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

LYME DISEASE 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., 1960Lyme Disease: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-84020-2 1. Lyme Disease-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 Lyme disease. 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 LYME DISEASE .......................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Lyme Disease................................................................................. 5 E-Journals: PubMed Central ....................................................................................................... 60 The National Library of Medicine: PubMed ................................................................................ 77 CHAPTER 2. NUTRITION AND LYME DISEASE............................................................................... 121 Overview.................................................................................................................................... 121 Finding Nutrition Studies on Lyme Disease ............................................................................. 121 Federal Resources on Nutrition ................................................................................................. 124 Additional Web Resources ......................................................................................................... 124 CHAPTER 3. ALTERNATIVE MEDICINE AND LYME DISEASE ........................................................ 127 Overview.................................................................................................................................... 127 National Center for Complementary and Alternative Medicine................................................ 127 Additional Web Resources ......................................................................................................... 132 General References ..................................................................................................................... 134 CHAPTER 4. DISSERTATIONS ON LYME DISEASE .......................................................................... 135 Overview.................................................................................................................................... 135 Dissertations on Lyme Disease .................................................................................................. 135 Keeping Current ........................................................................................................................ 136 CHAPTER 5. CLINICAL TRIALS AND LYME DISEASE ..................................................................... 137 Overview.................................................................................................................................... 137 Recent Trials on Lyme Disease .................................................................................................. 137 Keeping Current on Clinical Trials ........................................................................................... 139 CHAPTER 6. PATENTS ON LYME DISEASE ..................................................................................... 141 Overview.................................................................................................................................... 141 Patents on Lyme Disease............................................................................................................ 141 Patent Applications on Lyme Disease........................................................................................ 167 Keeping Current ........................................................................................................................ 175 CHAPTER 7. BOOKS ON LYME DISEASE ......................................................................................... 177 Overview.................................................................................................................................... 177 Book Summaries: Federal Agencies............................................................................................ 177 Book Summaries: Online Booksellers......................................................................................... 178 The National Library of Medicine Book Index ........................................................................... 183 Chapters on Lyme Disease ......................................................................................................... 184 CHAPTER 8. MULTIMEDIA ON LYME DISEASE .............................................................................. 185 Overview.................................................................................................................................... 185 Video Recordings ....................................................................................................................... 185 Bibliography: Multimedia on Lyme Disease .............................................................................. 185 CHAPTER 9. PERIODICALS AND NEWS ON LYME DISEASE ........................................................... 189 Overview.................................................................................................................................... 189 News Services and Press Releases.............................................................................................. 189 Newsletter Articles .................................................................................................................... 194 Academic Periodicals covering Lyme Disease............................................................................ 194 CHAPTER 10. RESEARCHING MEDICATIONS................................................................................. 197 Overview.................................................................................................................................... 197 U.S. Pharmacopeia..................................................................................................................... 197 Commercial Databases ............................................................................................................... 199 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 203 Overview.................................................................................................................................... 203

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NIH Guidelines.......................................................................................................................... 203 NIH Databases........................................................................................................................... 205 Other Commercial Databases..................................................................................................... 207 APPENDIX B. PATIENT RESOURCES ............................................................................................... 209 Overview.................................................................................................................................... 209 Patient Guideline Sources.......................................................................................................... 209 Associations and Lyme Disease.................................................................................................. 218 Finding Associations.................................................................................................................. 219 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 221 Overview.................................................................................................................................... 221 Preparation................................................................................................................................. 221 Finding a Local Medical Library................................................................................................ 221 Medical Libraries in the U.S. and Canada ................................................................................. 221 ONLINE GLOSSARIES................................................................................................................ 227 Online Dictionary Directories ................................................................................................... 232 LYME DISEASE DICTIONARY ................................................................................................. 233 INDEX .............................................................................................................................................. 295

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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 Lyme disease 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 Lyme disease, 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 Lyme disease, 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 Lyme disease. 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 Lyme disease, 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 Lyme disease. 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 LYME DISEASE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on Lyme disease.

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

Differentiation of Orofacial Pain Related to Lyme Disease from Other Dental and Facial Pain Disorders Source: Dental Clinics of North America. 41(2): 243-258. April 1997. Contact: Available from W.B. Saunders. Periodicals Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452. Website: www.wbsaunders.com. Summary: This article discusses ways to differentiate orofacial pain related to Lyme disease from other dental and facial pain disorders. The author notes that the facial pain of Lyme disease may simulate dental pathology, temporomandibular joint or masticatory muscle pain, headache, and neuropathic disorders. The author discusses the cause and diagnosis of odontogenic pain, normal and pathologic function of the temporomandibular joints, myofascial trigger points, and pain referral patterns. A

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screening examination of the odontogenic and masticatory structures as well as a summary of headache disorders is provided. These conditions are compared with their presentation in a patient with Lyme disease to facilitate the diagnostic process. 11 tables. 32 references. •

Recognition and Management of Lyme Disease Source: American Family Physician. 56(2):427,430-436. August 1997. Contact: American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237 or (913) 906-6000. E-mail: [email protected]. Website: www.aafp.org. Summary: This journal article for health professionals provides guidelines for recognizing and managing Lyme disease. This multisystem disorder, which is the most common tick-borne illness in the United States, has an annual incidence of 0.5 percent in endemic areas. It most commonly occurs in the Northeast and upper Midwest, in areas that encourage and harbor the deer tick. The tick transmits an infection of the spirochete Borrelia burgdorferi that typically manifests as a localized skin lesion, erythema migrans. Rarely, Lyme disease manifests as localized arthritis, heart block, or disease of the nervous system. Lyme disease is a clinical diagnosis, and laboratory tests should only be used to clarify diagnostic issues. The current standard for laboratory diagnosis includes a two-step approach using an initial immunoassay with a confirmatory Western blot. Treatment includes 10 to 21 days of oral doxycycline in nonpregnant adults or a similar course of amoxicillin in children or pregnant women. Overdiagnosis and overtreatment of Lyme disease have become common. 37 references, 5 figures, and 3 tables. (AA-M).

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Taking a Bite Out of Lyme Disease: Preventive Vaccine Is Now Available Source: Consultant. 39(2): 527-529. February 1999. Summary: This journal article provides health professionals with information on a vaccine for Lyme disease, the most common tick borne illness in the United States. Lyme disease is endemic to the Northeast, upper Midwest, and Pacific coastal States. It is a multisystem, multistage disorder typically presenting as a red papule that expands to an enlarging patch of erythema migrans. Flu like symptoms often accompany the rash. If the disease is left untreated neurologic and myocardial abnormalities may develop within weeks or months of infection. Arthritis occurs in approximately half of those with untreated Lyme disease. The first vaccine, LYMErix, was recently approved for marketing by the Food and Drug Administration. The vaccine is formulated from a lipoprotein, OspA, that stimulates the production of antibodies against Borrelia burgdorferi in vaccinated patients. A 20 month randomized, multicenter, placebo controlled trial of the vaccine indicated a 78 percent efficacy rate against definite Lyme disease and a 100 percent effectiveness rate against asymptomatic infection. The article provides information on dosage and reactions, identifies candidates for vaccination, and outlines precautions people should take to prevent tick bites. 1 figure, 1 table, and 5 references.

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Arthritis 101: Lyme Disease Source: Arthritis Today. 14(2): 34-35. March-April 2000. Summary: This journal article provides the general public and people who have arthritis with information on Lyme disease. This tick borne disease causes symptoms that can

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mimic those of mononucleosis, meningitis, multiple sclerosis, rheumatoid arthritis, and other diseases. The early localized stage of Lyme disease occurs 7 to 10 days after infection and is characterized by an expanding red rash and viral type symptoms. The early disseminated stage occurs after several weeks or months of infection. Additional symptoms, including nervous system problems, may appear. The late stage of the disease can occur from months to years after the initial infection. In this stage, arthritis pain and swelling may occur in a few large joints. Lyme disease is usually diagnosed from the signs and symptoms in the earlier stages. A blood test may help confirm the diagnosis. Treatment involves taking antibiotics. Although two vaccines have been developed, people should still take precautions such as clearing brush from a yard, wearing long sleeved shirts and long pants tucked into socks when walking through woods or high grasses, checking exposed skin regularly, and removing a tick gently. 2 figures. •

Diagnosis of Lyme Disease Source: Hospital Practice. p. 35-36. August 15, 1996. Summary: This letter to the editor responds to Leonard H. Sigal's editorial entitled Lyme Disease Over-diagnosis: Causes and Cure, which focused on the overdiagnosis of Lyme disease within the nonpsychiatric context, and as a result of this overdiagnosis (diagnosis by exclusion), subjecting patients to long-term and unnecessary antibiotic therapy. The letter's author indicates that there is a closed system of thinking that contributes to diagnostic error and that there is actually more underdiagnosis than overdiagnosis. Such underdiagnosis is laying the ground work for a large scale epidemic of neuropsychiatric Lyme disease in the future. Dr. Sigal responds that while diagnosis by exclusion may be imprecise, and that he does not known of any of the psychiatric signs and symptoms described by the letter's author, he suggests the only way to settle the questions raised is to perform scientific studies to demonstrate that the form of Lyme disease described in the author's letter does actually exist. 8 references.

Federally Funded Research on Lyme Disease The U.S. Government supports a variety of research studies relating to Lyme disease. 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 Lyme disease. 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 Lyme disease. The following is typical of the type of information found when searching the CRISP database for Lyme disease: 2

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: ALLERGY AND IMMUNOLOGY TRAINING GRANT Principal Investigator & Institution: Askenase, Philip W.; Professor of Medicine and Pathology; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2001; Project Start 01-SEP-1980; Project End 30-JUN-2006 Summary: (adapted from the application): This application is for support of a training program in Allergy and Clinical Immunology, that is designed for post-doctoral medical and pediatric trainees at Yale University School of Medicine. There is a double training faculty of firstly, clinician-researchers in the Department of Medicine, in the Sections of Allergy, and Clinical Immunology, Rheumatology, Pulmonary, and Infectious Diseases, and also in Pediatrics; and secondly, a basic sciences immunology training faculty in the Department of Immunobiology. The faculty's expertise spans the areas important to allergy, clinical immunology, and modern immunology; including: cellular, molecular, biochemical, antigen-processing/presenting, and signaling research. Some faculty are experts in Lyme disease, which was discovered at Yale in this training program. There is training in both medical and pediatric aspects of Allergy, and Clinical immunology, and also some training in Rheumatology, Dermatology, Gastroenterology, Pulmonary, and ENT. The training faculty is well equipped with major instruments including: 4 cytofluorographs, an oligonucleotide synthesizer, and peptide protein sequinator. This is a small training program, taking only one new fellow per year, with a large faculty emphasizing the need for at least of 3-5 years of research laboratory training to prepare trainees for positions in research medicine. The faculty have a strong training record and collaborative research interactions; especially under this Allergy and Clinical Immunology Training Grant. The fellows spend most of their first year engaged in clinical activities. The 2nd and 3rd years are spent almost entirely in the laboratory developing a research program, under the guidance of a faculty mentor, taking various immunobiology courses, participating in weekly seminars and journal clubs, and regularly giving talks on their research, and on subjects of mutual interest. The program offers unique and high quality training for future positions in academic medicine and pediatrics, and has been successful over more than 20 years of continuous funding. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AN ANALYSIS OF BORRELIA BURGDORFERI MOTILITY Principal Investigator & Institution: Charon, Nyles W.; Professor; Microbiology, Immunology and Cell Biology; West Virginia University P. O. Box 6845 Morgantown, Wv 265066845 Timing: Fiscal Year 2003; Project Start 01-JUN-1990; Project End 28-FEB-2008 Summary: (provided by applicant): Lyme disease is the most prevalent arthropod borne infection in the United States, and has shown a steady increase in incidence since its discovery. The spirochete Borrelia burgdorferi is the causative agent. Very little is known about the B. burgdorferi virulence attributes that bring disease to the host. The present proposal focuses on the chemotaxis and motility of B. burgdorferi, and their rote in the disease process. Chemotaxis and motility are likely to be important virulence attributes, as these organisms penetrate into tissues and organs where other bacteria fall to invade. Basic to an understanding of chemotaxis on a molecular level, in Aim 1 we will identify those compounds that serve as attractants. Putative chemoattractants will be identified from information drawn from the genome sequence and known metabolism of B. burgdorferi The chemotactic ability of these compounds will be tested using established methodology. Both high passage (avirulent) and tow passage

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(virulent) strains will be tested under appropriate environmental conditions. in Aim 2, we propose to construct both insertion-deletion and in-frame deletions mutations in specific motility and chemotaxis genes. Both high and low passage strains will serve as parental strains. We hypothesize that each of these mutants will have a distinct phenotype. These phenotypes will be analyzed with respect to motility, chemotaxis, structure, western blot, proteomics and transcriptional analysis using DNA-microarray technology. To insure that a given phenotype is due to the targeted mutation being studied, we will use gene-complementation analysis. in Aim 3, we will test the hypothesis that motility and chemotaxis are important virulence attributes of B. burgdorferi. To test this hypothesis, we will use standard cell penetration assays, and the mouse model of Lyme disease. We predict that the motility and chemotaxis mutants will be less invasive and virulent than the parental strains in both of these assays. The experiments proposed should yield information with respect to the roles of chemotaxis and motility of B. burgdorferi in Lyme disease, and perhaps lay the foundation for new methods for prevention and treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANALYSIS BURGDORFERI

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PH

DEPENDENT

REGULATION

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B.

