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

LYMPHADENOPATHY 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., 1960Lymphadenopathy: 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: 0-497-00687-1 1. Lymphadenopathy-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 lymphadenopathy. 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 LYMPHADENOPATHY ............................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Lymphadenopathy ......................................................................... 4 E-Journals: PubMed Central ....................................................................................................... 14 The National Library of Medicine: PubMed ................................................................................ 14 CHAPTER 2. NUTRITION AND LYMPHADENOPATHY ..................................................................... 61 Overview...................................................................................................................................... 61 Finding Nutrition Studies on Lymphadenopathy........................................................................ 61 Federal Resources on Nutrition ................................................................................................... 63 Additional Web Resources ........................................................................................................... 64 CHAPTER 3. ALTERNATIVE MEDICINE AND LYMPHADENOPATHY ............................................... 65 Overview...................................................................................................................................... 65 National Center for Complementary and Alternative Medicine.................................................. 65 Additional Web Resources ........................................................................................................... 65 General References ....................................................................................................................... 66 CHAPTER 4. BOOKS ON LYMPHADENOPATHY................................................................................ 67 Overview...................................................................................................................................... 67 Book Summaries: Federal Agencies.............................................................................................. 67 Chapters on Lymphadenopathy.................................................................................................... 69 CHAPTER 5. MULTIMEDIA ON LYMPHADENOPATHY ..................................................................... 71 Overview...................................................................................................................................... 71 Video Recordings ......................................................................................................................... 71 Audio Recordings......................................................................................................................... 72 CHAPTER 6. PERIODICALS AND NEWS ON LYMPHADENOPATHY .................................................. 73 Overview...................................................................................................................................... 73 News Services and Press Releases................................................................................................ 73 Academic Periodicals covering Lymphadenopathy ...................................................................... 75 APPENDIX A. PHYSICIAN RESOURCES ............................................................................................ 79 Overview...................................................................................................................................... 79 NIH Guidelines............................................................................................................................ 79 NIH Databases............................................................................................................................. 81 Other Commercial Databases....................................................................................................... 83 APPENDIX B. PATIENT RESOURCES ................................................................................................. 85 Overview...................................................................................................................................... 85 Patient Guideline Sources............................................................................................................ 85 Finding Associations.................................................................................................................... 87 APPENDIX C. FINDING MEDICAL LIBRARIES .................................................................................. 89 Overview...................................................................................................................................... 89 Preparation................................................................................................................................... 89 Finding a Local Medical Library.................................................................................................. 89 Medical Libraries in the U.S. and Canada ................................................................................... 89 ONLINE GLOSSARIES.................................................................................................................. 95 Online Dictionary Directories ..................................................................................................... 95 LYMPHADENOPATHY DICTIONARY ..................................................................................... 97 INDEX .............................................................................................................................................. 139

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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 lymphadenopathy 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 lymphadenopathy, 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 lymphadenopathy, 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 lymphadenopathy. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to lymphadenopathy, 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 lymphadenopathy. 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 LYMPHADENOPATHY Overview In this chapter, we will show you how to locate peer-reviewed references and studies on lymphadenopathy.

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

Metastatic Prostatic Carcinoma Presenting as Cervical Lymphadenopathy Source: Journal of Oral and Maxillofacial Surgery. 59(5): 571-573. May 2001. Contact: Available from W.B. Saunders Company. Periodicals Department, P.O. Box 629239, Orlando, FL 32862-8239. (800) 654-2452. Website: www.harcourthealth.com. Summary: Cervical lympadenopathy is a common presentation in patients seen by the oral and maxillofacial surgeon. In addition to a full medical examination, fine needle aspiration cytology (cell study) is a valuable diagnostic test in assessing this condition. If metastatic (spreading) carcinoma (cancer) is diagnosed, the search for the primary site involves panendoscopy, biopsy, and computed tomography (CT). If no primary site is identified, a neck dissection can still be effective treatment. Prostatic carcinoma (prostate

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cancer) is common in the elderly and can spread to the neck. This article presents a case to remind clinicians of this possibility. The case features a 67 year old, nonsmoking man who was referred for left cervical lymphadenopathy of 2 months duration. He had chronic obstructive pulmonary disease (COPD), and he had a 9 year history of primary detrusor (the bladder opening) instability. He had received no active treatment for these conditions. After detailed diagnostic testing was completed, with mostly normal results, the patient underwent a left modified radical neck dissection, following which he made a good recovery. Microscopic analysis of the surgical specimen revealed the lymphadenopathy to be caused by metastatic prostatic adenocarcinoma. He was referred to a urologic oncologist who diagnosed the prostate as the primary site and commenced treatment of it. The authors conclude that PSA assay should be part of the screening for cervical lymphadenopathy with an undiagnosed primary site in male patients. 2 figures. 15 references.

