy-2-(methylamino)-alpha-L-glucopyranosyl-(1-2)-O-5- deoxy-3-Cformyl-alpha-L-lyxofuranosyl-(1-4)-N,N'-bis(aminoiminomethyl)-D-streptamine. Antibiotic substance produced by the soil actinomycete Streptomyces griseus. It acts by inhibiting the initiation and elongation processes during protein synthesis. [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] Stringency: Experimental conditions (e. g. temperature, salt concentration) used during the hybridization of nucleic acids. [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] Structure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Other factors contributing to structure-activity relationship include chemical reactivity, electronic effects, resonance, and inductive effects. [NIH] Subacute: Somewhat acute; between acute and chronic. [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] 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] Subtrochanteric: Below a trochanter. [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] 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] Sulfuric acid: A strong acid that, when concentrated is extemely corrosive to the skin and mucous membranes. It is used in making fertilizers, dyes, electroplating, and industrial explosives. [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]

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Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [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] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Surface Plasmon Resonance: A biosensing technique in which biomolecules capable of binding to specific analytes or ligands are first immobilized on one side of a metallic film. Light is then focused on the opposite side of the film to excite the surface plasmons, that is, the oscillations of free electrons propagating along the film's surface. The refractive index of light reflecting off this surface is measured. When the immobilized biomolecules are bound by their ligands, an alteration in surface plasmons on the opposite side of the film is created which is directly proportional to the change in bound, or adsorbed, mass. Binding is measured by changes in the refractive index. The technique is used to study biomolecular interactions, such as antigen-antibody binding. [NIH] 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]

Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Synapses: Specialized junctions at which a neuron communicates with a target cell. At classical synapses, a neuron's presynaptic terminal releases a chemical transmitter stored in synaptic vesicles which diffuses across a narrow synaptic cleft and activates receptors on the postsynaptic membrane of the target cell. The target may be a dendrite, cell body, or axon of another neuron, or a specialized region of a muscle or secretory cell. Neurons may also communicate through direct electrical connections which are sometimes called electrical synapses; these are not included here but rather in gap junctions. [NIH] Syphilis: A contagious venereal disease caused by the spirochete Treponema pallidum. [NIH]

Systemic: Affecting the entire body. [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] 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

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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] Tetanus Toxin: The toxin elaborated by Clostridium tetani. It is a protein with a molecular weight of about 150,000, probably consisting of two fragments, tetanolysin being the hemolytic and tetanospasmin the neurotoxic principle. The toxin causes disruption of the inhibitory mechanisms of the CNS, thus permitting uncontrolled nervous activity, leading to fatal convulsions. [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] Thioamides: Organic compounds containing the radical -CSNH2. [NIH] Thoracic: Having to do with 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] 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] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]

Thymidine Monophosphate: 5-Thymidylic acid. A thymine nucleotide containing one phosphate group esterified to the deoxyribose moiety. [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] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] Tissue Extracts: Preparations made from animal tissues or organs; they usually contain many components, any one of which may be pharmacologically or physiologically active; extracts may contain specific, but uncharacterized factors or proteins with specific actions. [NIH]

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]

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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] 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] 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] Toxicokinetics: Study of the absorption, distribution, metabolism, and excretion of test substances. [NIH] 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] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Trachoma: A chronic infection of the conjunctiva and cornea caused by Chlamydia trachomatis. [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 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] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Transforming Growth Factor beta: A factor synthesized in a wide variety of tissues. It acts synergistically with TGF-alpha in inducing phenotypic transformation and can also act as a negative autocrine growth factor. TGF-beta has a potential role in embryonal development, cellular differentiation, hormone secretion, and immune function. TGF-beta is found mostly as homodimer forms of separate gene products TGF-beta1, TGF-beta2 or TGF-beta3. Heterodimers composed of TGF-beta1 and 2 (TGF-beta1.2) or of TGF-beta2 and 3 (TGFbeta2.3) have been isolated. The TGF-beta proteins are synthesized as precursor proteins. [NIH]

Translating: Conversion from one language to another language. [NIH]

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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] 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] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Treatment Outcome: Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, practicability, etc., of these interventions in individual cases or series. [NIH]

Tricuspid Atresia: Absence of the orifice between the right atrium and ventricle, with the presence of an atrial defect through which all the systemic venous return reaches the left heart. As a result, there is left ventricular hypertrophy because the right ventricle is absent or not functional. [NIH] Trypanosomiasis: Infection with protozoa of the genus Trypanosoma. [NIH] Trypsin: A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. [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] Tubercle: A rounded elevation on a bone or other structure. [NIH] Tubercular: Of, pertaining to, or resembling tubercles or nodules. [EU] Tuberculin: A sterile liquid containing the growth products of, or specific substances extracted from, the tubercle bacillus; used in various forms in the diagnosis of tuberculosis. [NIH]

Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tuberculostatic: Inhibiting the growth of Mycobacterium tuberculosis. [EU] 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] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] 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] 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] Urease: An enzyme that catalyzes the conversion of urea and water to carbon dioxide and

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ammonia. EC 3.5.1.5. [NIH] Ureters: Tubes that carry urine from the kidneys 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 urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [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] Uveitis: An inflammation of part or all of the uvea, the middle (vascular) tunic of the eye, and commonly involving the other tunics (the sclera and cornea, and the retina). [EU] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccines: Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa, or rickettsiae), antigenic proteins derived from them, or synthetic constructs, administered for the prevention, amelioration, or treatment of infectious and other diseases. [NIH]

Vaccinia: The cutaneous and occasional systemic reactions associated with vaccination using smallpox (variola) vaccine. [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] Valves: Flap-like structures that control the direction of blood flow through the heart. [NIH] Variola: A generalized virus infection with a vesicular rash. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasculitis: Inflammation of a blood vessel. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vegetative: 1. Concerned with growth and with nutrition. 2. Functioning involuntarily or unconsciously, as the vegetative nervous system. 3. Resting; denoting the portion of a cell cycle during which the cell is not involved in replication. 4. Of, pertaining to, or characteristic of plants. [EU] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venereal: Pertaining or related to or transmitted by sexual contact. [EU] Venous: Of or pertaining to the veins. [EU] 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

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body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Vibrio: A genus of Vibrionaceae, made up of short, slightly curved, motile, gram-negative rods. Various species produce cholera and other gastrointestinal disorders as well as abortion in sheep and cattle. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Proteins: Proteins found in any species of virus. [NIH] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [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] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] 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] Vulgaris: An affection of the skin, especially of the face, the back and the chest, due to chronic inflammation of the sebaceous glands and the hair follicles. [NIH] War: Hostile conflict between organized groups of people. [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]

Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to

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treat cancer. [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] Zebrafish: A species of North American fishes of the family Cyprinidae. They are used in embryological studies and to study the effects of certain chemicals on development. [NIH] Zoonoses: Diseases of non-human animals that may be transmitted to man or may be transmitted from man to non-human animals. [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]