Principal Investigator & Institution: Carroll, James A.; Molecular Genetics & Biochem; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): Lyme disease is a multi-systemic disorder caused by Borrelia burgdorferi that spreads to mammals by the bite of an Ixodes tick. In the U.S. alone over 17,000 cases were reported in 2000, making it the number one reportable arthropod-borne infectious disease. In unfed, infected ticks the bacteria reside in the tick midgut, which has a pH/temperature of 8.0-8.4/23degreesC. During tick feeding and transmission the spirochetes experience a shift in pH/temperature from 8.08.4/23degreesC to 6.0- 7.4/35degreesC due to the influx of blood from the host. B. burgdorferi adapts to its new surroundings by altering the expression of different genes in response to environmental cues, such as changes in pH and temperature. We propose to delineate the molecular mechanisms that are involved in gene regulation in response to pH. Using affinity chromatography, mass spectroscopy and DNase I footprinting we propose to identify, characterize and inactivate the positive regulator of paralogous gene family 54 in B. burgdorferi. This gene family contains 13 genes that are located on linear plasmids. The role of these genes in the infection or adaptation process is unknown, but gene family members bba64, bba65, bba66, and bba73 are regulated by changes in pH and have been implicated in contributing to acute Lyme arthritis in model systems. By understanding how this bacterium is able to sense the environment and alter gene expression in response to changes in environmental cues, we hope to gain insight into i) the regulatory components necessary for adaptation and infection and ii) the role of pH regulation of target genes in mammalian pathogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANALYSIS OF UHB-FLANKED GENES OF LYME DISEASE Principal Investigator & Institution: Mcdowell, John V.; Microbiology and Immunology; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2002; Project Start 25-DEC-2001; Project End 24-DEC-2003

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Summary: (provided by the applicant): It is our hypothesis that UHB-flanked genes contribute to immune evasion in the Lyme disease spirochetes (LDS). Previous studies of the closely related ospE gene family have demonstrated that genetic polymorphisms develop during infection in mice and that these OspE variants are antigenically distinct. To address our hypothesis, the genetic stability of the ospF and Family 163 genes during infection in mice will be analyzed by infecting mice with an isogenic population of spirochetes of known genetic composition. Isogenic clones will be recovered three months post-infection and their UHB-flanked genes will be analyzed using a combination of PCR and DNA sequencing approaches. The temporal pattern and specificity of the humoral immune response to variant proteins will be assessed using sera collected from mice during the course of infection. These studies will increase our understanding of the mechanisms utilized by LDS to maintain chronic infection, which can lead to neuroborreliosis, and maintain populations in their animal reservoirs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ASSAY TO DETECT ACUTE ACTIVE LYME DISEASE Principal Investigator & Institution: Schutzer, Steven E.; Professor; Bioscience Development, Inc. 1467 3Rd Ave, Ste 1R New York, Ny 10028 Timing: Fiscal Year 2000; Project Start 15-SEP-2000; Project End 14-MAR-2004 Summary: Lyme disease (LD) cases due to Borrelia burgdorferi (Bb) are increasing. Assays to detect active infection are urgently needed. The primary objective of this proposal is to develop an assay for active infection based upon Bb specific immune complexes (IC) for immediate public use. There are 2 Specific Aims to prove the principle and confirm that l). BbIC become positive before free Bb antibody (Ab) in early infection 2). BbIC indicate active infection Samples are already banked from LD patients with both the pathognomic erythema migrans (EM) rash AND microbiological confirmation by Bb cultures. The rationale is that in many infections IC Ab can be found bound to its antigen (Ag) target earlier than the free Ab, and in contrast to free Ab, specific IC Ab reflects active infection. We will study serial blinded serum specimens at key time points. ELISA, immunoblot and clinical histories will be available. BbIC will be isolated by a proven simple technique, polyethylene glycol. BbIC Ag and Ab will be examined by immunoblots and ELISA. Focus will be on specific and in vivo expressed Bb Ags. Results will be statistically analyzed. Phase 2 is designed for broadscale usage and refinement of the assay. PROPOSED COMMERCIAL APPLICATIONS: The need for accurate laboratory diagnosis of active infection in Lyme disease is imperative. There are over 5 million serologic Lyme disease tests performed per year. None indicate active infection. They only indicate past infection. A test such as the Borrelia burgdorferi immune complex assay has high potential as a marker of active infection. It can also detect infection early than free antibody assays. Therefore this assay can fulfill a great need in Lyme disease diagnosis and has high market potential. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AUTOIMMUNITY AND CHRONIC LYME ARTHRITIS Principal Investigator & Institution: Meyer, Abbie L.; Pathology; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2001; Project Start 23-MAR-2001 Summary: The overall objective of this application is to confirm the identity of a possible autoantigen in antibiotic-resistant chronic Lyme arthritis. A small population of people infected with Borrelia Burgdorferi (Bb), the causative agent of Lyme disease, develop

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long term arthritis in one or more joints. Because: 1) The arthritis is not cured by long term use of antibiotics, 2) Many susceptible individuals are HLA-DRB10401 (DR4), and 3) T cells responding to both Bb surface antigen, Osp A and a human protein, hLFA-1, can be isolated from synovial fluid, an autoimmune etiology is suspected. Our first objective is to develop a model of chronic Lyme arthritis in mice by generating a transgenic (Tg) mouse line that expresses human. LFA-1, the suspected autoantigen as well as DR4. In these mice we will demonstrate that T cells specific for hLFA1 mediate chronic arthritis and can transfer disease to naive mice. Additionally we will generate fluorescently labeled hLFA-1332-343 and Osp A164-173 peptide-MHC tetramers that can bind and label T cells which express TCR specific for peptide. This will enable us to analyze whether the Osp A specific cell is also hLFA-1 specific, identifying a population of self-recognizing cross-reactive cells. We will transfer these human autoantigen specific cells into hLFA-1 TgDR4+/+ Beige-SCID mice and confirm their ability to generate arthritis. Data supporting an autoimmune etiology of chronic arthritis will allow physicians to begin treating this disease as an autoimmune rather than infectious disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: B BURGDORFERI IMMUNODIAGNOSTICS FOR THE VACCINE ERA Principal Investigator & Institution: Glass, John D.; Brook Biotechnologies, Inc. Long Island High Tech Incubator Stony Brook, Ny 11790 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 30-APR-2002 Summary: Reliable immunodiagnosis of B. Burgdorferi infection is crucial for the timely diagnosis of Lyme disease. Early treatment of Lyme disease is important to limit or prevent serious damage to the nervous and musculoskeletal system. Current serologic assays use cultured B. burgdorferi as their antigen source. Because OspA is the major protein expressed in cultured organisms, with the advent of OspA vaccines, all current whole B. burgdorferi ELISA's will become obsolete. Although these vaccines are efficacious, there are vaccine failures and the duration of protection against B. Burgdorferi infection is limited. In this project we will reformulate the array of epitopes in our diagnostic recombinant antigens to avoid cross-reactivity with the vaccine antigen (a recombinant OspA). This will allow sensitive, specific diagnosis of B. Burgdorferi infection regardless of vaccination status. In preliminary studies we have already shown that an assay based on chimeric recombinant proteins devoid of OspA epitopes is nearly as good as our assay using chimers containing OspA epitopes. In this Phase I project we will further refine the balance of epitopes, adding some to give improved sensitivity or improved coverage of genetic diversity, and eliminating others that limit specificity. This will set the stage for validation of the new recombinant-based immunoassays in Phase II. PROPOSED COMMERCIAL APPLICATIONS: In the US and Europe, about 5 million Lyme tests are performed each year. When OspA-based Lyme vaccines come on the market, essentially the entire diagnostic market will be open to the first company with an approved assay that can detect B. burgdorferi infection regardless of vaccination status. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: B BURGDORFERI LIGAND FOR B3 INTEGRINS Principal Investigator & Institution: Coburn, Jenifer L.; Assistant Professor; New England Medical Center Hospitals 750 Washington St Boston, Ma 021111533

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Timing: Fiscal Year 2001; Project Start 30-SEP-1997; Project End 31-AUG-2002 Summary: (Adapted from the applicant's abstract): Borrelia burgdorferi is the causative agent of Lyme disease, a multisystemic illness that can affect the joints, heart, skin, and central nervous system. The spirochete is able to establish persistent infection in one or more of the affective tissues, despite the host immune response mounted. B. burgdorferi binds to several members of the integrin family of cell surface receptors, including alphaIIb beta/3, alpha/vbeta/3, and alpha/5 beta/1. The applicant's hypothesis is that binding to integrins contributes to the virulence of B. burgdorferi. As a step toward understanding the relevance of integrin binding to the pathogenesis of Lyme disease, the investigators have identified a strong candidate ligand for beta/3-chain integrins. To analyze the pathogenic significance of this candidate, the 66 kDa B. burgdorferi surface antigen, the following Aims will be pursued: Aim 1. Generation of recombinant p66 and of specific antibodies directed against p66. Recombinant p66 will be expressed in E. coli and purified. Rabbit antisera and mouse monoclonal antibodies will be generated against p66 and used in the experiments described in Aim 2 to assess the relevance of p66 in attachment to mammalian cells. Aim 2. Evaluation of the role of p66 in the attachment of live B. burgdorferi to alphaIIB beta/3 and other integrins in vitro. A series of independent experiments will be performed to determine whether the putative integrin binding domain of p66 is exposed on the surface of the spirochete, and whether p66 is relevant in the attachment of live spirochetes to purified integrins, platelets, and cultured epithelial cells. Aim 3. Evaluation of the importance of p66 in a mouse model of Lyme disease. Mutant B. burgdorferi that do not express p66, or that express altered forms of the protein, will be selected using the antibodies generated in Aim 1. These mutants will be tested for binding to integrins in vitro, and for infectivity in a mouse model of Lyme disease. Together, the in vitro investigation of the interaction between this novel B. burgdorferi ligand and the integrins that it recognizes, are likely to contribute to our understanding of the pathogenesis of Lyme disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIODIVERSITY, HABITAT FRAGMENTATION, & LYME DISEASE RISK Principal Investigator & Institution: Ostfeld, Richard S.; Institute of Ecosystem Studies Po Box Ab Millbrook, Ny 12545 Timing: Fiscal Year 2003; Project Start 15-JAN-2003; Project End 31-DEC-2006 Summary: (provided by the applicant): We propose a research program that focuses on the interactions among tick vectors, bacterial pathogens, the community of vertebrate hosts, and the ecological landscapes in which vectors, pathogens, hosts, and humans interact to affect exposure to Lyme disease. We focus on Lyme disease because of its high incidence, widespread distribution, large body of ecological and epidemiological background information, and potential as a model of other vector-borne zoonoses. Our research over the past 9 years has generated a conceptual model that we call the dilution effect. According to this model, high species diversity in the community of hosts for ticks reduces the infection prevalence of ticks by diluting the effects of the ubiquitous white-footed mouse, which is the principal natural reservoir for the disease agent, Borrelia burgdorferi. Other published research suggests that species diversity of vertebrate's decreases, and population density of mice increases, with decreasing forest patch size. We propose to test this model rigorously at sites in six northeastern states. Our research will focus on the generality of the dilution effect and on the mechanisms that underlie it. We will assess the species richness and relative abundance of vertebrate hosts, as a function of size of forest fragments, in suburban landscapes of the Northeast.