Federally Funded Research on Lymphadenopathy The U.S. Government supports a variety of research studies relating to lymphadenopathy. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to lymphadenopathy. 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 lymphadenopathy. The following is typical of the type of information found when searching the CRISP database for lymphadenopathy: •

Project Title: CELL CYCLE AND APOPTOSIS REGULATION BY NFAT Principal Investigator & Institution: Rao, Anjana; Senior Investigator; Cbr Institute for Biomedical Research 800 Huntington Ave Boston, Ma 02115 Timing: Fiscal Year 2004; Project Start 01-MAY-2004; Project End 30-APR-2007 Summary: (provided by applicant) The collaborative project proposed in this FIRCA application is an extension of the project funded by parent grant CA 42471 ("Role of bZIP proteins in lymphocyte function"). The long-term objectives of the parent grant are to define the functions of the NFAT family of transcription factors, and their transcription partners AP-1 (Fos/Jun), in lymphocytes and other cell types. There is strong evidence that NFAT proteins regulate lymphocyte proliferation and differentiation as well as cell cycle progression, apoptosis and oncogenesis in lymphocytes and other cell types. The objective of this collaborative FIRCA proposal is to investigate the involvement of NFAT proteins in lymphoproliferative disease and oncogenic transformation of lymphocytes and fibroblasts. As part of the parent grant, a

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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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large number of reagents have been or are currently being generated, including constitutively-active NFAT proteins, gene-targeted mice lacking specific NFAT proteins, and gene-targeted mice conditionally expressing the constitutively-active NFAT proteins. In Aim 1, the lymphoproliferative phenotype of NFATI-/- mice will be analyzed, asking specifically whether the splenomegaly and lymphadenopathy of NFATI-/- mice are associated with any malignant transformation of lymphocytes and whether polyclonal stimulation of lymphocytes in these mice might trigger such malignant transformation. We will also ask whether lack of NFAT1 promotes cancer development upon exposure to chemical carcinogens, and whether lack of NFAT1 influences the rate and extent of cancer development in selected cancer-prone mouse strains. In Aim 2, the relationship between lymphocyte transformation and Thl/Th2 cytokine expression will be examined, by repeating the experiments of Aim 1 in mice lacking either IL-4, IFN-7 or the IFN-7-induced transcription factor STATI. In Aim 3, the oncogenic potential of NFAT1 and NFAT2 will be compared in lymphocytes, in fibroblasts, and in vivo, in light of evidence that these two closely-related transcription factors may have tumor suppressor and oncogenic potential respectively. The results should provide new insights into NFAT function and may have important therapeutic implications, particularly if we find that NFAT selectively modulates oncogenic or cell death programs in lymphocytes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHARACTERIZATION OF A NEW MOUSE MODEL FOR LUPUS Principal Investigator & Institution: Lim, Bing; Associate Professor; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2003; Project Start 19-SEP-2003; Project End 31-DEC-2007 Summary: (provided by applicant): The central goal of this proposal is to exploit the use of a new mutant murine strain to advance the understanding of autoimmune disorders. A new line of mice has been derived in which animals develop a severe generalized lymphadenopathy together with autoimmune glomerulonephritis and hyperimmunoglobulinemia. Significantly, the animals produce auto antibodies against double-stranded DNA and Sm antigen, both of which are specific markers for Systemic Lupus Erythematosus (SLE). Immune function studies showed a combination of severe lymphoid dysfunction and developmental defect not seen in other murine autoimmune disease models. The disease is passed with a Mendelian frequency consistent with a recessive mutation of an autosomal gene. Therefore, the disease arose from a spontaneous mutation of a gene which we have named lag (lymphoproliferative autoimmune glomerulonephropathy). Using chromosomal satellite markers to scan the murine genome, preliminary data indicate that a putative locus for the lag gene is the telomeric end of chromosome 2. This is not a region that has been linked before to autoimmune disease. The goal of this proposal is to exploit this remarkable new murine model to learn about autoimmune disease. In Specific Aim 1, we will map the location of the gene and identify the lag gene by combining positional cloning with a candidate gene approach. In Aim 2 we will characterize the disease process for the lag phenotype and identify the cells causing the disease. In Aim 3 we will examine in detail the effect of the lag mutation on T cell development. In Aim 4 we will investigate how the lag mutation affects T cell function. To support these studies, various TCRxlag transgenic animals will be generated to help the study of lymphocyte development, function and signaling. We anticipate that our proposal to study this murine model carefully will contribute a significant amount of new information for understanding the diverse genetic and molecular bases of autoimmune diseases. The identification of new genes