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INDEX A Abdominal, 5, 233, 250, 265, 276, 277 Aberrant, 233, 248 Abscess, 107, 233 Acanthocephala, 233, 259 Acatalasia, 233, 242 Acetylcholine, 233, 274 Acquired Immunodeficiency Syndrome, 173, 184, 233, 260 Acute leukemia, 107, 233 Acute myelogenous leukemia, 233 Acute myeloid leukemia, 98, 233 Acute nonlymphocytic leukemia, 233 Acyl, 10, 75, 159, 162, 233 Adaptation, 34, 42, 87, 233, 272 Adduct, 9, 87, 234 Adenine, 234, 282 Adenosine, 115, 234 Adenosine Kinase, 115, 234 Adenovirus, 199, 234 Adenylate Cyclase, 22, 234, 244 Adjustment, 233, 234 Adjuvant, 24, 30, 38, 147, 234 Adoptive Transfer, 14, 234 Adrenal Medulla, 234, 242, 253, 274 Adrenergic, 234, 251, 253, 289 Adverse Effect, 32, 234, 286 Aerobic, 43, 178, 234, 271, 272 Aerosol, 4, 13, 25, 38, 58, 65, 99, 138, 156, 234 Affinity, 15, 31, 87, 98, 164, 234, 235, 286 Agar, 70, 80, 95, 174, 234, 235, 248, 262 Agarose, 235, 262 Agonist, 235, 251 Alanine, 54, 113, 235 Albumin, 235, 275 Alcohol Dehydrogenase, 150, 235 Algorithms, 182, 235, 240 Alimentary, 235, 276 Alkaline, 148, 235, 236, 242 Alkaloid, 140, 146, 235 Alleles, 26, 48, 171, 235 Allogeneic, 107, 235 Allogeneic bone marrow transplantation, 107, 235 Allylamine, 235, 236 Alternative medicine, 206, 235 Ambroxol, 146, 235

Amine, 13, 236, 260 Amino acid, 10, 46, 167, 171, 172, 173, 179, 235, 236, 237, 238, 245, 248, 249, 257, 258, 260, 268, 270, 274, 275, 277, 278, 280, 281, 284, 285, 288, 290, 292 Amino Acid Sequence, 167, 171, 236, 237, 257 Ammonia, 236, 258, 292, 293 Amplification, 67, 71, 72, 81, 83, 84, 93, 121, 123, 130, 161, 180, 193, 222, 236, 267 Anaerobic, 8, 32, 176, 236 Anaesthesia, 236, 263 Anal, 236, 253 Analog, 8, 15, 236 Analogous, 29, 52, 236, 251, 291 Analytes, 236, 289 Anaphylatoxins, 236, 246 Anemia, 236, 256, 269 Anergic, 30, 236 Anergy, 109, 178, 236 Angiogenesis, 236, 269 Animal model, 16, 20, 26, 27, 30, 35, 42, 44, 163, 237 Anions, 235, 237, 265, 289 Annealing, 237, 267, 279 Anthrax, 51, 199, 237 Antibacterial, 140, 168, 178, 237, 251, 265, 287 Anticoagulant, 237, 281 Antigen-Antibody Complex, 237, 246 Antigen-presenting cell, 237, 250 Anti-infective, 55, 237, 261 Anti-inflammatory, 237, 284 Antilymphocyte Serum, 237, 268 Antineoplastic, 237, 256 Antioxidant, 43, 237, 276 Antiserum, 238, 239 Antitoxin, 36, 238 Antituberculosis, 5, 15, 18, 53, 181, 185, 238 Antiviral, 140, 238, 256, 264 Aplastic anemia, 95, 238 Apolipoproteins, 238, 256, 267 Apoptosis, 6, 23, 48, 92, 94, 124, 137, 238 Aqueous, 125, 238, 242, 249, 252, 261 Archaea, 238, 270 Arginine, 46, 65, 236, 238, 274, 292 Arterial, 235, 238, 244, 248, 261, 281, 289

298


Arteries, 238, 241, 248, 267, 270, 282 Aspartic, 238, 253 Aspartic Endopeptidases, 238, 253 Aspiration, 136, 238 Asthenia, 236, 238 Asymptomatic, 27, 36, 162, 233, 238 Atrial, 239, 248, 292 Atrioventricular, 239, 248 Atrium, 239, 248, 292, 293 Attenuated, 6, 23, 31, 39, 40, 48, 54, 59, 67, 92, 175, 189, 195, 239, 293 Attenuation, 22, 35, 44, 61, 102, 239 Atypical, 13, 159, 170, 239 Autoantibodies, 176, 239 Autoantigens, 239 Autoimmune disease, 196, 239 Autonomic, 233, 239, 274, 277 Autopsy, 93, 239 Avidity, 96, 239 Axons, 239, 277 B Bacillus, 31, 36, 51, 59, 64, 73, 82, 110, 118, 127, 162, 188, 193, 194, 237, 239, 292 Bacteremia, 39, 93, 239 Bacterial Infections, 12, 17, 176, 187, 222, 239, 244, 266 Bacterial Physiology, 46, 234, 239 Bacterial Proteins, 23, 179, 239 Bacterial toxin, 238, 239 Bacterial Vaccines, 175, 239 Bactericidal, 8, 14, 54, 93, 239, 254 Bacteriophage, 49, 239, 291, 294 Bacteriophage lambda, 49, 239 Bacterium, 32, 54, 58, 166, 179, 181, 188, 200, 239, 240, 260, 272, 275, 282, 283 Basement Membrane, 240, 254 Basophils, 240, 259, 266 Benign, 240, 259, 273 Beta-Thromboglobulin, 240, 265 Bezafibrate, 8, 240 Bile, 240, 256, 261, 267, 287 Bioavailability, 29, 240 Biological therapy, 240, 259 Biological Transport, 240, 250 Biomolecular, 240, 289 Biopsy, 240, 277 Biosynthesis, 9, 29, 43, 54, 62, 63, 65, 77, 172, 188, 240, 285 Biotechnology, 45, 60, 89, 206, 217, 240 Bioterrorism, 38, 240 Biotransformation, 241 Bladder, 5, 241, 247, 293

Blast phase, 241, 245 Blastocyst, 241, 247 Blood Platelets, 241, 279, 285 Blood pressure, 241, 261, 271, 282, 286 Blood vessel, 236, 241, 242, 248, 253, 258, 260, 268, 277, 288, 290, 293 Blot, 63, 84, 88, 122, 179, 241, 275 Body Fluids, 161, 177, 241, 252, 286 Bone Marrow, 107, 233, 238, 241, 245, 254, 257, 262, 268 Bone Marrow Transplantation, 107, 241 Bowel, 236, 241, 265, 266, 277, 287 Bowel Movement, 241, 287 Bradykinin, 241, 274 Bronchi, 241, 253 Bronchiectasis, 50, 241 Bronchoalveolar Lavage, 98, 241, 242 Bronchoalveolar Lavage Fluid, 98, 242 C Calcium, 242, 246, 261, 269, 281 Canonical, 187, 242 Capsules, 37, 242 Carbohydrate, 160, 242, 258, 280, 285 Carbon Dioxide, 242, 283, 292 Carcinoembryonic Antigen, 199, 242 Carcinogen, 234, 242 Carcinogenic, 242, 264, 280, 287 Cardiac, 235, 242, 248, 252, 253, 273, 284, 287 Cardiovascular, 242, 285 Case report, 106, 150, 242, 255 Case-Control Studies, 23, 242, 253 Catalase, 9, 18, 76, 155, 188, 233, 242 Catecholamine, 242, 251 Cathepsins, 10, 242 Cations, 242, 265 Causal, 242, 253, 285, 289 Cause of Death, 9, 15, 24, 26, 30, 34, 40, 50, 54, 158, 160, 173, 193, 197, 242 Cell Cycle, 41, 243, 293 Cell Death, 238, 243, 257, 273 Cell Differentiation, 196, 243 Cell Division, 239, 243, 259, 271, 278, 285 Cell membrane, 165, 240, 243, 265, 278 Cell Physiology, 54, 243 Cell Respiration, 243, 271, 283 Cell Size, 243, 255 Cell Survival, 243, 259 Cellular adhesion, 7, 243 Cellulose, 243, 256, 278 Central Nervous System, 233, 235, 243, 258, 259, 285