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We will use both species diversity indices and patch size as independent variables in regressions that use either infection prevalence of nymphal ticks, or the abundance of infected nymphs, as dependent variables. Finally, we will use modeling approaches developed in our lab to both assess the generality of the dilution effect for other vectorborne diseases and increase the realism of the Lyme-disease system. Our research comprises a rigorous, multidisciplinary approach to understanding the linkages between ecology and risk of infectious disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOENGINEERED VACCINE ADJUVANTS Principal Investigator & Institution: Yalpani, Manssur; Biopolymerix, Inc. 1 Industrial Way Tyngsboro, Ma 01879 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 31-DEC-2001 Summary: (Provided by Applicant): We plan to develop a novel family of vaccine adjuvants through bioengineering a microbial glycolipid. This polymeric material is generated as a secreted product from the bacterium, Acinetobacter calcoaceticus and in preliminary studies demonstrates exceptional adjuvant activity. To further explore this application, we plan to correlate structural features of the polymer with macrophage response in vitro and antibody response in vivo to a series of these analogs. The Phase I studies will determine if the nature of the macrophage response is structure-specific, and if so, which structural features are most important. These features will then be assessed in vivo in a murine Lyme vaccine model. To accomplish this goal we will generate a family of structural analogs using methods we have recently developed, and then characterize these analogs for selectivity of responses of macrophages in terms of cytokine release followed by antibody response in vivo. The outcome of Phase I will be a selection of the best few candidate structures to move forward into more detailed in vivo testing in Phase II. PROPOSED COMMERCIAL APPLICATION: The development of a family of structurally related vaccine adjuvants is of considerable relevance for establishing structure-property relations and tailored therapeutics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOLOGY AND CONTROL OF LYME DISEASE BORRELIA Principal Investigator & Institution: Barbour, Alan G.; Professor; Microbiol & Molecular Genetics; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2001; Project Start 30-SEP-1994; Project End 30-APR-2005 Summary: (Adapted from Applicant's Abstract): The proposed collaborative project is based collectively on investigations of the pathogenesis and epidemiology of Lyme disease, the ecology, vector biology, and population genetics of vector-borne diseases, the molecular biology of Borrelia burgdorferi, and vaccine development. The emphases of the proposed studies are the evolutionary biology of B. burgdorferi and new strategies for Lyme disease prevention. The long term goals are the following: (1) To significantly reduce the risk of Lyme disease among humans and domestic animals by vaccine intervention in the natural maintenance cycle of B. burgdorferi in a highly endemic area. (2) To study the evolution of B. burgdorferi as an infectious agent through controlled intervention studies in a highly endemic area. (3)To provide for a vaccine that is highly effective and that can be expeditiously, safely, and inexpensively administered in the field. The hypotheses for the project are the following: (A) A high prevalence of anti-OspA antibodies among Peromyscus leucopus and/or other mammalian reservoirs in the field will reduce the transmission rate between reservoir hosts and vector ticks,

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thereby reducing the prevalence of B. burgdorferi infection in ticks. (B) Immunization of reservoirs in the field will not alter the population structure of B. burgdorferi at the vaccine field sites in comparison to the control sites. (C) Transmission-blocking immunity among P. leucopus and/or other mammalian reservoirs can be achieved by oral as well as by parenteral immunization with a single immunogen or combined immunogens. The specific aims are the following: (1) Field studies of the effect of immunization of P. leucopus on the rate of transmission of B. burgdorferi between reservoir host and vector ticks. (2) Assessment of the effects of vaccine intervention in the field on the population structure of B. burgdorferi in ticks and in vertebrate reservoirs. (3) Further development of single-vaccination and orally-delivered field vaccines and evaluation of second, supplementary antigens. The proposed studies may provide insights as molecular, organismal, and population levels about B. burgdorferi, its transmission, and reservoir host immunize responses. The results may also have relevance for the control of other vector-bone zoonotic diseases and perhaps for development of novel methods for vaccine delivery. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOMED RES FACIL: LYME DIS Principal Investigator & Institution: Cunningham, Dennis D.; Professor; None; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2002; Project Start 17-JUN-2002; Project End 16-JUN-2003 Summary: (provided by applicant): This application proposes construction of the Procedural and Behavioral Housing Suites (PBHS), a 5,215 sq. ft. vivarium expansion in the BRC at the UC- Irvine College of Medicine. Partially completed and under phased construction, the BRC is planned as a four building, 200,000 sq. ft. complex dedicated to interdisciplinary research in the areas of neuroscience, cancer, genetics, immunology, and infectious disease. Biomedical research by current faculty and those under recruitment relies heavily on animal research, creating an urgent need to increase vivarium space for PBHS. The project would expand the existing 12,320 sq. ft. Gillespie Vivarium and connect the underground vivarium complex to the four BRC buildings (one operational, two under construction, and one planned). The PBHS would consist of three suites, each efficiently combining rooms of three basic types: 1) procedure rooms; 2) behavioral testing rooms; and 3) rodent holding rooms. The construction also would include a smaller three-room Gillespie Vivarium Extension (one housing room, one behavioral testing room, and an anteroom). The procedure and behavioral testing rooms have been designed to allow conversion into animal housing or a different mix of testing and procedure rooms. There is an architectural option to convert one or more of the suites into barrier facilities if need arises. Temporary procedure and testing rooms would be released to revert to their original purpose of animal housing. The application identifies a group of PHS-funded faculty members who would use the PBHS to advance biomedical knowledge in areas important to the nation's health. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOSYSTEMATICS OF MEDICALLY IMPORTANT TICK VECTORS Principal Investigator & Institution: Keirans, James E.; Inst/Arthropodology/Parasitol; Georgia Southern University Statesboro, Ga 30458 Timing: Fiscal Year 2001; Project Start 01-SEP-1999; Project End 31-AUG-2004 Summary: (Adapted from the Applicant's Abstract): The proposed research involves a 5year systematic study of ticks on a worldwide basis including morphological, cladistic,

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molecular and genetic analyses. Ticks transmit more pathogens to humans and their animals than any other arthropods, and systematic studies of these disease transmitters are essential to the understanding of vector/host relationships and vectorial capacity. The basis for these systematic investigations in the U.S. National Tick Collection, the world's largest, its companion library on ticks and tick-borne diseases, and computer access to complete biosystematic data on over 122,000 tick collections from throughout the globe. These systematic resources are unique, allowing this type of research nowhere else. Specific aim one will be the study of the primary vectors of Lyme disease, i.e., the Ixodes (I.) ricinus complex of ticks on a global basis. These 15 known or potential vector species will be studied morphologically, morphometrically, and at the molecular level to investigate relationships among the species. Hybridization of Nearctic and Palearctic species will be conducted in Switzerland and/or Russia. Specific aim two will be preparation of a monograph on all 55 species of larval Ixodidae known from the United States. This monograph will fill a significant void, given the importance of ixodid larvae in pathogen maintenance, especially via transovarial transmission from female ticks. Both line drawings and SEM photomicrographs will be used in conjunction with keys. Complete data on hosts, geographical distribution, and medical and veterinary importance for each species will be presented. Specific aim three will be a monographic revision of the 44 known and approximately 20 undescribed species of the genus Ixodes from in Central and South America. Little information is available on Borrelia and Ehrlichia spp from Central and South America. We intend to check archived Ixodes species from this area using PCR methods. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BORRELIA BURGDORFERI GENE EXPRESSION IN TICK MIDGUT-ROL Principal Investigator & Institution: Narasimhan, Sukanya; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2003 Summary: (Taken from the application): The research application aims to study the gene expression pattern of the spirochete Borrelia in the Ixodes tick vector and to comprehend the molecular changes that occur on the spirochetes to facilitate disease transmission. Towards this goal, a novel approach will be utilized to study differential gene expression of tick-adapted spirochetes. Experiments will be carried out to: A) identify genes expressed by the spirochetes at specific feeding time points; B) analyze the temporal and spatial pattern of expression of these genes in an effort to focus on molecules that would be biologically relevant to transmission of disease; and C) to generate mutant Borrelia lacking specific genes of interest identified in this application and test the potential of these mutant Borrelia to transmit disease. The protein products of the genes that are inferred to have a physiological role in disease transmission will ultimately be tested as transmission blocking vaccines. The results of this investigation will enable a better understanding of molecules involved in transmission of Lyme disease and permit novel strategies for the intervention of disease. The investigation will also be conducive to the development of a useful molecular tool/approach to analyze the gene expression patterns of other vector-borne pathogens in their vector environment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BORRELIA BURGDORFERI LUXS-MEDIATED QUORUM SENSING Principal Investigator & Institution: Stevenson, Brian; Assistant Professor; Microbiology Immunology, and Molecular Genetics; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2003; Project Start 15-JUN-2003; Project End 30-NOV-2007 Summary: (provided by applicant): The spirochete Borrelia burgdorferi, the causative agent of Lyme disease, is transmitted to humans and other warm-blooded animals through the bite of infected Ixodes spp. ticks. The establishment of B. burgdorferi infection involves numerous interactions between the bacteria and a variety of vertebrate host and arthropod vector tissues. Different bacterial proteins are required at specific points of this infectious cycle, and precise regulation of the synthesis of such proteins is essential for successful infection to occur. We have discovered that these spirochetes utilize a regulatory mechanism to control protein expression patterns that involves a chemical signal known as autoinducer-2 (AI-2). This molecule is produced by the B. burgdorferi LuxS protein, which we have demonstrated to be a functional enzyme. Our preliminary studies suggest that B. burgdorferi can regulate LuxS synthesis. Addition of AI-2 to cultured B. burgdorferi dramatically alters the expression of more than 50 different proteins, increasing expression levels of some proteins, while decreasing expression of others. Through this mechanism, a population of Lyme disease spirochetes may synchronize production of proteins needed for infection processes. We hypothesize that B. burgdorferi uses AI-2 as an important signaling molecule to control expression of proteins during the natural infectious cycle of the Lyme disease spirochetes. The proposed studies will characterize the expression of LuxS during bacterial infection, the mechanisms by which B. burgdorferi controls synthesis of AI-2, and functions of AI-2-regulated proteins. Results from these studies will enhance our understanding of the complex interactions between B. burgdorferi and its hosts, as well as identifying potential bacterial targets for improved therapies to prevent and treat Lyme disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BORRELIA BURGDORFERI. INVASION AND CHRONICITY Principal Investigator & Institution: Benach, Jorge L.; Professor, Molecular Genetics and Microb; Molecular Genetics & Microbiol; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2001; Project Start 01-MAY-1990; Project End 30-APR-2006 Summary: (provided by applicant):In the past funding period, we have shown that there are critical associations between spirochetes and fibrmolytic proteases of the plasminogen activation system. We have shown how these organisms use plasmin to promote their own invasiveness. The Borrelia binds plasminogen on their surface where it is activated to plasmin by the plasminogen activator urokinase (uPA). In turn, uPA can be bound to its cell receptor, the urokinase plasminogen activator receptor (uPAR, CD87). Borrelia burgdorferi can also induce the upregulation of uPAR on the membrane and the release of the soluble isoform into the medium from peripheral blood monocytes, and from monocyte-like human cell lines. Patients with Lyme disease also have elevated levels of soluble uPAR in the serum and in the cerebrospinal fluid. The function of the soluble uPAR in body fluids in disease, particularly infection, is not known. The hypothesis of this competitive renewal application is that soluble uPAR has an effect on the levels of free uPA, leading to a procoagulant state, which is, in turn, a means to control bacterial dissemination. In this manner, soluble uPAR is a molecule

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with anti infection properties. The Specific Aims of this proposal are: to determine the biochemical nature of the soluble uPAR released from monocytes after exposure to Borrelia in experimental situations; and, to determine the cellular source and biochemical nature of uPAR in human and experimental infection, and to characterize the clinical conditions of uPAR production. The hypothesis will be tested by several biochemical and molecular approaches, and by animal and clinical studies. This proposal embodies extensive experimental evidence that other macromolecules of the PAS, namely, the uPAR (CD87), could also play a critical role in modulating spirochetal infections. There are also two murine models of spirochetal infection can be used effectively in transgenic animals. Furthermore, the availability of transgenic mice for most of the known components of the fibrinolytic system is advancing our knowledge of this system in areas that had not been previously envisioned. For this proposal, we have in vivo correlates (both at the experimental and clinical levels) to the in vitro observations. Specifically, our fully correlated in vitro and in vivo systems will permit translational conclusions within this funding period. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CD1-MEDIATED IMMUNITY OF LYME DISEASE Principal Investigator & Institution: Bockenstedt, Linda K.; Associate Professor; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2001; Project Start 05-APR-2001; Project End 31-MAR-2006 Summary: (provided by the applicant): Lyme disease is a multisystem disorder caused by infection with the tick-borne spirochete, Borrelia burgdorferi. The disease occurs in stages that reflect the biology of the spirochete as it adapts from survival in the tick to the more hostile environment of the mammal. B. burgdorferi contains an abundant array of highly immunogenic outer membrane lipoproteins (Osps) that are differentially expressed throughout the spirochete lifecycle. Lipoproteins incite inflammation and are believed to be the principal spirochete component causing disease. Lipoproteins can also elicit protective humoral immunity but current vaccines fail to elicit long-lived immunity. This proposal is based on our novel findings that absence of CD1d, a nonclassical antigen-presenting molecule that binds lipid Ag, renders mice susceptible to B. burgdorferi infection and disease. Pathology correlates with high-titer T-dependent antibody responses to spirochete lipoproteins, including lipoproteins only transiently expressed by spirochetes establishing infection in the host. We hypothesize that CD1d functions to facilitate the elimination of spirochetes and their disease-inciting lipoproteins by potentiating innate immune mechanisms. This proposal seeks to 1) understand the molecular and cellular mechanisms by which CD1d-mediated immunity controls spirochetal pathogens; 2) determine whether blocking CD1d will enhance the duration of lipoprotein vaccine-induced immunity; 3) examine the evolution of B. burgdorferi infection in the absence of CD1d, and effects the early strong adaptive immune response has on spirochetes that persist in the host; and 4) use the adaptive immune response that evolves in the absence of CD1d to identify key lipoproteins necessary for tick-borne spirochetes to infect and disseminate in the mammalian host. The completion of these studies will allow for broad insights into the role of CD1d in host defense against pathogens and clearance of their proinflammatory lipoprotein antigens that incite disease. In addition, these studies may suggest feasible strategies to improve vaccination-induced protective immunity. For the field of Lyme disease, defining the key molecules expressed by tick-borne spirochetes will move us one step closer toward understanding how this pathogen invades, disseminates and persists in the mammalian host.