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and new pathways may uncover new targets for the development of drugs to suppress the immune system in a specific way, instead of globally. The discovery of new disease genes may also be very useful in the management, care and diagnosis of the large number of patients with autoimmune diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DYNAMICS OF TCR REPERTOIRE FOLLOWING THYMUS TRANSPLANT Principal Investigator & Institution: Markert, M Louise.; Associate Professor; Pediatrics; Duke University Durham, Nc 27710 Timing: Fiscal Year 2004; Project Start 15-MAY-2004; Project End 30-APR-2009 Summary: (provided by applicant): The long term objective of this proposal is to identify mechanisms regulating human T cell diversity. We propose to do so using a model system of infants with complete DiGeorge syndrome who receive thymic allografts. Infants with DiGeorge syndrome are born with defects in the thymus, heart, and parathyroid glands. Patients with "complete" DiGeorge syndrome have no evidence ofthymic function. Twenty four patients have been treated in a separate, wellestablished research protocol by transplantation with allogeneic cultured postnatal human thymus. Seventeen patients survive, all with good immune reconstitution and function. The mechanism of T cell development in these patients is host bone marrow stem cells going to the transplanted donor thymic epithelium and developing there into mature host T cells. In the first specific aim, we will examine the mechanisms underlying selection of T cell receptor (TCR) variable-beta gene segments (TCRBV) in newly formed T cells. We hypothesize that early TCRBV usage is biased toward those gene segments that are associated with highly efficient recombination signal sequences (RSS) and toward those that are most proximal to the TCRBJ cluster. We will compare the selection in the early oligoclonal T cell populations, which develop at 3-4 months after transplantation, to those present at 1 year. In aim 3, we will examine T cells in "atypical" complete DiGeorge patients who develop oligoclonal T cells prior to thymus transplantation. These T cells are associated with rash and lymphadenopathy. The same hypothesis will be tested regarding TCRBV selection - that it is based on RSS efficiency and TCRBJ proximity. These T cells develop without thymic input, so the effect of thymic selection on TCRBV usage will be ascertained. In aim 2, we will use mathematical modeling and multivariate statistical analysis of patient data to evaluate the relationship between T cell hemeostasis and TCRBV diversity with emphasis on distinguishing the roles of TCR-specific resources (e.g., MHC-peptide complexes) and TCR non-specific resources, such as IL-7. Thus, this unique model of thymus development will provide insights into development of T cell diversity in man. These findings will have application to thymus and bone marrow transplantation for immunodeficiency and cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC INFLUENCES & GENE EXPRESSION IN KAWASAKI DISEASE Principal Investigator & Institution: Burns, Jane L.; Professor of Pediatrics; Pediatrics; University of California San Diego La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2004 Summary: (provided by applicant): Kawasaki disease (KD) is the most common cause of acquired cardiovascular disease in childhood in the United States. This acute vasculitis