299

Centrifugation, 16, 243 Cerebral, 112, 243, 247, 253, 269 Cerebrospinal, 63, 66, 120, 243, 286 Cerebrospinal fluid, 66, 120, 243, 286 Cerebrum, 243 Cervical, 123, 243 Cervix, 243 Chaperonin 10, 244 Chaperonin 60, 244 Chaperonins, 176, 244, 271 Chemical Warfare, 244, 249 Chemical Warfare Agents, 244, 249 Chemokines, 12, 32, 33, 51, 60, 94, 116, 244 Chemotactic Factors, 244, 246 Chemotherapeutic agent, 50, 244 Chemotherapy, 19, 91, 93, 97, 98, 103, 107, 112, 123, 126, 135, 150, 151, 181, 182, 244 Chlorophyll, 244, 256 Cholera, 33, 189, 244, 285, 294 Cholera Toxin, 33, 189, 244 Cholera Vaccines, 189, 244 Cholesterol, 240, 244, 245, 256, 267, 287 Cholesterol Esters, 244, 267 Chromatin, 238, 244 Chromosomal, 27, 49, 55, 236, 244, 245, 257, 278 Chromosome, 27, 32, 34, 35, 49, 186, 245, 259, 267, 285 Chronic lymphocytic leukemia, 245 Chronic myelogenous leukemia, 241, 245 Chronic phase, 127, 245 Chylomicrons, 245, 267 Ciprofloxacin, 76, 135, 245 CIS, 21, 245 Clear cell carcinoma, 245, 250 Clinical trial, 6, 14, 217, 245, 247, 269, 272, 281, 283 Clone, 19, 27, 33, 45, 58, 186, 245 Cloning, 49, 78, 141, 150, 165, 171, 240, 245, 248, 267 Cluster Analysis, 21, 245 Codon, 66, 88, 165, 245, 257 Coenzyme, 13, 245 Cofactor, 245, 274, 281, 290 Cohort Studies, 246, 253 Coliphages, 239, 246 Collagen, 236, 240, 246, 254, 255, 269, 279 Colloidal, 235, 246, 252 Colon, 125, 242, 246 Combinatorial, 13, 55, 246 Complement, 40, 92, 98, 176, 236, 246, 257, 268

Complementary and alternative medicine, 145, 154, 246 Complementary medicine, 145, 246 Complementation, 88, 247 Compliance, 4, 40, 162, 247 Computational Biology, 46, 217, 247 Computed tomography, 5, 247 Computerized axial tomography, 247 Computerized tomography, 247 Conception, 186, 247, 255 Conjugated, 189, 195, 247, 249 Conjunctiva, 247, 263, 291 Connective Tissue, 241, 246, 247, 255, 268, 277 Consciousness, 247, 249, 251, 283 Contamination, 65, 72, 79, 83, 106, 118, 119, 247 Contraindications, ii, 247 Controlled study, 49, 247 Convulsions, 247, 290 Coordination, 9, 41, 247 Cor, 18, 247, 248 Cor pulmonale, 18, 248 Cornea, 248, 285, 291, 293 Coronary, 248, 270 Coronary Thrombosis, 248, 270 Corpus, 248, 280, 294 Cosmids, 186, 248 Cranial, 248, 259, 277 Crossing-over, 248, 283 Cross-Sectional Studies, 248, 253 Culture Media, 234, 248 Cultured cells, 248 Curative, 248, 290 Cutaneous, 51, 150, 158, 237, 248, 266, 293 Cyclic, 22, 53, 234, 248, 259, 274, 285 Cysteine, 10, 29, 53, 244, 248, 249, 253, 288 Cysteine Endopeptidases, 248, 253 Cystine, 248, 249 Cytochrome, 39, 249 Cytokine, 17, 19, 20, 23, 24, 28, 35, 48, 75, 99, 114, 142, 151, 163, 168, 176, 177, 196, 199, 249, 264 Cytoplasm, 87, 238, 240, 243, 244, 249, 253, 284, 293 Cytoplasmic Vesicles, 249, 277 Cytotoxic, 20, 41, 113, 114, 140, 169, 249, 263 Cytotoxicity, 24, 235, 249, 266 D Data Collection, 202, 249 De novo, 19, 249

300


Decontamination, 104, 249 Degenerative, 249, 260 Dehydration, 244, 249 Deletion, 31, 40, 49, 59, 64, 65, 82, 99, 106, 175, 238, 249 Dementia, 233, 249 Denaturation, 249, 267, 279 Dendrites, 249, 274 Dendritic, 11, 33, 51, 114, 124, 249, 250 Dendritic cell, 11, 33, 51, 114, 124, 250 Density, 50, 134, 240, 243, 250, 255, 267, 275 Deoxyribonucleic, 250, 284 DES, 41, 140, 142, 179, 236, 250 Desensitization, 250, 262 Detergents, 18, 250 Detoxification, 29, 43, 125, 250 Deuterium, 250, 261 Developed Countries, 187, 250 Developing Countries, 4, 16, 47, 119, 161, 162, 166, 182, 184, 185, 187, 197, 250 Diagnostic procedure, 157, 206, 250 Dialyzer, 250, 259 Diaphragm, 250, 279 Diarrhea, 189, 250 Diastolic, 250, 261 Diffusion, 35, 240, 250, 262, 263 Digestion, 235, 240, 241, 250, 265, 267, 287 Dihydrotestosterone, 250, 283 Diphtheria, 12, 238, 250 Diphtheria Toxin, 12, 250 Diploid, 247, 251, 278 Direct, iii, 10, 11, 18, 24, 28, 39, 40, 44, 47, 52, 57, 58, 63, 64, 65, 68, 70, 71, 72, 76, 77, 81, 82, 84, 88, 89, 101, 104, 118, 121, 123, 128, 130, 135, 146, 164, 174, 183, 222, 251, 261, 283, 289 Discrimination, 64, 68, 70, 83, 251 Disinfectant, 251, 254 Disinfection, 4, 251 Dissociation, 234, 251, 265 Distal, 27, 251 Domesticated, 251, 259 Dopamine, 13, 251, 274, 278 Drug Design, 20, 35, 45, 55, 210, 211, 251 Drug Interactions, 210, 251 Drug Resistance, 6, 21, 55, 61, 78, 80, 87, 122, 123, 129, 136, 142, 162, 173, 180, 202, 251 Drug Tolerance, 251, 290 Duct, 252, 268 Dura mater, 252, 270, 276