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

Project Title: CEFTRIAXONE AND DOXYCYCLINE IN PATIENTS WITH SERONEGATIVE CHRONIC LYME DISEASE Principal Investigator & Institution: Klempner, Mark S.; New England Medical Center Hospitals 750 Washington St Boston, Ma 021111533 Timing: Fiscal Year 2001 Summary: These studies will explore treatment strategies for chronic lyme disease and will be conducted at two centers, New England Medical Center/Tufts University School of Medicine and Westchester County Medical Center affiliated with New York Medical College. The coordinating center, and the central laboratory facility will be at New England Medical Center. Investigators will perform an initial assessment of each patient for collection of demographic data, a history of exposure to ticks in geographic regions with endemic B. burgdorferi infection. Treatment interventions and clinical endpoints will be assessed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CEFTRIAZONE&DOXYCYCLINE IN SEROPOSTIVE CHRONIC LYME DISE Principal Investigator & Institution: Evans, Janine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2001 Summary: The primary objective of this study is to determine whether; 1) intensive antibiotic treatment benefits seropositive patients with Chronic Lyme Disease: 2) evidence of persistent infection with Borrelia burgdorferi can be found in patients with CLD: 3) evidence of co-infection with other microorganisms can be found in patients with CLD: 4) specific clinical or laboratory parameters improve in patients who receive antibiotic therapy compared to patients who receive placebo and 5) specific parameters are predictive of a response to therapy should it be observed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CENTRAL NERVOUS SYSTEM INVASION IN EARLY LYME DISEASE Principal Investigator & Institution: Coyle, Patricia K.; Associate Professor; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2001 Summary: Lyme disease, due to the spirochete Borrelia burgdorferi, is a major emerging infection in our country. Neurologic involvement has become the significant morbidity of this infection, but has not been well studied. Effective public health poll is being hampered by lack off basic information on clinical and laboratory features and pathogenetic mechanisms of Lyme disease. The objective of this proposal is to identify the frequency, clinical correlate and outcome of central nervous system (CNS) infection in early Lyme disease. This study will focus on 3 adult case groups (N=100) with newly acquired infection: 1) single lesion erythema migrans (EM) (N=25); 2) multifocal EM (N=25); 3) neurologic Lyme disease (N=50). All eligible patient will meet Centers for Disease Control and Prevention diagnostic criteria for Lyme disease. After an initial comprehensive evaluation (self report forms to assess clinical symptoms, psychosocial and psychiatric measures, and health outcome; skin, blood and cerebrospinal fluid (CSF)

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studies; cognitive assessment) subjects will receive standard antibiotic treatment, and then be followed prospectively for 18 months. Comparison groups will be healthy subjects (N=1 00) frequency matched to cases on age, education and gender; and subjects with other neurologic diseases (N=50). Specific Aim 1: To determine the frequency of CNS invasion in early local and disseminated Lyme disease (invasion will be defined by positive CSF culture, Borrelial antigen, Borrelial DNA, or intrathecal Borrelial antibodies); to document neurologic complaints and health function status of early infection patients. Hypothesis: CNS invasion by B. burgdorferi is common during early infection. Corollary: neurologic complaints are frequent in early Lyme disease. Corollary: in this population new onset of headache is a clinical marker of CNS invasion, while CSF IgM reactivity to B.burgdorferi is an immune marker of CNS invasion. Specific Aim 2: To examine the outcome of neurologic involvement in,early Lyme disease. Hypothesis: Following infection, patients with persistent CSF abnormalities (defined as CNS invasion markers; Borrelial immune complexes; or abnormal cell count or protein) will be symptomatic. Corollary: clearance of CSF is associated with clinical improvement. Specific Aim 3: To determine the proportion of early Lyme disease patients who develop late encephalopathy. Question: what proportion of early Lyme patients will develop persistent neurobehavioral dysfunction in domains of attention and memory? This proposal will help characterize the neurologic aspects of early Lyme disease, will aid in diagnosis and management, and will help guide the formulation of a rational and cost effective health care program for Lyme disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHRONIC LYME ARTHRITIS: IS THIS AUTOIMMUNITY? Principal Investigator & Institution: Huber, Brigitte T.; Professor; Pathology; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2001; Project Start 20-SEP-1998; Project End 31-MAY-2006 Summary: (provided by applicant): Lyme disease is a multifaceted illness, initiated upon infection with the spirochete Borrelia burgdorferi (Bb). One manifestation of the disease is arthritis that can become a debilitating, chronic disease in genetically susceptible individuals. During the tenure of this grant, a candidate auto-antigen, hLFA1, was identified which may elicit an autoimmune response in T cells by molecular mimicry with outer surface protein A (OspA) of Bb. These data form the basis for the current proposal. I. The analysis of the inflammatory T cell response will be expanded and refined by: a) single cell sorting of OspA-reactive T cells from Lyme arthritis patients, using cytokine secretion/capture assays to identify and clone OspA-reactive T cells, regardless of epitope fine specificity. The T cell response of patients in the acute and the chronic phase of the disease will be compared that will provide insights into the mechanism of treatment resistant Lyme arthritis. b) Analyses of OspA responses in HLA.DRB1 transgenic mice. DRB1*0401 and *0101 are associated with susceptibility to chronic Lyme arthritis, while the presence of *1101 seems to protect from this disease. To study the underlying mechanism, the OspA immune response in Bb infected C3H mice expressing these human DRB chains will be mapped and compared. c) testing hLFA-1/DRIB 1*0401 transgenic mice as an animal model for chronic Lyme arthritis. These mice will be infected with Bb and screened for the development of a chronic arthritic disease. II. The contribution of Abs to the inflammatory joint disease will be assessed. A prominent OspA-specific Ab response is observed during the chronic phase of the disease, correlating with the onset of prolonged bouts of arthritis. These Abs will be tested for an autoimmune reaction, and their involvement in joint inflammation will

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be determined by: a) the identification of immune complexes in synovial lesions of Lyme arthritis patients; b) the use of OspA Abs from chronic Lyme arthritis patients as probe for autoantigen; c) Bb infection in FcRn-deficient, hLFA-1/ DR*0401 transgenic mice: FcRn-/- mice clear serum IgG fast and are protected from Ab-mediated autoimmune diseases. III. A new candidate for molecular mimicry of OspA, hMAWDBP, will a) be tested for cross reaction with OspA specific T cells and Abs, b) its aa sequences in the OspA-homologous regions of human and mouse will be compared; c) if significant differences are observed, hMAWD-BP transgenic mice will be prepared; finally, d) Genebank searches will be carried out for the identification of other human homologues of bacterial OspA. These experiments are designed to elucidate the mechanism of treatment resistant Lyme arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COINFECTION OF TICK-BORNE DISEASES IN AREAS OF WISCONSIN Principal Investigator & Institution: Caporale, Diane A.; Biology; University of Wisconsin Stevens Point 2100 Main St Stevens Point, Wi 54481 Timing: Fiscal Year 2001; Project Start 15-SEP-2001; Project End 14-SEP-2004 Summary: (provided by the applicant): Close to 400 human cases of Lyme disease and several --cases of Babesiosis and Human Granulocytic Ehrlichiosis (HGE) are reported in the State of Wisconsin each year. For several years, Lyme disease has been known to be highly endemic in the northwestern region of the state. But little is known about the coinfection rate of these three diseases. Past deer surveys have suggested no existence of deer ticks in the eastern part of Wisconsin, except Marinette County near Green Bay. However, I recently identified deer ticks on mice in the Lower Kettle Moraine, and 3.6 percent were found infected with Borrelia burgdorferi. Deer tick populations have progressively been spreading to Central Wisconsin. It is important to investigate more thoroughly the population structure of deer ticks and associated diseases. Study sites in Wisconsin will include Dunn County, Portage County and Marinette County. For three years, adult ticks will be collected in each fall season by dragging flags. The microgeographic distribution of Ixodes scapularis will be determined. The 16S rDNA sequence of the ticks will be compared to determine whether gene flow exists among these areas. The DNA from crushed tick parts will also be tested for tick-borne pathogens using the polymerase chain reaction (PCR). The genes targeted will be OspB for B. burgdorferi, the 16S-like gene for Babesia microti and the 1 6S rRNA gene for Ehrlichia (HGE). DNA sequencing for all three pathogens will be used for species verification. The microgeographic distribution and co-infection rates of tick-borne diseases, from their main vector are major contributions to the understanding of the spread of tick-borne diseases in Wisconsin. A Lyme disease vaccine is now available to the public, which is a recombinant form that includes the ospA gene of a New York B. burgdorferi strain. I recently discovered a highly mutated strain from southeastern Wisconsin. It is possible that the vaccine may not be effective against this strain. I propose to monitor the frequency and spread of this strain in northwestern, central, and northeastern Wisconsin. If this strain is prevalent in this state, vaccine developers should investigate the efficacy of their vaccine on this strain. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COMPARATIVE GENOMICS OF LYME DISEASE SPIROCHETES Principal Investigator & Institution: Casjens, Sherwood R.; Professor; Oncological Sciences; University of Utah 200 S University St Salt Lake City, Ut 84112

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Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 30-JUN-2005 Summary: (provided by the applicant): This project aims to obtain an understanding of the nature, variability and evolution of the unusual genome of the spirochete bacteria (genus Borrelia) that cause human Lyme disease. Many of the genes that are thought to encode host-interaction genes in Borrelia are encoded on the numerous extrachromosomal DNA elements (plasmids) that these bacteria carry. Most of these "plasmids" (21 different ones in the only isolate to be exhaustively studied) may be present in nearly all natural isolates, and so could be thought of as "mini-chromosomes." Current evidence indicates that at least ten of the linear plasmids of the North American Lyme agent bacteria, Borrelia burgdorferi, are in the midst of a "rapid evolutionary spurt," as is evidenced by the presence in the one individual studied in detail, of many recent duplicative rearrangements and mutationally decaying duplicates of genes that are thought to be important to the organism. This application proposes to compare the complete nucleotide sequences of the plasmids several B. burgdorferi isolates, a B. garinii and a B. afzelii isolate (causative agents of Lyme disease in Eurasia), and isolates of a very closely related species that does not cause Lyme disease (B. bissettii). In addition, the chromosome of B. garinii will be sequenced. This "comparative genomics" approach is a powerful way to begin to deduce which plasmid genes are important in causing Lyme disease as indicated by their conservation among Lyme causative isolates, to deduce other general similarities and differences among the species under study, as well as to understand the mechanisms involved in the "rapid evolutionary changes" mentioned above. A longer term objective is to use this information to study a larger panel of independent strain isolates to understand the nature of the plasmid gene pool in the Lyme disease Borreliae, as well as to understand the relative rates of the "rapid evolution" (above), plasmid spread, and bacterial clonal expansion in the B. burgdorferi population. These findings will impact the study of the molecular pathogenesis of Lyme disease in many ways. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONST OF ANIMAL FACIL: LYME DISEASE Principal Investigator & Institution: Stancel, George M.; Dean; Integrative Biology and Pharmacology; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 30-MAY-2003 Summary: (provided by applicant): This application requests support for construction of a permanent facility for housing, breeding and care of genetically engineered (transgenic and knockout) and immuno-compromised rodents. The facility will be located in a new research building being designed by the UTHSC-H. UTHSC-H Investigators hold approximately $100 million (total costs) of active National Institutes of Health (NIH)funding for studies involving animals, and $7 million in yearly direct costs for active and pending studies with specialized mice. Tropical Storm Allison totally destroyed the Animal Care Center that housed most of the animals used for this research. Tragically, hundreds of animals drowned. To prevent this from ever happening again, the proposed facility will be on the top floor of a new nine-story building. The new building will have enclosed connections to the UTHSC-H Medical School and Institute for Molecular Medicine Buildings, so that it will support the work of investigators in all three buildings. The proposed facility will contain 5,945 sq. ft., including a large barrier suite, for genetically engineered and immuno-comprised rodents. It will occupy roughly half a floor devoted exclusively to animal care and accommodate up to 11,000 animals. The facility will be under the control of the Center for Laboratory Animal Medicine and Care (CLAMC), which manages and operates all animal care and use activities at the