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primarily affects children under the age of 5 yrs. who present with fever, rash, conjunctival injection, red mucosal membranes, cervical lymphadenopathy, and swollen extremities. The cause of KD remains unknown and there is no specific laboratory test to identify affected children. Nonetheless, high dose intravenous gamma globulin administered within the first 10 days of fever significantly reduces the risk of coronary artery damage by unknown mechanisms. Without treatment, one in four children will develop permanent damage to the coronary arteries that may lead to ischemic heart disease, myocardial infarction, and death. KD thus presents a unique dilemma: the disease may be difficult to recognize, there is no diagnostic laboratory test, there is an extremely effective therapy, and there is a 25 percent chance of serious cardiovascular damage or death if the therapy is not administered. Recent advances in the field of functional genomics allow the analysis of gene expression in complex biologic events such as the response to infection or vascular injury. These advances coincide with the emerging recognition that the hosts innate immune system responds to pathogen-associated molecular patterns with stereotypic patterns of gene expression. Thus, a survey of the transcriptional response can yield clues about the nature of the stimulus. This proposal brings together clinicians with expertise in KD, molecular biologists skilled in the application of these new genomic tools, and a statistical genetics team expert in evaluating genetic influences on disease susceptibility and outcome. This interdisciplinary team will discover the pattern of gene expression in acute KD and in patients with similar appearing, non-KD illness using DNA microarray techniques and mRNA quantitation by kinetic reverse transcriptase-polymerase chain reaction. Unique features of the transcriptional response in KD children will be used to develop a diagnostic test for KD. The role that genetic polymorphisms play in these gene expression patterns and their influence on disease susceptibility, response to therapy, and outcome will also be examined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEMOLYSIN AND IMMUNOBIOLOGY OF CHANCROID Principal Investigator & Institution: Totten, Patricia A.; Professor; Medicine; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-MAR-2005 Summary: (provided by applicant): H. ducreyi is the causative agent of chancroid, a disease characterized by genital ulcers, and in 50 percent of the cases, inguinal lymphadenopathy. The occurrence of chancroid outbreaks in the United States coupled with its association with the heterosexual transmission of HIV in Africa makes understanding the pathogenesis of this disease imperative so that rational intervention strategies can be devised. We have developed a primate model for chancroid that measures the effect of disease progression from the pustular to the ulceral to the resolution stages of disease at a genital site in an animal closely related to humans. We now intend to use the primate model to study the local and systemic immune response induced by infection with H. ducreyi and the immunobiology of chancroidal disease. We hypothesize that a predominant Th1 response will be induced and will be correlated with clearance of the organism from genital tissues. H. ducreyi produces a toxin, which has been termed a hemolysin, based on its ability to lyse red blood cells, although its role in pathogenesis undoubtedly depends upon its ability to affect other cells important in chancroidal lesions. We have shown that immunization with hemolysin increases the clearance of a homologous strain of H. ducreyi from lesions in the temperaturedependent rabbit model and now intend to study the nature of immune response that enhances clearance of this organism from genital tissues in the primate model. Thus, we

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propose to study the ability of immunization with hemolysin (compared to immunization with H. ducreyi cell envelopes) to attenuate lesion development and enhance clearance of H. ducreyi from genital ulcers. We also propose to study the effect of immunization on the systemic and local immune response, localization of H. ducreyi in primate lesions, cellular and antibody response to individual antigens, and the possible mechanism of protection by antibodies from immunized primates. We have previously shown that the target cell range of hemolysin includes keratinocytes, fibroblasts, lymphocytes, and macrophages and hypothesize that hemolysin enhances ulcer development, evasion of the immune response in chancroidal disease, and survival of H. ducreyi in genital lesions. Thus we will study the contribution of hemolysin to lesion progression and survival of H. ducreyi in primate genital ulcers and the effect of hemolysin expression on the local and systemic immune response. These studies will provide a better understanding of the role of the H. ducreyi hemolysin in the pathogenesis and immunobiology of chancroid and will provide a groundwork on which to base future strategies for vaccine development for chancroid. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNOGENETICS OF SMALLPOX VACCINATION Principal Investigator & Institution: Stanley, Samuel L.; Professor; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: The goal of this project is to identify genes that are involved in susceptibility and resistance to human vaccinia infection, and, consequently, in some of the adverse effects seen with smallpox vaccination. We (R.B.B.) recently led a multi-center prospective study on the clinical response to vaccinia immunization in 680 naive individuals. Among the 665 individuals responding to the vaccine, 84 (13%) developed fever, muscle aches and lymphadenopathy giving rise to what we have called Acute Vaccinia Syndrome (AVS) in approximately 30% of vaccines. The timing of the onset of these symptoms matched the timing of the highest levels of viral shedding, indicating that fever, and the other components of AVS appear to be secondary to the virus. We hypothesize that individuals developing AVS (and especially fever) have diseasepredisposing alleles that are associated with abnormal innate immune or delayed adaptive immune responses to vaccinia. These individuals may be more susceptible to poxviruses in general, and could constitute a group at increased risk for mortality if exposed to smallpox. We propose to identify genes that are expressed in response to vaccinia infection at the site of inoculation and systemically using a transcriptional analysis. We will compare responses between individuals that develop AVS, and those individuals who develop no adverse reactions to immunization. These studies will provide us with a transcriptional profile of the host response to vaccinia infection, identify key molecules in the host response, and, establish parameters for protective immune responses that could be used to test the efficacy of new vaccines. We will also identify alleles associated with adverse effects to vaccinia immunization and abnormal innate immune responses to the virus through the analysis of haplotypes based on single nucleotide polymorphisms in candidate genes. The identify of these alleles may provide clues to the critical elements of the host response to poxvirus, and could provide a method to identify individuals at increased risk for adverse effects to the vaccine, or more severe disease with poxvirus infection. The design of the study, with the inclusion of transcriptional profiling of individuals receiving vaccinia immunization coupled with a detailed virologic and immunologic profile, ensures that we will obtain valuable information on the host response to vaccinia immunization.