Dyes, 240, 252, 255, 288 E Effector, 6, 10, 19, 33, 72, 74, 233, 246, 252, 266 Effector cell, 252, 266 Efficacy, 11, 16, 19, 26, 30, 44, 48, 76, 81, 134, 162, 168, 189, 199, 251, 252, 292 Elastic, 252, 289 Electrolyte, 252, 286 Electrons, 238, 252, 265, 276, 282, 289 Electrophoresis, 21, 73, 88, 98, 100, 252, 262 Electroplating, 252, 288 Emaciation, 233, 252 Embryo, 26, 241, 243, 252, 263 Emollient, 252, 258 Emulsions, 235, 252 Endemic, 48, 167, 244, 252, 269 Endocarditis, 93, 136, 252 Endocardium, 252 Endogenous, 199, 239, 251, 252, 291 Endopeptidases, 37, 238, 242, 248, 252, 270, 277, 285 Endothelial cell, 252, 253, 264, 290 Endothelium, 253, 274, 279 Endothelium-derived, 253, 274 Endotoxins, 246, 253 Enteropeptidase, 253, 292 Environmental Health, 59, 216, 218, 253 Enzymatic, 29, 172, 236, 242, 246, 253, 260, 279 Eosinophil, 114, 253 Eosinophilia, 141, 175, 253 Eosinophilic, 253 Epidemic, 26, 164, 186, 188, 191, 253 Epidemiologic Studies, 4, 46, 253 Epidemiological, 22, 25, 29, 46, 64, 78, 81, 158, 166, 253, 255 Epidermal, 199, 253, 266 Epidermis, 253, 266 Epinephrine, 234, 251, 253, 274, 292 Epistaxis, 253, 282 Epithelial, 54, 80, 87, 117, 189, 240, 244, 253 Epithelial Cells, 54, 80, 87, 244, 253 Epitope, 30, 39, 41, 99, 113, 199, 200, 254 Erythrocytes, 236, 241, 254 Erythropoietin, 196, 254 Ethanol, 17, 235, 254, 255 Eukaryotic Cells, 254, 263, 275 Excitation, 254, 255, 274 Exhaustion, 254, 269

301

Exogenous, 29, 163, 199, 200, 241, 252, 254 Expiration, 254, 283 Extracellular, 6, 16, 30, 37, 42, 48, 50, 133, 158, 173, 247, 254, 255, 269, 271, 286 Extracellular Matrix, 37, 50, 247, 254, 255, 269 Extracellular Matrix Proteins, 254, 269 Extracellular Space, 254 Extrapyramidal, 251, 254 Extremity, 171, 254 Eye Infections, 234, 254 F Family Planning, 217, 254 Farnesyl, 52, 254 Fat, 241, 247, 254, 267, 289 Fatal Outcome, 254, 282 Feces, 242, 255, 287 Fermentation, 45, 235, 255, 284 Fertilizers, 255, 288 Fetus, 254, 255, 280, 293 Fibrinogen, 255, 279, 290 Fibroblasts, 255, 264, 272 Fibrosis, 18, 37, 50, 235, 255, 284 Filtration, 170, 198, 200, 255 Fistula, 125, 255 Flatus, 255, 256 Flow Cytometry, 14, 17, 32, 104, 255 Fluorescence, 14, 23, 67, 132, 255 Fluorescent Dyes, 255 Folate, 19, 43, 255, 256 Fold, 8, 14, 45, 47, 176, 255 Folic Acid, 255, 256 Free Radicals, 237, 251, 256 Fungi, 254, 256, 270, 287, 293, 295 Fungus, 158, 173, 200, 256 G Gallbladder, 233, 256 Gamma-interferon, 140, 256 Gangrenous, 256, 285 Gas, 75, 109, 236, 242, 250, 255, 256, 261, 274, 288 Gastric, 28, 47, 100, 256, 260 Gastrin, 256, 261 Gastrointestinal, 126, 241, 242, 245, 253, 254, 256, 269, 285, 288, 294 Gastrointestinal tract, 242, 254, 256, 285 Gels, 22, 256 Gemfibrozil, 8, 256 Gene Expression, 21, 22, 27, 28, 32, 34, 42, 44, 47, 50, 59, 101, 115, 120, 128, 168, 256, 257 Gene Expression Profiling, 59, 257

Gene Therapy, 234, 257 Generator, 70, 103, 257 Genetic Code, 257, 274 Genetic Engineering, 240, 245, 257 Genetic Markers, 60, 61, 257 Genetic Techniques, 46, 257 Genetic testing, 257, 279 Genetic Vectors, 248, 257 Genetics, 7, 9, 20, 34, 40, 45, 49, 55, 69, 103, 110, 111, 128, 134, 190, 257 Genital, 5, 245, 257 Genitourinary system, 4, 257 Genomics, 20, 45, 46, 186, 257 Genotype, 69, 70, 86, 103, 110, 257, 278 Giant Cells, 257, 284 Ginseng, 257 Gland, 234, 258, 268, 269, 273, 276, 285, 287, 290 Glomerular, 5, 258 Glomerulus, 258, 273 Glucose, 69, 150, 243, 258, 260, 264, 284 Glutamic Acid, 256, 258, 274 Glutamine, 74, 76, 111, 113, 198, 258 Glycerol, 174, 258, 278 Glycine, 236, 258, 274, 285 Glycoprotein, 105, 199, 242, 254, 255, 257, 258, 272, 290, 292 Glycoside, 258, 261, 284 Glycosylation, 105, 258 Gonadal, 258, 287 Governing Board, 258, 280 Gp120, 121, 199, 258 Grade, 4, 258 Gram-negative, 170, 258, 284, 294 Gram-Negative Bacteria, 258, 284 Gram-positive, 37, 168, 170, 258, 272, 287 Gram-Positive Rods, 37, 259 Granulocyte, 196, 259, 264 Granuloma, 26, 32, 37, 50, 259 Growth factors, 50, 259 Guanylate Cyclase, 259, 274 Guinea Pigs, 58, 59, 74, 86, 102, 111, 259 H Habitat, 259, 272, 274 Hair follicles, 259, 294 Haploid, 259, 278 Haplotypes, 169, 259 Haptens, 234, 259 Headache, 259, 263, 282 Heart failure, 248, 259 Heat-Shock Proteins, 127, 259, 271 Heat-Shock Proteins 90, 259, 271

302


Helminths, 27, 259, 273 Heme, 9, 249, 259 Hemiparesis, 5, 259 Hemodialysis, 5, 250, 259 Hemoglobin, 236, 254, 259, 260 Hemolytic, 260, 290 Hemorrhage, 5, 259, 260, 288 Hemostasis, 260, 285 Hepatitis, 3, 171, 260 Hepatocyte, 130, 260 Hereditary, 260, 277 Heredity, 256, 257, 260 Heterogeneity, 74, 79, 112, 114, 234, 260 Histamine, 236, 260 Histidine, 35, 260 Histology, 14, 260 Homeless Persons, 4, 260 Homodimer, 260, 291 Homologous, 12, 41, 68, 235, 248, 257, 260, 272, 285 Homotypic, 7, 260 Hormone, 53, 250, 253, 254, 256, 261, 269, 280, 285, 289, 290, 291 Hospices, 160, 261 Human growth hormone, 196, 261 Humoral, 28, 163, 261 Humour, 261 Hybrid, 55, 59, 186, 245, 261, 275 Hybridoma, 163, 261 Hydrogen, 148, 152, 181, 192, 235, 236, 242, 249, 250, 254, 261, 267, 271, 276, 281, 289 Hydrogen Peroxide, 152, 192, 242, 261, 267, 289 Hydrogenation, 261, 282 Hydrolases, 45, 261, 278 Hydrolysis, 53, 238, 241, 261, 277, 278, 280, 281, 292 Hydrophobic, 13, 133, 250, 261, 265, 267 Hydroxyproline, 236, 246, 261 Hypercalcemia, 5, 261 Hyperreflexia, 261, 290 Hypersensitivity, 28, 72, 167, 250, 253, 261 Hypertension, 4, 259, 261 Hyperthermia, 259, 261 Hypertrophy, 248, 262, 292 Hypoxia, 8, 262 Hypoxic, 84, 262 I Idiopathic, 262, 284 Immune function, 262, 263, 291 Immune Sera, 262