20

Lyme Disease

UTHSC-H. The CLAMC was initially accredited by the AAALAC International in 1978 and remains fully accredited today. The Director of the CLAMC reports directly to the Executive Vice President for Research of the UTHSC-H. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--CENTRAL LABORATORY Principal Investigator & Institution: Dattwyler, Raymond J.; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2001 Summary: Core C, the Central Laboratory Core, will be responsible for standardized cerebrospinal fluid, blood and skin tests carried out by the Clinical Projects 2,3,4. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--DATA COORDINATION Principal Investigator & Institution: Hyman, Leslie; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2001 Summary: This Program Project Grant application is a collaborative, interdisciplinary effort to characterize the neurologic, neuropsychologic, and psychosocial features of Lyme disease among persons residing in a highly endemic area of Suffolk County, New York. The application consists of four individual projects, three of which involve patients with early- and late Lyme disease in adults and children, and one which uses data collected from these projects to test hypotheses related to pathogenesis and psychosocial factors. In addition, the Program Project consists of four cores that will provide shared resources for the different projects. Core B, the Data Coordinating Center Core (DCCC), is responsible for: the coordination and flow of data across all of the Projects and Cores and is a central unit to the program project. The major goal of the DCCC is to assure that high quality data are collected from all Projects and Cores in a systematic and standardized manner. The DCCC is responsible for the epidemiologic and biostatistical aspects of each of the Projects and Cores; quality assurance; identification of the control group for Projects 2 and 3; data processing and management; data analyses and preparation of reports. The specific aims are: 1) to serve as a collaborating center to the Program Project and to provide epidemiologic and biostatistical input to the organization, design, conduct and analysis of Projects 2, 3 and 4; 2) to coordinate the flow of data among the projects and cores; 3) to collaborate in the development of study forms, documents and protocols; 4) to develop, implement and maintain quality assurance procedures for all aspects of the projects and cores; 5) to develop and implement data management and processing procedures, including design of data entry and editing systems for data collected for each project and from each of the other Cores; 6) to prepare periodic reports for the Steering Committee and Advisory Committee to monitor recruitment and data collection; 7) to outline and perform the analyses needed to evaluate the aims of each project and collaborate in preparing publication of results; and 8) to identify a population based healthy control group for Projects 2 and 3 using random digit dialing. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--NEUROPSYCHOLOGY Principal Investigator & Institution: Calev, Avraham; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2001 Summary: This neuropsychological core will provide centralized, cost-effective data collection. It will coordinate reliable neuropsychological test administration, scoring, and data collation. The goal of Core D is to further define observed attention and memory deficits in Lyme disease and to more fully characterize neurobehavioral function in adult and pediatric patients with early and late stages of infection. The specific aims of the Core are: 1. To coordinate neuropsychological data collection in a cost-effective manner 2. To provide a centralized and standardized means of assessment which is consistent across Projects and subject groups. 3. To provide initial data reduction in preparation for project specific statistical analyses 4. To train and supervise study psychometricians 5. To ensure quality assurance with respect to all neuropsychological assessment procedures. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DBPA/B PROTEINS OF BORRELIA BURGDORFERI & LYME ARTHRITIS Principal Investigator & Institution: Parveen, Nikhat; Molecular Genetics & Microbiol; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 28-FEB-2006 Summary: (provided by applicant): Lyme disease presents a unique clinical system to study cellular and molecular mecahnisms responsible for chronic inflammatory diseases. The disease, caused by the spirochete Borrelia burgdorfen, is the most prevalent arthropod borne disease in the United States. It is a multisystemic illness that affects skin, muscles, joints, heart and nervous system. If left untreated, chronic manifestations are frequenctly observed and Lyme arthritis is the most common symptom in North America. My Iong term qoal is to identify the virulence factors of B. burgdorferi involved in attachment to host cells and in colonization of various tissues, and characterize their role in the pathogenesis, diagnosis and prevention of chronic Lyme disease. Glycosaminoglycans (GAGs), ubiquitously expressed on the surface of all nucleated cells, are recognized by various Lyme spirochetes and several bacterial molecules are involved in this adherence. Decorin binding lipoproteins DbpA and DbpB of B. burgdorferi show affinity for heparin and dermatan sulfate GAGs in addition to the proteoglycan decorin. My hypothesis is that DbpA and DbpB contribute to the colonization of various tissues by B. burgdorferi binding to GAGs and decorin present on the host cells and trigger an inflammatory response in skin and joints causing erythema migrans and Lyme arthritis. The major question to be addressed in this study are: (1) Do DbpA and DbpB contribute to the GAGsmediated attachment of B. burgdorferi to host cells and to the inflammatory response in the joints of susceptible mice? (2) Does deletion of dbpA and dbpB genes affect attachment of B. burgdorferi to the host cells? (3) Are DbpA and DbpB lipoproteins essential virulence factors of B. burgdorferi that trigger Lyme arthritis? Si,qniflcance: Lyme arthritis exhibits several symptoms similar to those of rheumatoid arthritis. However, unlike rheumatoid arthritis, the causative agent is known in Lyme disease and hence, it is feasible to analyze the molecular mechanisms involved in this form of destructive arthritis. In addition, B. burgdorfer/ infected mouse exhibits symptoms similar to those of human

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Lyme Disease

Lyme disease, and hence, murine model provides an ideal system to analyze the mechanisms of Lyme borreliosis. This study will characterize the role of two spirochete lipoprotein adhesins in Lyme arthritis in the murine model. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DECORIN-BINDING PROTEINS OF BORRELIA BURGDORFERI Principal Investigator & Institution: Hagman, Kayla E.; Microbiology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2003; Project Start 15-DEC-2002; Project End 30-NOV-2007 Summary: (provided by applicant): Lyme disease continues to represent a major public health problem, and many aspects of Lyme disease pathogenesis and immunology thus warrant further investigation. Decorin-binding protein A (DbpA), a membrane lipoprotein of Borrelia burgdorferi, has been implicated in subserving the parasitic strategy of B. burgdorferi by functioning as a cell matrix-binding adhesin during mammalian tissue invasion. DbpA also has emerged as the most prominent new human Lyme disease vaccine candidate. However, many features of DbpA, such as its temporal expression, membrane topology, role in B. burgdorferi virulence, and overall utility as a protective immunogen, remain poorly understood. The current study addresses these important information gaps. To this end, the Specific Aims of this proposal are: (1) To examine the temporal expression pattern(s) of DbpA by tick-transmitted B. burgdorferi in the mammalian (mouse) host, (2) To examine the membrane topology of DbpA expressed by tick-transmitted B. burgdorferi in the mammalian (mouse) host, (3) To construct a DbpA-deficient mutant of virulent B. burgdorferi by insertional inactivation of dbpA, with emphasis on examining the role of DbpA expression in B. burgdorferi infectivity, virulence, and disease pathogenesis, and (4) To examine further the overall efficacy of DbpA as a vaccinogen in the mouse model of Lyme borreliosis. Regarding the latter, emphasis will be placed on (a) purifying recombinant DbpA (as immunogen) to preserve its native conformation and (b) tick infestation (challenge route for B. burgdorferi) of DbpA-immunized mice to mimic natural B. burgdorferi transmission. The current proposal represents a comprehensive study of the role of DbpA in both the pathogenesis of Lyme disease and its potential as a human Lyme disease vaccine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DEVELOPMENT OF A VACCINE FOR MURINE LYME DISEASE Principal Investigator & Institution: Hu, Linden T.; Associate Professor of Medicine; New England Medical Center Hospitals 750 Washington St Boston, Ma 021111533 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 28-FEB-2007 Summary: (provided by applicant): The incidence and geographic distribution of Lyme disease in the U.S. has increased steadily since its first description in 1977. Efforts to stem the spread of the disease through controlling the population of its tick vector and/or the mouse reservoirs of the disease have met with only limited success. The only approved human vaccine to protect against Lyme disease was recently removed from the market by its manufacturer further highlighting the need for new approaches to controlling the disease. In this project, we propose the development of an orallyavailable vaccine targeted towards the mouse and tick reservoirs of the disease. The project is modeled on the highly successful oral rabies vaccine, Raboral, which uses a vaccinia virus (VV) vector to deliver its immunogen to wild foxes and raccoons. We will take advantage of the enormous amount of immunogenicity and safety data that has been generated for vaccinia virus in hopes of rapidly developing a release-able vaccine.

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The vaccine itself will consist of outer surface protein A (OspA) recombinantly expressed from a VV vector. OspA was the antigen used in the human vaccine. Extensive research has shown that it is immunogenic in mice, that mice vaccinated against OspA are protected against infection with Borrelia burgdorferi and that B. burgdorferi infected ticks feeding on mice vaccinated with OspA are sterilized of their infection and cannot transmit the disease to other animals. Prior attempts to use OspA to vaccinate wild animals have been hampered by the lack of an efficient, oral delivery system which is both stable under natural environmental conditions and can generate an intense immune response. The three aims of this project are to: 1) create a recombinant VV expressing OspA (W/OspA); 2) establish the kinetics and durability of the immune response to the recombinant W/OspA; and 3) test the efficacy of W/OspA administered orally in preventing transmission of B. burgdorferi to mice and in sterilizing infection in infected ticks. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LEUKOCYTE

EFFECT

OF

TICK

SALIVA

ON

POLYMORPHONUCLEAR

Principal Investigator & Institution: Montgomery, Ruth R.; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2004 Summary: In a natural Borrelia burgdorferi infection, spirochetes are inoculated into the mammalian host skin by salivating ticks during their blood meal. Polymorphonuclear leukocytes (PMN) accumulate at the inflammatory center of the skin lesion, while free spirochetes are often seen at the periphery. Tick saliva may promote the survival of infecting spirochetes by inhibiting PMN functions. We will examine the inhibitory effects of saliva in the mouse model of Lyme borreliosis by infecting animals via syringe with B. burgdorferi either alone or with saliva, or via infected tick. We will evaluate the effect of salvia on spirochete dissemination using real time PCR to quantify the number of spirochetes both in blood and arriving at a distal skin site. By microscopic analysis of skin, we will determine the recruitment of MIN to the inoculation site and the expression level of key functional markers on cells at eh site. In addition, we will survey the chemokines expressed in the skin first in vitro via array analysis, using relevant cells in culture stimulated with spirochetes in the presence and absence of saliva, and subsequently in infected skin in situ. These preliminary studies will be extended the future with a more detailed time course and with doses of saliva, purified components of saliva, and recombinant salivary proteins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENDOTHELIAL RECRUITMENT OF T CELLS IN LYME DISEASE Principal Investigator & Institution: Furie, Martha B.; Professor; Pathology; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2001; Project Start 15-DEC-2000; Project End 30-NOV-2005 Summary: (Adapted from the Applicant's Abstract): This project proposes to investigate the interactions between T lymphocytes in the context of chronic inflammation and infection. The hypothesis is that B. burgdorferi infection activates the vascular endothelium, enhancing extravasation of T lymphocytes that secret type 1 proinflammatory cytokines. To test this central hypothesis, the PI will use in vitro models to pursue the following specific aims: 1) Determine the subpopulations of T lymphocytes that migrate across endothelium exposed to B. burgdorferi; 2) Identify the

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adhesion molecules and chemo-attractants involved in the migration of T lymphocytes across spirochete-stimulated endothelium; and 3) Explore the capacity of the host cytokine, interleukin (IL)10, to modulate interactions of T lymphocytes with endothelium activated by B. burgdorferi. These studies will provide greater insight into how accumulation of T lymphocytes is regulated not only in Lyme disease, but also in chronic inflammation in general. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTIONAL BURGDORFERI