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

Project Title: INHIBITORY RECEPTORS AND THEIR MODE OF ACTION Principal Investigator & Institution: Cambier, John C.; Professor and Chairman; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2002; Project Start 01-MAY-1993; Project End 30-NOV-2002 Summary: The growth, differentiation, and effector functions of many tissues are regulated by cell surface receptors that transduce signals via the activation of protein tyrosine kinases. It has become clear only in the past three years that a parallel receptor set exists which functions to attenuate or deviate responses transduced by many of these activating receptors. As a general rule, these receptors must associate physically or be coaggregated with their counterparts in order to function and utilize phosphatases as effectors. The best studied examples of these receptors, FcgammaRIIB1, KIR, and CTLA4, are found in the immune system where they function to modulate various immunologic functions. Functional deficiency in the receptors or their effectors appears to lead to autoimmunity and, in the case of CTLA4, to life-threatening lymphadenopathy. Hyperactivity presumably leads to immunodeficiency. This proposal is focused on defining the molecular mode of action of a prototypic member of this family, FcgammaRIIB1. FcgammaRIIB1 is a receptor for IgG constant regions that functions to modify signals transduced through coaggregated antigen receptors, most notably the B cell antigen receptor. It is hypothesized that the FcgammaRIIB1 cytoplasmic tail contains distinctly compartmentalized structural information for the activation of multiple distinct biochemical pathways that impinge on antigen receptor signaling. The proposed studies will utilize genetic, biochemical, and biologic approaches in an effort to achieve the long term goals of elucidating these pathways and their targets. Specific aims of this proposal are to: 1) identify previously unrecognized receptor tyrosil phosphorylation sites and define their effectors; 2 and 3) undertake mutational analysis to define the sites within the receptor that function in transduction of specific inhibitory signals; and 4) define the role of the adaptor p62Dok in FcgammaRIIB1 signaling. The proposed studies will advance our understanding of signal transduction by this family of regulatory receptors and may reveal new and attractive targets for therapeutic intervention in cancer, inflammation, autoimmunity and immunodeficiency. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MERCURY INDUCED AUTOIMMUNITY Principal Investigator & Institution: Pollard, Kenneth Michael.; Associate Professor; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2004; Project Start 01-MAY-2004; Project End 30-APR-2008 Summary: (provided by applicant): Exposure to xenobiotics can produce aberrant immune reactions, including autoimmunity. Exposure of mice to the heavy metal mercury leads to systemic autoimmunity with characteristic lymphadenopathy, hypergammaglobulinemia, autoantibodies and immune complex disease. In both idiopathic and mercury-induced autoimmunity (mHglA) reductions in IFN-gamma levels are associated with reductions in both autoantibody levels and immune-complex mediated pathology. Prior studies have revealed that genes, which control IFN-gamma expression, such as IL-4, IL-12, STAT4 and ICE, do not significantly influence the development of mHglA. However absence of genes involved in IFN-gamma function (IFN-gamma, IFN-gamma receptor, IRF-1) suppresses development of mHglA,