Immunization, 11, 16, 39, 74, 116, 195, 198, 199, 234, 262, 263 Immunoassay, 101, 131, 195, 262 Immunocompromised, 44, 159, 168, 191, 262 Immunodeficiency, 3, 4, 5, 18, 51, 68, 69, 78, 79, 92, 114, 125, 182, 184, 191, 233, 260, 262 Immunodeficiency syndrome, 4, 262 Immunodiffusion, 235, 262 Immunoelectrophoresis, 151, 235, 262 Immunogenic, 147, 158, 173, 176, 194, 195, 262 Immunoglobulin, 96, 116, 237, 262, 271 Immunohistochemistry, 14, 262 Immunologic, 27, 234, 244, 260, 262, 268 Immunosuppression, 17, 177, 262, 263, 268, 275, 288 Immunosuppressive, 38, 262, 263 Immunosuppressive Agents, 262, 263 Immunotherapy, 234, 240, 250, 263 Implantation, 247, 263 In situ, 26, 116, 263 In Situ Hybridization, 26, 67, 263 Incision, 263, 265 Incubation, 116, 263, 266 Induction, 6, 12, 17, 19, 24, 50, 72, 113, 117, 152, 156, 165, 263 Infarction, 240, 248, 263, 270 Infection Control, 3, 97, 126, 128, 203, 263 Infiltration, 48, 263 Influenza, 199, 263 Ingestion, 68, 146, 237, 264, 270 Inhalation, 44, 168, 234, 264 Initiation, 33, 41, 49, 68, 165, 264, 275, 283, 286, 288, 291 Initiator, 41, 264 Inorganic, 192, 264 Inositol, 7, 264, 285 Inotropic, 251, 264 Insight, 25, 26, 36, 37, 42, 54, 60, 168, 264 Instillation, 59, 264 Interferon, 16, 34, 37, 67, 87, 97, 115, 118, 124, 156, 162, 177, 256, 264 Interferon-alpha, 264 Interleukin-1, 61, 87, 118, 124, 131, 137, 156, 162, 177, 264 Interleukin-10, 87, 131, 137, 156, 264 Interleukin-12, 61, 118, 124, 162, 177, 264 Interleukin-2, 163, 264 Interleukin-4, 118, 264 Interleukin-8, 76, 137, 149, 264

303

Interleukins, 163, 196, 263, 265 Intermittent, 14, 265, 277 International Agencies, 29, 265 Interstitial, 5, 33, 48, 242, 254, 265, 273 Intestinal, 27, 244, 253, 265 Intestine, 241, 265, 283, 286, 287 Intramuscular, 265, 276 Intraperitoneal, 17, 265 Intravenous, 4, 5, 17, 34, 148, 152, 265, 276 Intrinsic, 78, 234, 240, 265 Invasive, 47, 158, 173, 198, 199, 265 Invertebrates, 265 Involuntary, 265, 273, 286 Ion Channels, 265 Ionization, 41, 265 Ions, 149, 251, 252, 261, 265 Isocitrate Lyase, 197, 265 Isoenzyme, 73, 265 Isonicotinic, 9, 265 Isoprenoid, 53, 265 K Kb, 34, 49, 216, 265 Keratinocytes, 264, 266 Killer Cells, 266 Kinetic, 10, 13, 45, 266 L Labile, 246, 266 Laceration, 266, 290 Laryngeal, 4, 266 Larynx, 266 Latency, 8, 31, 34, 41, 266 Latent, 8, 14, 27, 30, 31, 34, 36, 41, 42, 44, 56, 94, 96, 112, 119, 178, 266 Laxative, 234, 266 Leishmaniasis, 158, 266 Lentivirus, 260, 266 Leprosy, 45, 158, 163, 165, 167, 179, 266 Lesion, 134, 259, 266, 267, 284 Lethal, 41, 51, 60, 199, 239, 250, 266 Leucocyte, 114, 253, 266 Leukemia, 107, 245, 257, 266 Leukocytes, 30, 240, 241, 244, 264, 265, 266, 272, 277, 292 Levofloxacin, 97, 266 Ligands, 7, 55, 197, 266, 289 Ligase, 29, 55, 69, 75, 106, 194, 267 Ligase Chain Reaction, 69, 106, 194, 267 Ligation, 63, 83, 267 Linkage, 23, 27, 57, 89, 120, 257, 267 Lipid, 8, 120, 151, 156, 160, 238, 252, 256, 258, 267, 276 Lipid Peroxidation, 267, 276

Lipopolysaccharides, 267, 284 Lipoprotein, 87, 98, 156, 162, 258, 267, 294 Liposarcoma, 5, 267 Liposomes, 16, 267 Liver, 39, 233, 235, 240, 254, 255, 256, 260, 267, 284, 292 Lobe, 261, 267, 276 Localization, 30, 34, 262, 267 Localized, 5, 233, 250, 263, 267, 272, 278, 290 Locomotion, 267, 278 Loop, 30, 121, 267 Low-density lipoprotein, 267 Luciferase, 61, 77, 83, 85, 121, 267 Lymph, 51, 53, 81, 122, 133, 243, 253, 260, 261, 268, 273, 284 Lymph node, 51, 122, 133, 243, 268, 273, 284 Lymphadenitis, 94, 123, 268, 273 Lymphadenopathy, 260, 268 Lymphatic, 253, 263, 268, 287, 290 Lymphatic system, 268, 287, 290 Lymphocyte, 4, 62, 72, 175, 233, 237, 262, 266, 268, 269, 272 Lymphocyte Count, 233, 268 Lymphocyte Depletion, 4, 262, 268 Lymphoid, 237, 266, 268 Lymphokines, 268 Lysine, 175, 268, 292 Lysosome, 54, 268, 277 Lytic, 268, 285, 294 M Macrophage Activation, 52, 268 Major Histocompatibility Complex, 10, 259, 264, 268 Malaria, 199, 268, 269 Malaria, Falciparum, 268, 269 Malaria, Vivax, 268, 269 Malate Synthase, 197, 269 Malignant, 233, 237, 269, 273 Malnutrition, 30, 235, 269 Manifest, 32, 188, 269 Mannans, 256, 269 Mastitis, 269, 285 Matrix metalloproteinase, 37, 50, 269 Maximum Tolerated Dose, 44, 251, 269 Median survival time, 22, 269 Mediate, 23, 25, 30, 34, 178, 251, 266, 269, 271 Mediator, 264, 269, 279, 285 MEDLINE, 217, 269 Melanin, 269, 278, 292