GENOMIC/PROTEOMIC

ANALYSIS

OF

B

Principal Investigator & Institution: Akins, Darrin R.; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2001 Summary: There is no text on file for this abstract. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GAMMA DELTA T CELLS IN LYME ARTHRITIS Principal Investigator & Institution: Budd, Ralph C.; Director, Immunobiology Program; Medicine; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405 Timing: Fiscal Year 2001; Project Start 30-SEP-1994; Project End 31-MAY-2006 Summary: (provided by applicant): Lyme disease is the most common vector-borne disease in the United States. It is caused by the spirochete Borrelia burgdorferi and transmitted by lxodes ticks. This renewal application examines the contribution of synovial gamma delta T lymphocytes in Lyme arthritis. Preliminary studies show that gamma delta T cells of the V delta 1 subset accumulate in Lyme arthritis synovial fluid (1 0-15 percent) and proliferate vigorously in response to lipidated but not delipidated Borrelia proteins in the presence of dendritic cells (DC) and IL-2. This may occur through Toll-like receptor 2 (TLR2), which is known to bind Borrelia lipoproteins. The synovial V delta 1 clones recognize the MHC class I-like molecules MICA and CD1b and express high and prolonged levels of surface Fas-ligand (FasL). Finally, we have observed that DC contain very high levels of the Fas death receptor inhibitor, FLIP, and are very resistant to Fas-induced death. In fact, Fas ligation on DC actually promotes upregulation of B7.1, B7.2, and CD4O, similar to TNF alpha. We have identified a signal pathway for this in which high levels of FLIP can divert signals to the MAP kinase, ERK, and NF-KB by binding to adaptor proteins that like to these pathways. In this manner death signals can be switched to signals for cell growth or proliferation. The model emerging from the preliminary studies is that lipoproteins from B. burgdoderi bind to TLR2 on DC to upregulate molecules such as MICA and CD1b that are stimulatory for synovial V delta 1 cells. The V delta 1 cells express high and prolonged surface FasL which is lytic to some synovial components, but may be stimulatory toward DC due to their high expression of FLIP. Each of the three aims studies one aspect of this model. Aim 1 examines whether B. burgdorferi activates V delta 1 cells directly or indirectly through TLR2. We will examine cells expressing or not expressing TLR2 for their ability to activate V delta 1 clones in the presence of Borrelia proteins, either lipidated or delipidated. Aim 2 studies two important aspects of synovial V delta 1 clones: how their high expression of surface FasL is regulated, and whether the actual gamma delta TCR is responsible for the response to MICA and CD1b. Aim 3 will study development of DC from CD34+ precursors using a newly developed in vitro culture technique using Flt3

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ligand. This will be paralleled by studies of FLIP expression, the ability of soluble FasL to promote cell death or growth/differentiation, depending on the levels of FLIP. The FasL stimulated DC will be analyzed for surface induction of CD1b, CD4O, B7.l/2, MICA, and their ability to stimulate the V delta 1 clones. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE BURGDORFERI

EXPRESSION

BY

TICK

TRANSMITTED

BORRELIA

Principal Investigator & Institution: De Silva, Aravinda M.; Assistant Professor; Microbiology and Immunology; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001; Project Start 01-JUL-1998; Project End 30-JUN-2003 Summary: After obtaining graduate and postdoctoral training in basic Cell Biology, I recently changed the focus of my research to study pathogens transmitted by arthropods. To pursue this new direction of study, I returned to Yale and joined the section of Rheumatology as a postdoctoral fellow to work on Lyme disease. I also enrolled as a part- time student (MPH) at the Yale School of Public Health which as a strong training program in vector-borne diseases. In July 1997 I will be joining the faculty of the section of Rheumatology to continue my research on Lyme disease. Since Lyme disease is a new area of research for me, I would greatly benefit from an additional period of mentored research at Yale during my initial years on the faculty. My research proposal aims to test the hypothesis that Borrelia burgdorferi, the most common cause of infectious arthritis in the USA, relies on differential gene expression in order to leave the tick vector and successfully infect the vertebrate host. The principal goals of this proposal are to characterize B. burgdorferi genes selectively expressed in the vector and to develop a strategy for blocking transmission and preventing Lyme arthritis. Specifically, studies will be initiated to 1) identify B. burgdorferi genes selectively expressed in ticks, 2) characterize the spatial and temporal pattern of expression of these genes within the vector, 3) to test B. burgdorferi genes expressed in the vector as vaccines for blocking transmission from the vector to the host. Concurrently with experiments to characterize novel genes, studies will be initiated with B. burgdorferi outer surface protein (Osp) A. OspA is primarily expressed in the vector and an OspA based Lyme disease vaccine currently in clinical trials protects hosts by killing spirochetes within feeding ticks and blocking transmission. Detailed experiments will be done using the OspA vaccine as a model to understand how antibodies block transmission from the vector to the host. This study will provide insight into tick-borne transmission of bacterial pathogens and lead to novel strategies for blocking transmission and preventing Lyme arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE COINFECTION

EXPRESSION

OF

BORRELIA

DURING

BABESIA

Principal Investigator & Institution: Coleman, James L.; Wadsworth Center Empire State Plaza Albany, Ny 12237 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): Coinfection with Borrelia burgdorferi and Babesia microti is a clinically documented, emerging public health concern in the Northeastern United States. However, to date, it still remains unclear whether or not concurrent infection with these pathogens leads to greater disease severity in humans. To explore

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Lyme Disease

whether concurrent infection with these two emerging human pathogens leads to greater disease severity, we have proposed to develop an animal model to quantify the polymicrobial burden as well as several clinical parameters during single and concurrent experimental infection in mice of different predisposing conditions and genetic backgrounds. In addition to evaluating disease severity during single and concurrent Borrelia and Babesia infection in mice, we will also monitor the differential genetic expression of B. burgdorferi in response to B. microti in feeding larval ticks and infected mouse tissues utilizing whole genome DNA arrays. To further define the innate immunological response of the vertebrate host during polymicrobial infection, genomic expression analysis will be carried out in murine and human monocytic cells stimulated with live B. burgdorferi and B. microti alone and concurrently. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GRANULOCYTIC EHRLICHIAS IN TICKS AND TICK CELL CULTURE Principal Investigator & Institution: Munderloh, Ulrike G.; Research Associate Professor; Entomology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2001; Project Start 01-MAY-1998; Project End 30-APR-2003 Summary: The human granulocytic ehrlichiosis (HGE) agent is a newly identified zoonotic pathogen capable of causing a potentially fatal illness. In the USA, it is transmitted by Ixodes ticks in areas that essentially overlap the distribution of Lyme disease owing to the fact that both agents share the same vector. Serologic surveys indicate that the disease is widespread also in Europe where it has recently been identified in a human patient. Last year, two research groups isolated the etiologic agent from human patients (Goodman et al. 1996) and a horse (Munderloh et al. 1996), utilizing cell culture systems that represent the spectrum of the life cycle of the agent in nature, a human promyelocytic leukemia cell line and an Ixodes scapularis tick cell line, respectively. These achievements have opened the way to investigate the cellular and molecular biology of the agent in vitro in human and vector cell systems. The development of the agent in tick cell culture differs strikingly from its growth in human cells, hinting at specific adaptations to these divergent hosts. In collaboration with Dr. Goodman, I have identified hamsters as a small laboratory animal that is susceptible to the agent from human and tick cell culture, and I. scapularis ticks have experimentally transmitted it to hamsters. Hamsters developed infections of bone-marrow cells and developed hematologic signs similar to those seen in humans. This proposal aims 1) to elucidate in detail the interaction of the HGE agent with its vector in vivo and in vitro, focussing on environmental cues that stimulate development and expression of surface proteins which could serve as ligands during invasion. These changes will be related to infectivity and pathogenicity for cultured cells and mammalian hosts; 2) to determine the role of transstadial vs transovarial maintenance in the natural history of the HGE agent; 3) to characterize the antigenic profile of the agent in tick cell culture and in ticks which are presumably representative of the make-up of immunogens first encountered by the mammal, and which may have implications for diagnosis and vaccine development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HEALTH BURDERN OF COINFECTING DEER ASSOCIATED ZOONOSES Principal Investigator & Institution: Krause, Peter J.; Professor; Connecticut Children's Medical Center 282 Washington St Hartford, Ct 06106 Timing: Fiscal Year 2001; Project Start 01-JUL-1997; Project End 30-JUN-2003 Summary: Although public attention has focused largely on Lyme disease, an array of spirochetal, protozoan, viral and rickettsial pathogens concurrently infect residents of sites in the eastern US in which deer are abundant. The abundance of deer and that of the vector arthropods that depend on this host recently have increased. Our objective, therefore, is to describe the frequency of human coinfection associated with the presence of deer in this region and to determine whether the resulting spectrum of disease may reflect a synergy between pathogens. In particular, we shall: (1) Determine how frequently deer-associated pathogens infect residents of the northeastern US and how frequently these pathogens occur in combination. Although we shall focus on the agents of Lyme disease, babesiosis, human granulocytic ehrlichiosis and TBE-group arboviruses, we shall seek to document the presence of other tick-borne microbes and the frequency of infection by such deer-associated, mosquito- transmitted agents as Jamestown Canyon virus and Cache Valley fever virus. We shall determine prospectively how frequently deer-associated pathogens infect residents of our study sites by means of a seroprevalence study and how frequently they cause disease by means of a case-finding study. (2) Estimate the burden on human health imposed by these deer-associated pathogens and determine whether coinfection synergizes pathogenesis. In particular, we shall determine whether coinfected people experience a greater diversity of symptoms or duration of illness than the sum of symptoms due to each pathogen. The severity of apparent deer-associated disease will be compared in a previously described population of patients with Lyme disease alone, babesiosis alone and Lyme disease and babesiosis coinfection. A cohort of patients expressing symptoms of deer-associated infection will be enrolled in a prospective longitudinal study. We shall compare the clinical outcome of patients with a single infection alone to that of coinfected patients. (3) Determine how frequently people become exposed to these deerassociated pathogens by deriving a series of entomological inoculation rates which synthesize estimates of vector density and prevalence of infection by particular pathogens. In each study site, we shall describe the prevalence of deer-associated pathogens in their vector populations and the density of these vectors relative to people. The density of deer will be estimated in each site. This proposed effort will help define the health burden imposed on people residing in proximity to deer and will contribute to diagnosis and case-management of apparent Lyme disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HOST CELL INTERACTIONS BY PATHOGENIC BORRELIAE Principal Investigator & Institution: Leong, John M.; Associate Professor; Molecular Genetics & Microbiol; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2001; Project Start 01-APR-1995; Project End 31-DEC-2005 Summary: (Adapted from the Applicant's Abstract): Borrelia burgdorferi is the causative agent of Lyme disease, and B. hermsii and B. turicatae are causative agents of tick-borne relapsing fever. Pathogen-host cell interactions are thought to be critical determinants of the site and severity of infection, and Dr. Leong's group has focused on Borreliae recognition of two classes of host cell molecules: (1) glycosaminoglycans (GAGs); and

28

Lyme Disease

(2) integrins and their associated proteins. For B. burgdorferi, they have found that differences in GAG recognition were associated with differences in host cell typespecific binding, and identified a surface protein, Bgp, that may be the major B. burgdorferi GAG receptor. This bacterium also recognizes the activation-dependent platelet integrin alphaIIbbeta3 and thereby selectively binds to activated (vs. resting) platelets. This integrin-binding activity is predicted to target the Lyme disease spirochete to the vessel wall at sites of platelet adherence, and could explain a salient feature of Lyme disease: vascular pathology of the arterial circulation. In Dr. Leong's studies of relapsing fever spirochetes, high-level GAG-binding correlated with highlevel growth in the bloodstream, and a variable major protein, VspB, promoted attachment to GAGs. Additionally, in contrast to B. burgdorferi, B. hermsii bound and activated resting platelets. The platelet activation activity is apparently mediated by the integrin-associated platelet-signaling molecule CD9. Dr. Leong speculates that prior to the development of an antibody response, attachment of relapsing fever spirochetes to the vessel wall, either directly via GAGs or indirectly, via activated and adherent platelets, could diminish the clearance of bacteria from the bloodstream by the reticuloendothelial system. Continued replication by these adherent bacteria would result in high level bacterial seeding of the bloodstream. Interaction of spirochetes with platelets could also contribute to thrombocytopenia, a common manifestations of relapsing fever. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HUMAN GRANULOCYTIC EHRLICHIOSIS: NORTH CENTRAL U.S. Principal Investigator & Institution: Johnson, Russell C.; Professor; Microbiology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2001; Project Start 01-FEB-2001; Project End 31-JAN-2006 Summary: Human granulocytic ehrlichiosis (HGE) is an emerging tick-borne acute febrile illness. The agent of HGE is closely related to or identical to the horse pathogen Ehrlichia equi and is transmitted by Ixodes scapularis, the same tick that transmits the agents of Lyme disease and babesiosis. The HGE agent infects blood polymorphonuclear neutrophils resulting in neutropenia and a thrombocytopenia. HGE may be a mild to potentially fatal disease. HGE was first described in Minnesota and Wisconsin in 1994 and subsequently more than 400 cases have been described in the U.S. In contrast to Lyme disease which frequently occurs in children, the rates and severity of HGE increase with age. This age-specific incidence of HGE and our large aging population presents a potentially major public health problem with corresponding economic consequences. This emerging public health problem highlights the importance of early diagnosis and treatment in preventing complications of infection, and targeting of prevention and control studies to populations at highest risk. The research proposed in this application is designed to aid in achieving the above goals by analyzing the epizootiology of HGE in the North Central U.S. Our specific aims are: to investigate the hypothesis that white-tailed deer serve as a large mammal reservoir of the agent of HGE and to identify the small mammal reservoirs of the HGE agent. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IL 10 MODULAT PROINFLAMMAT CYTOKINES INDUC BY BORRELIA LIPOPROTEINS: LYME DIS Principal Investigator & Institution: Dennis, Vida A.; Tulane University of Louisiana New Orleans, La New Orleans, La 70112