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suggesting that specific defects in signaling pathways and gene expression subsequent to IFN-gamma/IFN-gamma receptor interaction control disease expression. These observations underlie the hypothesis that mHgIA is dependent upon IFN-gamma and that the severity of disease is regulated by molecular and cellular events downstream of IFN-gamma expression. This hypothesis will be addressed by four specific aims:- 1) Determination of the Site and Kinetics of IFN-gamma Production in mHglA, 2) Determination of the Cellular Requirements Leading to IFN-gamma Dependent mHglA, 3) Determination of the Genetic Requirements Leading to lFN-gamma Dependent mHglA, and 4) Examination of the Suppression of the IFN-gamma Response as a Therapy for IFN-gamma Dependent mHglA. Identification of the role that IFN-gamma plays in the development of induced murine systemic autoimmunity should prove applicable to murine models of idiopathic systemic autoimmunity and to human lupus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOGENESIS OF MAIDS AND SPECIFIC T CELL RESPONSES Principal Investigator & Institution: Green, William R.; Professor; Microbiology and Immunology; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2002; Project Start 01-MAR-1990; Project End 30-APR-2004 Summary: (Adapted from the applicant's abstract) The murine model MAIDS is used to ask fundamental questions about the mechanisms of retroviral pathogenesis. MAIDS induces a immunosuppression of both B and T lymphocyte responses, polyclonal B cell activation and hypergammaglobulinemia, lymphadenopathy, increased susceptibility to opportunistic infections and an increased incidence of non-Hodgkin's B cell lymphomas. The overall goals of this proposal are to examine: (1) CD40L mediated signaling o B cells leading to their activation, hypergammaglobulinemia and ultimately B cell tumors; (2) the specificity of cytotoxic T cells (CTL) responses of MAIDS-resistant mouse strains or to an immunodominant gag epitope; and (3) the potential contribution of open reading frame (ORF2) directed expression of this gag epitope. The experimental approach utilizes CD40 or CD40L knock out mice to examine the role of these molecules in the genesis of disease, and mutational analysis of ORF2 and CTL epitopes to examine immune resistance and susceptibility. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PILOT--IMPACT OF ALCOHOLISM ON AIDS ASOCIATED MUSCLE WASTING Principal Investigator & Institution: Molina, Patricia E.; Associate Professor; Louisiana State Univ Hsc New Orleans New Orleans, La 70112 Timing: Fiscal Year 2002 Summary: Alcohol consumption and HIV infection are frequently co-existent pathologies. Muscle wasting is a common feature of both conditions. The alterations in immune responses resulting from chronic alcohol consumption have been hypothesized to enhance the transmission and acquisition of HIV or the progression from HIV infection to acquired immunodeficiency syndrome (AIDS). Based on available information, it is possible to speculate that these are either related to the direct effects of alcohol on the immune system, or are secondary to the impact of alcohol consumption on the nutritional state of the individual. Excess alcohol consumption is associated with a approximately 50% incidence of skeletal muscle myopathy. Alcohol consumption impairs the nutritional state of the individual either as a result of decreased food consumption or as a result of decreased absorption. affecting micronutrients which in

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turn have been shown to modulate circulating and tissue levels of growth factors. Hence the effects of alcohol consumption on muscle wasting appear to be multifactorial. Alcohol-induced myopathy appears to be predominantly the result of decreases in muscle protein synthesis, and is characterized by decreased weight, protein, RNA and DNA contents in skeletal muscle. The general hypothesis of the present proposal is that alcohol consumption accelerates and worsens the muscle wasting associated with HIV infection, leading to increased morbidity and mortality. Infection of Rhesus monkeys with simian immunodeficiency virus (SIV) has been established as an excellent model system for studying the pathogenesis of HIV-like infection. The disease is characterized by diarrhea, weight loss, lymphopenia, thrombocytopenia, and lymphadenopathy/lymphoid hyperplasia progressing to immunosuppression with marked reduction in CD4+ cells and in the CD4+/CD8+ cell ratio, and opportunistic infections. The aim of the present proposal is to characterize the time-course and relative contribution of alterations in muscle protein synthesis and proteolysis to the progression of muscle wasting associated with chronic alcohol consumption and SIV infection individually and combined. These studies will allow for the longitudinal investigation of the progression of the alterations in muscle metabolism beginning with a healthy, non-infected animal, throughout the acute infectious period and throughout progression to full blown AIDS. These will provide the preliminary data for a more mechanistic approach to the study of the etiology of alcohol-induced muscle wasting and its impact on a chronic infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROX1 IN MAMMALIAN LYMPHANGIOGENESIS Principal Investigator & Institution: Oliver, Guillermo C.; Associate Member; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2007 Summary: (provided by applicant): The lymphatic system is crucial for the maintainance of good health and for the prevention and cure of disease. Congenital hypoplasia and failed regeneration of lymphatic tissue result in lymphedema. Primary lymphedema appears at birth (Milroy disease) or, more commonly, after puberty (Meige disease). Although lymphedema was first described more than a century ago, little progress has been made in understanding the mechanisms that cause it. Furthermore, little progress has been made in identifying the players that participate in the normal development of the lymphatic vasculature. Investigation of the normal development of the lymphatic system has been hindered by the lack of known lymphatic-specific markers. Consequently, hypotheses about the origin of the lymphatic vessels are still controversial. The most widely accepted view, which was proposed by F. Sabin in 1902, is that isolated primitive lymph sacs bud from the endothelium of veins during early development; from these primary lymph sacs, the peripheral lymphatic system spreads by endothelial sprouting into tissues where local capillaries form. This grant proposal is based in our identification of the homeobox gene Proxl as the first specific marker of lymphatic endothelial cells. Functional inactivation of Proxl in mice leads to phenotypic alterations in lymphatic vasculature and, ultimately, to embryo death. Detailed analyses of Proxl-null and Proxl heterozygous mice have indicated that lymphangiogenesis requires activity of Proxl in a subpopulation of endothelial cells in embryonic veins. Proxl-null mice are devoid of lymphatic vasculature. Proxl activity also determines the final lymphatic fate of budding endothelial cells. The elucidation of the molecular mechanisms by which Proxl participates in the formation of the lymphatic vasculature and the identification of other novel molecules that participates in this process will