304


Membrane Proteins, 267, 269 Memory, 14, 20, 30, 33, 40, 74, 77, 118, 183, 249, 270 Meninges, 243, 252, 270 Meningitis, 30, 63, 120, 270 Mental, iv, 6, 216, 218, 222, 249, 251, 270, 282, 285 Mental Health, iv, 6, 216, 218, 270, 282 Mentors, 29, 54, 270 Mercury, 255, 270 Metabolite, 235, 241, 270, 280 Metalloendopeptidases, 253, 270 Metastasis, 269, 270 Methanol, 170, 270 Methionine, 270, 288 Methyltransferase, 141, 270 MI, 84, 87, 92, 125, 231, 270 Mice Minute Virus, 270, 276 Microbe, 15, 42, 46, 270, 291 Microorganism, 32, 36, 54, 90, 159, 189, 245, 270, 276, 294 Micro-organism, 173 Micro-organism, 270 Micro-organism, 278 Micro-organism, 285 Microspheres, 7, 16, 270 Migration, 26, 51, 202, 268, 271 Mitochondria, 244, 271, 275 Mitochondrial Swelling, 271, 273 Mitogen-Activated Protein Kinase Kinases, 271 Mitogen-Activated Protein Kinases, 25, 149, 271 Mitosis, 238, 271 Modeling, 20, 77, 251, 271 Modification, 15, 55, 77, 79, 120, 161, 236, 257, 271 Molecular Chaperones, 176, 244, 259, 271 Monitor, 8, 37, 148, 162, 167, 242, 271, 274 Monoclonal, 79, 85, 163, 164, 179, 271 Monoclonal antibodies, 79, 163, 164, 179, 271 Monocyte, 50, 51, 67, 68, 72, 117, 124, 131, 137, 146, 156, 162, 272 Monocyte Chemoattractant Protein-1, 137, 272 Mononuclear, 11, 19, 34, 48, 87, 134, 137, 162, 259, 272, 292 Morphological, 252, 256, 272 Morphology, 5, 61, 238, 268, 272 Motility, 272, 285 Mucociliary, 235, 272

Mucocutaneous, 266, 272 Mucolytic, 241, 272 Mucositis, 272, 290 Multicenter study, 105, 272 Multidrug resistance, 187, 188, 191, 272 Multivalent, 239, 272 Mutagenesis, 13, 19, 58, 59, 272 Mutagens, 272 Mutate, 8, 272 Myalgia, 264, 272 Mycobacterial disease, 179, 272 Mycobacteriophages, 77, 121, 272 Mycobacteriosis, 272, 273 Mycobacterium avium, 16, 17, 54, 67, 72, 77, 103, 140, 148, 177, 181, 187, 202, 272, 273 Mycobacterium avium Complex, 77, 177, 202, 273 Myeloma, 261, 273 Myocarditis, 250, 273 Myocardium, 270, 273 N Nasal Mucosa, 263, 273 Natural killer cells, 176, 264, 273 Nausea, 273, 282 NCI, 1, 215, 245, 273 Necrosis, 6, 80, 134, 238, 263, 270, 273, 284, 285 Nematoda, 259, 273 Neoplasm, 199, 273, 292 Nephrectomy, 5, 273 Nephritis, 5, 273 Nerve, 234, 239, 249, 269, 273, 274, 276, 284, 285, 287, 292 Nervous System, 243, 269, 273, 274, 282, 288, 289, 293 Networks, 21, 89, 273 Neural, 261, 273 Neurologic, 260, 274 Neuronal, 274, 277 Neurons, 249, 274, 289 Neuropeptide, 53, 274 Neurotoxic, 274, 290 Neurotransmitter, 233, 234, 236, 241, 251, 258, 260, 265, 274, 285, 288 Neutrophil, 95, 274 Niche, 46, 274 Nickel, 176, 274 Nitric Oxide, 24, 31, 117, 149, 193, 274 Nitrogen, 31, 83, 192, 193, 235, 236, 254, 258, 274, 292 Norepinephrine, 13, 234, 251, 274

305

Nuclear, 199, 252, 254, 273, 274 Nuclei, 168, 198, 252, 257, 271, 274, 281 Nucleic Acid Amplification Techniques, 99, 274 Nucleotidases, 261, 275 Nucleus, 238, 240, 244, 248, 249, 250, 254, 272, 275, 281, 287 O Occupational Exposure, 4, 275 Oligonucleotide Probes, 267, 275 Oligopeptides, 46, 275 On-line, 74, 231, 275 Opacity, 250, 275 Open Reading Frames, 49, 266, 275 Operon, 44, 49, 125, 275, 283 Opportunistic Infections, 56, 185, 233, 275 Organ Culture, 275, 290 Organelles, 243, 249, 275, 279 Ori region, 275, 283 Osteoporosis, 175, 275 Outpatient, 100, 275 Ovalbumin, 10, 141, 275 Oxazolidinones, 178, 275 Oxidation, 238, 241, 249, 267, 275, 276 Oxidative Stress, 81, 151, 276 Oxygen Consumption, 276, 283 P Pachymeningitis, 270, 276 Palliative, 261, 276, 290 P-Aminosalicylic Acid, 181, 276 Panax ginseng, 147, 276 Pancreas, 233, 276, 292 Paralysis, 259, 276 Parasite, 158, 159, 173, 276 Parasitic, 158, 173, 233, 259, 276, 284 Parenteral, 189, 276 Parietal, 276, 277, 279 Parotid, 276, 285 Particle, 276, 291 Parvovirus, 95, 270, 276 Patch, 17, 276 Paternity, 171, 276 Pathogen, 8, 17, 22, 23, 25, 26, 28, 32, 35, 42, 43, 50, 54, 55, 56, 57, 115, 123, 132, 151, 158, 162, 169, 173, 184, 185, 192, 199, 263, 276, 288 Pathologic, 18, 238, 240, 248, 261, 276, 277 Pathologic Processes, 238, 277 Pathologies, 179, 277 Pathophysiology, 25, 277 Patient Education, 222, 226, 228, 231, 277

Peptide, 13, 24, 30, 39, 67, 76, 95, 121, 169, 182, 236, 244, 252, 253, 261, 277, 280, 281 Peptide Hydrolases, 252, 261, 277 Percutaneous, 136, 277 Perfusion, 262, 277 Peripheral blood, 30, 134, 162, 264, 277 Peripheral Nerves, 167, 266, 277, 280, 287 Peritoneal, 5, 17, 265, 277 Peritoneal Cavity, 265, 277 Peritoneal Dialysis, 5, 277 Peritoneum, 277 Peroxidase, 9, 18, 76, 114, 155, 188, 267, 277 Peroxide, 148, 277 Phagocytosis, 7, 12, 28, 40, 52, 54, 142, 146, 151, 277 Phagosomes, 42, 77, 277 Pharmacodynamic, 14, 277 Pharmacokinetic, 278 Pharmacologic, 278, 291 Pharynx, 263, 278 Phenotype, 22, 49, 118, 141, 163, 247, 278 Phenylalanine, 278, 292 Phospholipids, 254, 264, 267, 278, 281 Phosphoric Monoester Hydrolases, 261, 278 Phosphorylated, 245, 271, 278 Phosphorylating, 121, 278 Phosphorylation, 271, 278, 281 Phylogeny, 110, 278 Physicochemical, 25, 278 Physiologic, 27, 235, 240, 278, 283 Physiology, 8, 42, 55, 130, 278, 288 Pigments, 278, 279 Pilot study, 19, 278 Plants, 146, 148, 150, 235, 240, 242, 257, 258, 272, 274, 278, 284, 287, 291, 293 Plasma, 235, 237, 240, 243, 244, 249, 255, 260, 273, 278, 279 Plasma cells, 237, 273, 278 Plasmid, 34, 36, 49, 172, 278, 293 Plasmin, 278, 279 Plasminogen, 95, 278, 279 Plasminogen Activators, 278, 279 Plastids, 244, 275, 279 Platelet Aggregation, 236, 274, 279 Platelet Factor 4, 265, 279 Platelets, 240, 274, 279 Platinum, 267, 279 Platyhelminths, 259, 279 Pleura, 279 Pleural, 98, 163, 279