Studies

29

Timing: Fiscal Year 2001 Summary: Borrelia burgdorferi lipoproteins are known to induce local and systemic production of the proinflammatory cytokines IL-6, IL-1( and TNF-( in macrophages. These cytokines are implicated in the pathogenesis of Lyme disease. We have reported that heat-killed B. burgdorferi spirochetes (Bb) and lipidated outer surface protein A (LOspA) but not unlipidated OspA (U-OspA) are able to stimulate not only the production of inflammatory cytokines but also that of the anti-inflammatory cytokine IL-10 in peripheral blood mononuclear cells from uninfected humans and rhesus monkeys. Monocytes are the cells that transcribe both types of cytokines. We have now demonstrated in a kinetic study that in the monocytic cell line THP-1, stimulation with Bb, L-OspA and LPS but not U-OspA induces the production of IL-1(, IL-6, IL-10, IL-12 and TNF-(. TNF-( was detected at 1 hr, with peak levels observed at 2 hr, followed by a decline at 48 hr. IL-1( was detected at 2 hr; its level peaked at 24 hr and rema ined high throughout. Cells stimulated with L-OspA, Bb or LPS produced IL-6 after 8 hr with maximal levels seen at 48 hr; levels remained high up to 168 hr. IL-12 production kinetics mirrored that of IL-6. IL-10 was detected at 8 hr with peaked level occurring between 8 to 16 hr; its level remained stable between 24-72 hr followed by a gradual decline thereafter. Exogenously added recombinant IL-10 (rIL-10) to L-OspA or LPS cultures elicited 100% inhibition of IL-12 production using 0.1 ng/ml. The inhibitory effect of rIL-10 on IL-1(, IL-6 and TNF-( production was dose dependent. Conversely, the addition of anti-IL-10 enhanced only IL-6 and IL-12 production. These results show that IL-10 induced by B. burgdorferi lipoproteins downregulates proinflammatory responses similarly induced by lipoproteins. They further suggest that IL-10 induced by the spirochete may contribute to control inflammation in Lyme disease and that exogenous rIL-10 might be therapeutically useful. FUNDING CDC PUBLICATIONS None Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNE EVASION MECHANISMS IN LYME DISEASE Principal Investigator & Institution: Marconi, Richard T.; Associate Professor; Microbiology and Immunology; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2002; Project Start 15-JUN-1996; Project End 28-FEB-2007 Summary: (provided by applicant): Lyme Disease (LD) continues to be a serious health problem in the USA. The chronic nature of the infection can lead to debilitating and serious clinical manifestations. While early diagnosis of LD is the key to successful treatment, accurate diagnosis continues to be a significant problem. In addition, while a vaccine has been developed and licensed there are concerns about the duration of protection it affords and about possible autoimmune responses (IR) in certain genetic backgrounds. These concerns highlight the need for a better understanding of the genetic and antigenic properties of this organism and the molecular mechanisms associated with chronic infection. Our studies on chronic infection and immune evasion by B. burgdorferi (Bb) have focused on a diverse group of plasmid-carried genes and operons that are 5'-flanked by a common upstream promoter-carrying sequence that we call the upstream homology box or UHB element. UHB-flanked genes are organized into 3 distinct gene families: the ospE family, the ospF family, and family 163 (a TIGR designation). The data described below demonstrate that the ospE gene family undergoes mutational and recombinational changes during infection. In addition, members of the ospF gene family are temporally expressed during infection. These different processes culminate in the presentation of new antigenic variants of OspE and

30

Lyme Disease

OspF on the cell surface that can contribute to immune evasion. Little is known about the role of other UHB-flanked gene families in chronic infection and immune evasion. However, the polymorphic nature of these genes suggests that their organization has been influenced by recent molecular events that may include recombination and rearrangement. The major hypotheses of this proposal are that the OspE, OspF and family 163 proteins contribute to immune evasion in LD and play stage specific roles during infection. The analyses described within will also test the utility of these proteins in vaccine development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNOLOGIC POLYMORPHISM IN EXPERIMENTAL LYME ARTHRITIS Principal Investigator & Institution: Reiner, Steven L.; Professor; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 01-DEC-1996; Project End 30-NOV-2002 Summary: Lyme disease is a major source of morbidity due to the high incidence of rheumatic, cardiovascular and neurologic complications that follow infection with the etiologic agent, Borrelia burgdorferi. In the U.S., close to 10,000 cases are reported annually and it was recently named a "High Priority Research Topic" by the NIAID. Among humans infected but not treated with antibiotics, 80% develop complications but 20% remain disease-free after resolution of a self-limited skin rash. An undetermined number of patients never develop any overt sign of infection and, despite adequate antibiotic therapy, a significant subpopulation still develops debilitating complications. Although described almost twenty years ago, the pathogenesis as well as the immunologic and genetic basis for differing host responses to Lyme disease are poorly understood. Experimental infection of lymphocyte-deficient mice indicates that the innate immune system has sufficient capacity to mediate the most extreme pathologic outcome in this model. Infection of immunocompetent inbred strains of mice recapitulates the spectrum of responses seen in humans. The genetic model of Lyme arthritis using inbred mice is a powerful system to delineate the mechanisms by which adaptive immunity can regulate innate immunity and pathology. Our preliminary evidence indicates that a major immunologic difference between susceptible and resistant hosts is the magnitude of pro-inflammatory response directed by T helper type I cells. Pathology-prone hosts also uniquely exhibit increased activation of NK cells following infection as well as an MHC association with the H-2k haplotype. This proposal seeks to define the immunoregulatory requirements, host polymorphisms and genetic control that lead to differing phenotypic outcomes in experimental Lyme arthritis. Specific aims encompass the following areas: Cytokine gene expression in the lymphoid organs and sites of pathology of infected mice, in vitro analysis of inter-strain differences in cellular immunoresponse, infection of immunologically perturbed mice with reconstitution of immune cell populations, and genetic analysis of select interstrain crosses of susceptible and resistant mice. Because this model deals with the microbiologic control of a foreign pathogen, the pathogenesis of inflammation and differential host response to a fixed stimulus, the proposed studies should provide broad insight into microbial pathogenesis, inflammatory conditions of multiple organ systems and the genetic basis for susceptibility to infectious and rheumatic diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INCOMPLETE RECOVERY FOLLOWING LYME DISEASE Principal Investigator & Institution: Shadick, Nancy A.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 01-AUG-1997; Project End 30-JUN-2002 Summary: The candidate is an Instructor in Medicine in the Division of Rheumatology/Immunology and a clinical investigator in the Multipurpose Arthritis and Musculoskeletal Diseases Center at the Brigham and Women's Hospital, who coordinates the Nantucket Island Lyme disease cohort study. Her goal is to become a clinical researcher, focusing on the epidemiology, prognosis and management of Lyme disease. The applicant's sponsor, Dr. Matthew Liang, Director, Multipurpose Arthritis and Musculoskeletal Diseases Center and Professor of Medicine at Harvard Medical School, has acted as her mentor and will continue to do so for this proposal. This project, combined with course work and regular participation in conferences, will prepare her for a career as an independent clinical investigator. The Division of Rheumatology/Immunology and the Multipurpose Arthritis and Musculoskeletal Diseases Center have faculty with expertise in epidemiology and health services research including survey techniques, forms design, statistical programming and analyses. Computer facilities in the Center's Biometry Core are available to the candidate. The resources of the Brigham and Women's Hospital allow the opportunity to collaborate with members of other departments and to participate in graduate school courses at the Harvard School of Public Health. The overall goal of the present study is to improve our understanding of the long term outcomes of Lyme disease. Specific aims include l) determination of the chronicity of musculoskeletal and neurologic impairment in a well characterized population-based cohort of individuals with prior Lyme disease and 2) development of a predictive model of chronic Lyme disease with particular attention to potentially modifiable biological and psychosocial risk factors in order to define an intervention strategy to reduce chronic Lyme disease. A retrospective cohort of 349 Lyme subjects and community controls on Nantucket Island, MA, will receive a standardized and blinded physical examination, symptom review, health status measure, psychometric test battery, and serologic analysis at a three year follow-up interval to assess outcomes. Baseline clinical and psychosocial variables will be evaluated as risk factors for objective and subjective morbidity. This study will help develop better treatment and management guidelines for people with Lyme disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INFLUENCE ADAPTATION

OF

INFLAMMATION

ON

B

BURGDORFERI

Principal Investigator & Institution: Liang, Fang-Ting; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: (provided by the applicant): Borrelia burgdorferi, the Lyme disease spirochete, is maintained within a complex enzootic life cycle involving the tick vector and the mammal. The spirochete adapts to these diverse environments, in part, by selective gene expression. Environmental cues such as temperature, pH and nutrients influence in vitro B. burgdorferi gene expression. Analysis of the gene expression of lipoproteins in the infected murine skin has defined two remarkably different microenvironments for B. burgdorferi adaptation: naive status and immune status. In the naive state, B. burgdorferi expresses 116 of its lipoprotein genes while only 34 of them are expressed during chronic infection. B. burgdorferi is able to invade almost all