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increase our understanding of normal lymphangiogenesis, and therefore, advance the treatment and prevention of disorders of the lymphatic system. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RHESUS HHV8 HOMOLOGUE IN AIDS RELATED MALIGNANCIES Principal Investigator & Institution: Wong, Scott W.; Associate Scientist; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002 Summary: Despite the growing body of evidence to support Kaposi=s sarcomaassociated herpesvirus (KSHV) as the etiological agent in many AIDS and non-AIDSrelated malignancies, understanding how KSHV is involved in these malignancies is important for the generation of therapies against the spectrum of KSHV-associated diseases. Last year we reported that SIV-infected rhesus macaques experimentally infected with the rhesus HHV8 homologue, now referred to as rhesus rhadinovirus (RRV), developed B cell hyperplasia and persistent lymphadenopathy that resembled multicentric Castleman=s disease. This past year, we made the following observations from in vitro and in vivo experiments. 1) Sequence and genomic analysis of the RRV genome reveals that it is closely related to KSHV/HHV8, as it is essentially co-linear with and encodes several of the unique cellular homologues that are found in the KSHV genome. 2) Experimental inoculation of SIV-infected rhesus macaques with RRV strai n 17577 confirms our pilot studies, that RRV-infection of SIV-infected macaques results in the induction of B cell hyperplasia and persistent lymphadenopathy. 3) Expression of the RRV IL-6-like cytokine gene, in either COS-1-transfected cells or as a Glutathione Stransferase fusion protein in E. coli, possesses IL-6-like activity when measured by bioassay using IL-6-dependent cell lines. Combined, these studies support our initial hypothesis that this virus can cause disease manifestations in SIV-infected rhesus macaques that resemble some of those manifested in AIDS patients with Kaposi=s sarcoma. FUNDING NIH CA75922 PUBLICATIONS Kaleeba JAR, Bergquam E, Swanson R, Searles RP, Wong SW. Characterization of gene expression by a rhesus gamma-2 herpesvirus related to Kaposi=s sarcoma-associated herpesvirus. In Kaposi=s Sarcoma-Associated Herpesvirus (KSHV) and Related Agents Program & Abstracts 1st Annual Meeting (held in Santa Cruz, CA, July 25-28, 1998) (abstract 31). Kaleeba JAR, Bergquam EP, Wong SW. A strain of rhesus rhadinovirus (RRV 17577) related to Kaposi=s sarcoma-associated herpesvirus encodes a functional homologue of cellular interleukin 6. In 16th Annual Symposium on Nonhuman Primate Models for AIDS (held in Atlanta, GA, October 7-10, 1998) (abstract 32). Searles, RP, Bergquam EP, Axthelm MK, Wong SW. Characterization of a rhesus macaque gamma-2 herpesvirus with homology to Kaposi=s sarcoma-associated herpesvirus (KSHV). In Kaposi=s SarcomaAssociated Herpesvirus and Related Agents Program & Abstracts 1st Annual Meeting (held in Santa Cruz, CA, July 25-28, 1998) (abstract 29). Wong SW, Bergquam EP, Swanson R, Shiigi S, Axthelm MK. A rhesus gamma-2 herpesvirus related to Kaposi=s sarcoma-associated herpesvirus is associated with B cell abnormalities in SIV-infected rhesus macaques. In Kaposi=s Sarcoma-associated Herpesvirus and Related Agents Program & Abstracts 1st Annual Meeting (held in Santa Cruz, CA, July 25-28, 1998) (abstract 30). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF ORF K13 IN AIDS RELATED MALIGNANCIES Principal Investigator & Institution: Chaudhary, Preet M.; Associate Professor; Internal Medicine; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105