306


Pneumonia, 102, 176, 247, 279 Point Mutation, 59, 66, 100, 180, 181, 279 Polymerase, 47, 62, 68, 77, 101, 106, 120, 125, 128, 134, 136, 168, 180, 279, 283, 286 Polymerase Chain Reaction, 47, 68, 77, 101, 106, 120, 125, 134, 136, 279 Polymorphic, 70, 85, 131, 140, 279 Polyneuritis, 250, 280 Polypeptide, 171, 175, 177, 194, 236, 246, 255, 278, 280, 281, 295 Polysaccharide, 160, 167, 235, 237, 243, 280 Postmenopausal, 275, 280 Potentiates, 264, 280 Practicability, 280, 292 Practice Guidelines, 218, 222, 280 Precursor, 251, 252, 253, 254, 274, 278, 279, 280, 291, 292 Prenatal, 252, 280 Presumptive, 8, 61, 65, 280 Prevalence, 6, 42, 52, 65, 73, 74, 90, 111, 112, 121, 172, 202, 280 Probe, 9, 10, 63, 64, 65, 68, 70, 71, 72, 76, 80, 82, 89, 120, 128, 134, 181, 194, 222, 267, 275, 280 Prodrug, 280 Progesterone, 280, 287 Progression, 23, 46, 51, 178, 184, 203, 237, 280 Progressive, 42, 168, 243, 249, 251, 273, 280, 292 Projection, 274, 280 Promoter, 35, 63, 280 Prophylaxis, 17, 176, 281, 293 Prospective study, 27, 49, 281 Protease, 18, 113, 281 Protein C, 35, 60, 160, 165, 179, 235, 236, 238, 239, 245, 267, 281, 292, 294 Protein Conformation, 236, 281 Protein Kinase C, 271, 281 Protein S, 19, 41, 45, 55, 181, 240, 250, 257, 261, 281, 284, 288 Protein-Serine-Threonine Kinases, 271, 281 Proteolytic, 246, 253, 255, 278, 279, 281 Proteome, 98, 281 Protocol, 4, 22, 164, 281 Protons, 261, 281, 282 Protozoa, 158, 173, 266, 270, 281, 287, 292, 293 Protozoal, 281 Protozoan, 199, 268, 281 Psittacosis, 159, 282

Public Health, 15, 21, 23, 25, 31, 32, 36, 39, 40, 56, 58, 59, 161, 165, 182, 185, 218, 282 Public Policy, 217, 282 Publishing, 3, 60, 201, 203, 282 Pulmonary hypertension, 248, 282 Pulse, 271, 282 Purines, 282, 285 Purulent, 5, 282 Pyrazinamide, 48, 65, 66, 67, 72, 80, 82, 86, 89, 91, 105, 109, 133, 138, 149, 282 Pyridoxal, 45, 282 Pyrimidines, 282, 285 Q Quinolones, 178, 282 R Rabies, 199, 282 Race, 271, 282 Radiation, 255, 256, 261, 262, 282, 294 Radioactive, 249, 261, 263, 265, 272, 274, 282 Radiological, 277, 282 Radiopharmaceutical, 257, 282 Randomized, 17, 49, 252, 283 Reactivation, 4, 8, 16, 20, 36, 56, 131, 168, 177, 283 Reagent, 184, 267, 283 Receptors, Serotonin, 283, 285 Recombinant, 16, 22, 33, 38, 39, 52, 58, 70, 76, 142, 151, 165, 169, 171, 172, 179, 186, 195, 199, 283, 293 Recombination, 41, 49, 257, 283 Rectum, 125, 241, 246, 255, 256, 283 Reductase, 8, 10, 29, 43, 75, 81, 82, 87, 142, 283 Refer, 1, 184, 246, 256, 267, 283, 291 Refraction, 283, 287 Refractory, 19, 83, 283 Regimen, 73, 162, 187, 188, 252, 283, 284 Reinfection, 56, 283 Relapse, 14, 24, 182, 283 Replication Origin, 41, 283 Replicon, 165, 283 Repressor, 12, 275, 283 Research Support, 36, 283 Respiration, 8, 32, 242, 271, 283, 284 Respirators, 130, 283 Resuscitation, 76, 117, 283 Retina, 284, 293, 294 Retreatment, 49, 284 Reversion, 14, 284 Rhamnose, 69, 172, 284 Rhinitis, 284, 286

307

Ribonuclease, 147, 284 Ribonucleic acid, 147, 284 Ribose, 234, 284 Ribosome, 284, 292 Rickettsiae, 284, 293 Rifamycins, 111, 284 Risk factor, 16, 107, 130, 203, 253, 281, 284 Rod, 168, 239, 240, 259, 284 S Salicylate, 87, 284 Salicylic, 181, 284 Saline, 241, 284 Saponins, 284, 287 Sarcoid, 18, 284 Sarcoidosis, 18, 90, 284 Sclera, 247, 285, 293 Screening, 7, 27, 28, 31, 34, 42, 55, 61, 63, 94, 104, 116, 126, 165, 174, 179, 196, 245, 285 Sebaceous, 285, 294 Second Messenger Systems, 285 Secretion, 12, 16, 61, 105, 114, 142, 146, 149, 151, 165, 168, 176, 260, 261, 265, 285, 291 Sedimentation, 243, 285 Segregation, 283, 285 Senescence, 177, 285 Senile, 275, 285 Sepsis, 107, 285 Septicaemia, 285 Sequence Analysis, 99, 187, 285 Sequencing, 19, 45, 49, 62, 63, 66, 83, 92, 100, 137, 171, 186, 206, 279, 285 Sequester, 15, 285 Serine, 53, 113, 253, 271, 281, 285, 292 Serine Endopeptidases, 253, 285 Serologic, 262, 285 Serotonin, 13, 274, 283, 285, 292 Serotypes, 168, 285 Serum, 174, 234, 235, 236, 237, 238, 246, 256, 262, 267, 285, 286, 292 Shock, 24, 86, 108, 179, 199, 244, 286, 292 Shunt, 197, 286 Side effect, 44, 160, 209, 211, 234, 240, 286, 289, 291 Sigma Factor, 59, 64, 65, 99, 133, 168, 286 Signs and Symptoms, 5, 283, 286 Silicon, 37, 286 Silicon Dioxide, 286 Skin test, 16, 19, 24, 56, 90, 97, 118, 119, 161, 286 Small intestine, 245, 261, 265, 286, 292

Smallpox, 286, 293 Sneezing, 198, 286 Sodium, 97, 170, 276, 286 Solvent, 35, 170, 254, 258, 270, 286 Somatic, 261, 271, 286 Specialist, 224, 286 Specificity, 20, 29, 45, 49, 234, 252, 286 Spectrum, 162, 287 Sperm, 245, 287 Spheroplasts, 148, 287 Spinal cord, 243, 244, 252, 270, 273, 276, 277, 287 Spinal Nerves, 277, 287 Spirochete, 287, 289 Spleen, 17, 22, 168, 261, 268, 284, 287 Spores, 37, 51, 168, 287 Sputa, 66, 97, 287 Stem Cells, 235, 254, 287 Sterile, 189, 287, 292 Sterilization, 4, 287 Steroid, 53, 259, 284, 287 Stimulus, 252, 254, 264, 265, 266, 287, 290 Stomach, 233, 256, 261, 273, 277, 278, 286, 287 Stool, 47, 246, 287 Strand, 66, 74, 100, 279, 287 Streptococci, 178, 287 Streptomycin, 48, 84, 105, 288 Stress, 29, 36, 37, 127, 150, 168, 189, 242, 244, 271, 273, 276, 288 Stringency, 121, 288 Stroke, 53, 216, 288 Structure-Activity Relationship, 20, 288 Subacute, 263, 288 Subclinical, 263, 288 Subcutaneous, 256, 276, 288 Subspecies, 76, 81, 156, 286, 288 Substance P, 270, 285, 288 Substrate, 13, 29, 45, 116, 261, 288 Substrate Specificity, 13, 45, 288 Subtrochanteric, 106, 288 Suction, 255, 288 Sulfur, 181, 254, 270, 288 Sulfuric acid, 53, 288 Superinfection, 182, 288 Superoxide, 48, 65, 84, 113, 120, 148, 192, 289 Superoxide Dismutase, 48, 65, 84, 113, 120, 192, 289 Supportive care, 261, 289 Suppression, 41, 96, 178, 289 Surface Plasmon Resonance, 44, 289

308


Surfactant, 52, 54, 289 Sympathomimetic, 251, 253, 274, 289 Synapses, 289 Syphilis, 176, 177, 289 Systemic, 17, 51, 114, 198, 199, 241, 250, 253, 263, 284, 289, 291, 292, 293 Systolic, 261, 289 T Tachycardia, 239, 289 Tachypnea, 239, 289 Teichoic Acids, 258, 289 Testosterone, 283, 289 Tetani, 289, 290 Tetanic, 289, 290 Tetanus, 199, 238, 289, 290 Tetanus Toxin, 199, 290 Therapeutics, 22, 167, 168, 197, 210, 290 Thermal, 251, 259, 279, 290 Thioamides, 188, 290 Thoracic, 250, 268, 279, 290 Threonine, 271, 281, 285, 290 Threshold, 261, 290 Thrombin, 255, 279, 281, 290 Thrombolytic, 279, 290 Thrombomodulin, 281, 290 Thrombosis, 240, 281, 288, 290 Thymidine, 99, 290 Thymidine Monophosphate, 99, 290 Thymus, 153, 262, 268, 290 Thyroid, 290, 292 Tissue Culture, 5, 22, 35, 167, 290 Tissue Extracts, 18, 290 Tolerance, 176, 259, 290 Tomography, 291 Tooth Preparation, 234, 291 Topical, 198, 254, 261, 291 Toxic, iv, 43, 45, 188, 239, 249, 250, 270, 291 Toxicity, 15, 19, 44, 188, 251, 269, 270, 291 Toxicokinetics, 291 Toxicology, 44, 218, 291 Toxin, 12, 36, 51, 189, 199, 238, 250, 289, 290, 291 Toxoid, 238, 291 Trace element, 142, 274, 286, 291 Trachoma, 159, 291 Transcription Factors, 50, 291 Transduction, 28, 34, 35, 73, 108, 197, 259, 264, 291 Transfection, 240, 257, 291 Transfer Factor, 262, 291 Transferases, 258, 291

Transforming Growth Factor beta, 102, 291 Translating, 178, 291 Translation, 193, 199, 236, 292 Translational, 57, 292 Transmitter, 233, 251, 265, 269, 274, 289, 292 Transplantation, 237, 262, 268, 292 Trauma, 106, 259, 273, 292 Treatment Outcome, 116, 292 Tricuspid Atresia, 248, 292 Trypanosomiasis, 159, 292 Trypsin, 147, 253, 292, 295 Tryptophan, 246, 285, 292 Tubercle, 21, 31, 36, 42, 59, 164, 166, 182, 185, 188, 193, 292 Tubercular, 21, 34, 292 Tuberculin, 19, 56, 90, 97, 109, 130, 292 Tuberculostatic, 265, 292 Tumor Necrosis Factor, 6, 40, 72, 88, 92, 130, 131, 292 Tumour, 134, 292 Tyrosine, 149, 251, 292 U Urea, 292 Urease, 151, 274, 292 Ureters, 293 Urethra, 293 Urinary, 5, 245, 292, 293 Urinary tract, 5, 293 Urine, 4, 161, 241, 257, 293 Uterus, 243, 248, 280, 293 Uvea, 293 Uveitis, 125, 293 V Vaccination, 11, 19, 67, 162, 177, 179, 182, 189, 293 Vaccinia, 169, 293 Vacuole, 46, 293 Vagina, 243, 250, 293 Valves, 283, 293 Variola, 293 Vascular, 235, 253, 263, 274, 279, 293 Vasculitis, 112, 293 Vasodilator, 241, 251, 260, 293 Vector, 165, 179, 198, 199, 200, 291, 293 Vegetative, 51, 293 Vein, 265, 274, 276, 293 Venereal, 289, 293 Venous, 240, 281, 292, 293 Ventricle, 239, 248, 282, 289, 292, 293, 294 Ventricular, 248, 292, 294

309

Veterinary Medicine, 217, 294 Vibrio, 244, 294 Viral, 169, 171, 176, 177, 199, 257, 263, 282, 291, 294 Viral Proteins, 169, 294 Viral vector, 169, 199, 294 Virion, 239, 294 Virulent, 6, 7, 11, 12, 28, 32, 34, 37, 38, 40, 46, 48, 54, 59, 62, 67, 68, 72, 85, 92, 124, 137, 146, 175, 186, 190, 272, 294 Visceral, 158, 266, 277, 294 Vitamin A, 264, 294 Vitreous, 125, 284, 294 Vitreous Body, 284, 294 Vitro, 11, 14, 15, 17, 21, 24, 25, 30, 31, 34, 35, 36, 40, 44, 45, 50, 54, 58, 61, 63, 64, 72, 74, 75, 76, 82, 83, 91, 117, 134, 146, 148, 172, 175, 180, 182, 257, 263, 274, 279, 288, 290, 294

Vivo, 9, 12, 15, 17, 30, 32, 34, 35, 40, 42, 44, 48, 49, 50, 52, 58, 59, 61, 72, 73, 74, 76, 88, 117, 133, 146, 159, 168, 176, 257, 263, 268, 294 Vulgaris, 153, 294 W War, 132, 160, 244, 294 White blood cell, 5, 237, 241, 245, 259, 266, 268, 272, 273, 274, 278, 294 Wound Healing, 269, 294 X Xenograft, 237, 294 X-ray, 13, 16, 35, 43, 44, 45, 172, 192, 193, 247, 255, 274, 294 Y Yeasts, 256, 278, 295 Z Zebrafish, 26, 295 Zoonoses, 282, 295 Zygote, 247, 295 Zymogen, 281, 295

310


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312


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