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Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2005 Summary: Infection with the human herpes virus 8 (HHV8) has been linked to the occurrence of Kaposi's sarcoma (KS) and several lymphoproliferative disorders, such as primary effusion lymphoma (PEL), multi-centric Castleman's disease, angioimmunoblastic lymphadenopathy with dysproteinemia, and multiple myeloma. However, the exact mechanism of action of HHV8 in the pathogenesis of these disorders is still unclear. Although HHV8 has been found to encode homologs of several cellular oncogenes and growth factors, almost all of them lack expression in latently infected KS and PEL cells, thereby arguing against their casual role in the pathogenesis of these disorders. We have discovered that orf-K13, an HHV8-encoded vFLIP (viral FLICE inhibitory protein), is capable of blocking apoptosis induced by death receptors belonging to the Tumor Necrosis Factor Receptor (TNFR) family. More importantly, orfK13 is capable of activating the NF-kappaB pathway, which has been previously implicated in the pathogenesis of EBV (Epstein Barr virus)- and HTLV1 (Human T cell Leukemia virus 1)- associated lymphoproliferative disorders. As orf-K13 is one of the few HHV8 encoded proteins which are expressed in latently infected KS and PEL cells, the above results make it an ideal candidate for causing the cellular transformation associated with infection by HHV8. The overall objective of this proposal is to test the above hypothesis using in vitro and in vivo models. In aim 1, biochemical and molecular characterization of the mechanisms underlying the NF-kappaB activating ability of orfK13 will be carried out with the hope of identifying the interactions critical for this activity. In aim 2, biological consequences of orf-K13 mediated NF-kappaB will be studied and its effect on cellular activation, proliferation and transformation characterized. Aim 3 will focus on further characterization of the anti-apoptotic properties of orf-K13 and its biological consequences. In aim 4, transgenic approach will be used to study the in vivo role of orf-K13 in the pathogenesis of AIDS- related malignancies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STUDY OF MONKEYPOX VIRUS IN RODENTS Principal Investigator & Institution: Buller, Robert M.; Professor; Molecular Microbiol and Immun; St. Louis University St. Louis, Mo 63103 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 30-JUN-2006 Summary: (provided by applicant): Monkeypox, orf, and molluscum contagiosum viruses cause the most frequent poxvirus infections worldwide. Of these, monkeypox virus has the greatest potential to cause significant disease in human populations either as a natural infection or through a criminal event. Unlike smallpox, person-to-person transmission of monkeypox virus is very inefficient, and there is rarely more than three generations of transmission from an index case. With cessation of the smallpox vaccination program in the Sub-Saharan region of Africa in 1982, and the increased encroachment of humans into habitat maintaining animal reservoirs of monkeypox virus, this virus is reemerging as a human pathogen. Increased frequency of human infections provides the opportunity for selection of genotypes that can be maintained in human populations without the necessity of periodic reintroductions from animal reservoirs. Thus monkeypox virus has the potential to become more than a nuisance zoonosis. The 2003 outbreak of human monkeypox in the Midwest indicated how little we know concerning the natural biology of this virus, and its potential to cause human disease. African rodents imported from Ghana into the U.S. showed none of the expected signs of a lethal infection with monkeypox virus (e.g. conjunctivitis, lymphadenopathy and skin lesions) yet were able to efficiently transmit the disease to

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prairie dogs that were responsible for 71 cases of human monkeypox. Although much research has been done on simian monkeypox, the monkey like the human is thought to be an incidental host. There is a lack of information on monkeypox virus biology in rodent species that in Africa may act as natural reservoirs. This proposal is aimed at studying the biology of monkeypox virus in susceptible rodent species that will permit the evaluation of monkeypox virus transmissibility, virulence, and host range. This information will contribute to our understanding of epizootic outbreaks of disease. Furthermore, since human monkeypox is indistinguishable from smallpox, a small animal monkeypox model that recapitulates natural disease may provide us with insights into human monkeypox and smallpox. And finally, a small animal model that yields a fulminant lethal infection at low doses of virus (