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Lyme Disease

organs and tissues of the mammalian host and these diverse microenvironments may influence its lipoprotein gene expression. This pathogen causes murine carditis and arthritis that parallel two major manifestations of human Lyme disease. It is unknown whether inflammation influences B. burgdorferi adaptation. In this project, the tissue differential expression of lipoprotein genes and the influence of inflammation on lipoprotein gene expression of B. burgdorferi will be investigated using the murine model. To achieve these goals, the following specific aims will be completed. 1. To investigate the tissue differential expression of B. burgdorferi lipoprotein genes in the bladder, heart and joint during murine infection; 2. To examine the influence of inflammation on B. burgdorferi adaptation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INOSINE MONOPHOSPHATE DEHYDROGENASE Principal Investigator & Institution: Hedstrom, Lizbeth K.; Markey Associate Professor; Biochemistry; Brandeis University 415 South Street Waltham, Ma 024549110 Timing: Fiscal Year 2001; Project Start 01-AUG-1998; Project End 31-JUL-2003 Summary: Inosine 5'-monophosphate dehydrogenase (IMPDH) is among the most attractive targets for drug design. IMPDH catalyzes the conversion of IMP to XMP with the concomitant reduction of NAD. This reaction is an unusual hydride transfer reaction; an adduct is formed between IMP and a Cys residue. Hydride is transferred to NAD, leaving a covalent E-XMP* intermediate. E-XMP* is hydrolyzed to produce XMP. The IMPDH reaction controls guanine nucleotide biosynthesis. IMPDH inhibitors have antiproliferative activity and the clinical utility of IMPDH inhibitors is well established in viral, immunosuppressive and cancer therapy. The significant differences between microbial and mammalian IMPDH's indicate that this enzyme is also a target for antiinfective chemotherapy. This proposal outlines a multidisciplinary investigation into the mechanism of IMPDH catalysis and inhibitor action. This fundamental information is important for the further development of IMPDH-based chemotherapy. The formation and hydrolysis of E-XMP* is of particular interest because the immunosuppressive drug pycophenolic acid binds to E-XMP*. Mycophenolic acid is also the only known species selective inhibitor of IMPDH. The origin of this species selectivity will be determined. The mechanism of IMPDH inhibition by oxanosine, an antibiotic agent, will be delineated. The structure of the enzyme-IMP complex of IMPDH from Borrelia burgdorferi, the causative agent of Lyme disease, will be refined. Preliminary results suggest that this structure will be more ordered than the currently available crystal structures of the apoenzyme and E*XMP complexes of IMPDH from Tritrichomonas foetus. The structures of IMPDH complexed with inhibitors will also be solved. These experiments will utilize steady state kinetic, pre-steady state kinetic, site-directed mutagenesis and x-ray crystallography. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IXODES TICKS AND BORRELIA BURGDORFERI IN SE USA Principal Investigator & Institution: Oliver, James H.; Callaway Professor; Inst/Arthropodology/Parasitol; Georgia Southern University Statesboro, Ga 30458 Timing: Fiscal Year 2001; Project Start 01-JUL-1987; Project End 31-JAN-2006 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LYME ARTHRITIS- A NEW EPIDEMIC DISEASE Principal Investigator & Institution: Steere, Allen C.; Chief; New England Medical Center Hospitals 750 Washington St Boston, Ma 021111533 Timing: Fiscal Year 2001; Project Start 01-JUL-1987; Project End 28-FEB-2006 Summary: (Verbatim) - About 10 percent of patients with Lyme arthritis have persistent knee swelling for months or even several years after oral and intravenous antibiotic therapy. After treatment, such patients, in our experience, have no remaining spirochetal DNA in synovial tissue or joint fluid, suggesting that live spirochetes have been eliminated from the joint. During the past grant cycle, we identified a possible autoimmune mechanism that may partially explain the persistence of Lyme arthritis after antibiotic therapy. The mechanism in DRB1*0401-positive individuals involves molecular mimicry between the dominant T cell epitope of B. burgdorferi outer-surface protein A (OspA165-173) and a homologous sequence of human lymphocyte function associated antigen-1 (hLFA-1alpha332-340). In this proposal, we test the hypothesis that synovial inflammation may persist in treatment-resistant arthritis patients with a range of MHC alleles because of molecular mimicry between this dominant T cell epitope of OspA and hLFA-1. Our plan is to determine the frequencies of various MHC alleles in patients with treatment-resistant arthritis compared with those in treatment-responsive patients and those in a control population. PBL and synovial fluid lymphocytes (SFL) from treatment-responsive and treatment-resistant patients will be screened for reactivity with OspA165-173 and LFA-1alpha332-340, and cloned OspA165-173-reactive T cells from selected patients with a range of MHC alleles will be tested for reactivity with hLFA-1alpha332-340. Using an in vitro peptide binding assay, DR or DQ molecules obtained from selected patients' EBV-transformed B cells will be tested for their ability to bind the OspA and hLFA-1 peptides. Finally, after appropriate antibiotic treatment, the efficacy and safety of DMARD therapy will be observed in treatment-resistant patients. Lyme arthritis is the only human form of chronic inflammatory arthritis in which the triggering agent, immunogenetic susceptibility, and a candidate autoantigen are known. Thus, it is currently the only human system in which it is possible to explore specific infectious and autoimmune mechanisms that may lead to chronic inflammatory arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LYME EPIDEMIOLOGY

DISEASE

IN

WESTERN

USA:

ECOLOGY

AND

Principal Investigator & Institution: Lane, Robert S.; Environmntl Sci Policy & Mgmt; University of California Berkeley Berkeley, Ca 94720 Timing: Fiscal Year 2001; Project Start 01-SEP-1985; Project End 31-AUG-2005 Summary: (Adapted from the Applicant's Abstract): The broad objectives of this research are to determine environmental correlates of natural foci of the Lyme disease (LD) spirochete, Borrelia burgdorferi sensu stricto (Bb ss) and closely related spirochetes in the Bb sensu lato (sl) complex in highly endemic areas of the Far West; to elucidate and model landscape ecologic and epidemiologic factors that place humans at elevated risk of exposure to Bb ss infection in meso- and macroscales by means of remote sensing and ground-truthing ecologic studies; and to evaluate intrinsic factors that may affect the reservoir competence of vertebrates or the vector competence of ticks for Bb sl. Environmental correlates of natural foci of LD spirochetes will be determined quantitatively by sampling populations of vector ticks and their small vertebrate hosts in relation to Bb sl infection and over 20 biotic and abiotic factors. Two categorical

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Lyme Disease

measures will be used to assess risk of exposure to nymphs of the primary vector tick, Ixodes pacificus, in leaf-litter habitats, an indirect measure (entomologic risk index) based on drag-sampling and direct measures of specific human behaviors (e.g., walking, sitting). A combination of field and laboratory methods will be employed to calculate the relative reservoir potential (Rs) of small mammals for Bb sl in deciduous woodlands. The prevalence of infection in free-living or host-fed ticks and their attendant vertebrates with Bb sl and two other emerging tick-borne disease agents (Ehrlichia spp.) Will be determined by tick xenodiagnosis and with standard microbiologic and genetic techniques. Bb sl isolates cultured from vector ticks, reservoir hosts, or skin lesions of patients with early-stage LD infection will be characterized genetically with several methods, and their phylogenetic relatedness to other genospecies of Bb sl will be determined by maximum parsimony analyses. Risk of human exposure to Bb-infected I. pacificus nymphs inhabiting all three climatic zones and seven major vegetational types of northwestern California (Mendocino County) will be modeled using satellite imagery, geographic information systems, and spatial statistical methods in conjunction with ground-verifying ecologic studies an dLD case surveillance data. Borreliacidal assays will be used to evaluate the potential role of complement in vertebrate-host sera (16 spp.) And anti-complement activity in saliva of human-biting vector ticks (2 spp.) As determinants of reservoir-host competence or vector competence for Bb sl or relapsing fever group spirochetes present in the western USA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LYME DISEASE MODEL--PATHOGENESIS AND IMMUNITY Principal Investigator & Institution: Miller, James N.; Professor; Microbiology and Immunology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 30-SEP-1994; Project End 30-JUN-2004 Summary: We have developed a rabbit Lyme Disease model in which early erythema migrans (EM) lesions and disseminated infection occur and in which complete infectionderived immunity results. The long term - objectives of this study are to determine protective and pathological immune mechanisms operative during the course of rabbit infection with Borrelia burgdorferi (Bb). The rabbit model of Lyme disease provides a unique opportunity to address local and disseminated disease manifestations similar to those in human infection, and to address the cellular and humoral immune mechanisms in infection-derived immunity. Specific and cross-reactive immunity to challenge will be determined utilizing several well-defined strains. The in situ localization and fate of Bb in skin following intradermal challenge will be correlated with the presence and distribution of PMN's, B cells, and T cell subsets both in situ and in peripheral blood. correlations with acquired resistance will also be made with in vitro lymphocytic cell proliferative responses and humoral immune responses including quantitative ELISA and Western blot analysis, passive protection, opsonophagocytosis, complemetdependent borreliacidal activity, adherence inhibition, and freeze-fracture electron microscopy for the detection of antibody against Bb outer membrane proteins. The rabbit model will also be employed to address the efficacy of Bb challenge following vaccination with OspA, OspB, an avirulent Bb OspA- and OspB-less mutant, and with a recombinant gene product encoding an exported plasmid protein antigen (EppA). The cellular and humoral arms of the immune response as it relates to the development and healing of the EM lesion will also be addressed utilizing the above described procedures. Further, continued persistence, location, and subsequent elimination of the spirochete after EM healing will be determined by specific in situ analysis. Passive

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protection studies will be conducted with serum obtained at the time of Bb clearance from the skin in order to determine the immune status of these animals. The possibility of exotoxin in EM formation will be determined by injecting rabbits intradermally with concentrated supernatants from in vitro Bb cultures and by the use of filtrates prepared and concentrated from surgically implanted subcutaneous chambers containing Bb. The rabbit model permits the elucidation of those mechanisms that control persistence versus elimination in tissues to which the organism has disseminated. Studies directed toward the elucidation of dermatotropic, arthritogenic, and/or neurotropic strains utilizing several isolates of Bb are proposed and should contribute toward our understanding of chronicity in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LYME DISEASE--HOST PARASITE INTERACTIONS Principal Investigator & Institution: Malawista, Stephen E.; Professor of Medicine; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2003; Project Start 15-MAR-1999; Project End 29-FEB-2004 Summary: (Adapted from the applicant's abstract) - Understanding the capacity of the cellular immune response to clear Borrelia, the etiologic agent of Lyme disease, is essential to a proper understanding of the pathogenesis of this disorder. We know that both neutrophils and macrophages take up and kill Borrelia rapidly in vitro. Yet, intact spirochetes can be observed in skin and other tissues, and have been isolated from uninflamed peritoneal cavity despite the presence of resident macrophages. In order to examine the failure of phagocytes to clear the spirochetes in vivo, the killing mechanisms of phagocytes will be characterized. In situ microscopic examination of spirochete- phagocyte interactions, in situ hybridization and ex vivo RT-PCR of cytokine and other genes will be used to establish a profile of the macrophages' state of activation and deactivation. Different strains of Borrelia will be used to elucidate mechanisms of clearance versus persistence in vivo. Finally, it is proposed to use cDNA arrays to examine differences in host gene expression patterns during activation of neutrophils and macrophages by these types of Borrelia. These studies may provide the technical and conceptual basis for improvements in diagnostic and prognostic aspects of inflammatory diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MEMBRANE PROTEINS OF BORRELIA BURGDORFERI Principal Investigator & Institution: Radolf, Justin D.; Director/ Professor; Ctr for Microbial Pathogenesis; University of Connecticut Sch of Med/Dnt Bb20, Mc 2806 Farmington, Ct 060302806 Timing: Fiscal Year 2002; Project Start 01-APR-1990; Project End 30-NOV-2006 Summary: (Adapted from the Applicant's Abstract): Borrelia burgdorferi, the Lyme disease spirochete, is maintained in nature via a complex enzootic cycle that typically involves wild rodents and Ixodes ticks. To sustain itself, the spirochete must not only adapt physiologically to two markedly different host milieus, but it must also express virulence determinants and evade immune-mediated clearance mechanisms during mammalian infection. A finely orchestrated expression of arthropod- and mammalian host-specific genes, a process termed 'differential gene expression', is now believed to be responsible for many of these physiological, ultrastructural, and virulence-associated adaptations. Over the past several years, we and a number of other researchers have

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Lyme Disease

generated a substantial body of evidence that the bacterium's complement of linear and supercoiled plasmids comprises the primary substrate for genes expressed preferentially in vivo; this notion, however, requires more stringent examination. Equally important, despite the availability of the complete genomic sequence for the B31-MI isolate, Lyme disease researchers have made only modest progress in delineating and functionally characterizing the spirochete's complex array of differentially expressed genes, and we know even less about the mechanisms which regulate and coordinate these genetic programs. The underlying hypothesis of our proposal is that plasmid-encoded, differentially expressed genes are essential to the Lyme disease spirochete's parasitic strategy within the mammalian host. To address this hypothesis and its corollaries, we will characterize the differentially expressed portion of the B. burgdorferi proteome using two-dimensional electrophoresis and peptide mass fingerprinting (Specific Aim One); identify differentially expressed B. burgdorferi genes using high-density DNA microarrays (Specific Aim Two); continue our molecular and evolutionary analysis of B. burgdorferi cp32 plasmids (Specific Aim Three); and use newly developed plasmid shuttle vectors to study differential gene expression by B.burgdorferi (Specific Aim Four). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METAL BURGDORFERI

REGULATION

IN

HOST

COLONIZATION

BY

B

Principal Investigator & Institution: Hoover, Timothy R.; Microbiology; University of Georgia 617 Boyd, Gsrc Athens, Ga 306027411 Timing: Fiscal Year 2001; Project Start 01-MAR-1999; Project End 28-FEB-2003 Summary: (Adapted from the Applicant's Abstract): Unlike other bacterial pathogens which must overcome host iron restriction to establish a successful infection, Borrelia burgdorferi, the causative agent of Lyme disease, is able to bypass iron limitation within a host by minimizing or perhaps even eliminating the need for iron. They accomplish this by eliminating pathways that include important iron- containing proteins and substituting other trace metals in metalloproteins that are found in B. burgdorferi. As a result, they do not appear to regulate gene expression based upon intracellular levels of iron as is seen in other bacterial pathogens. Instead, B. burgdorferi appears to regulate gene expression by monitoring levels of other metals, such as manganese or zinc. To investigate the observed metal- dependent gene expression, the PI has identified and cloned a gene encoding a putative metal-dependent repressor protein (PerR) from B. burgdorferi and identified a target sequence using a mobility shift DNA- binding assay. This sequence is 91 bp upstream of the start codon of a putative 2 gene operon encoding a glutamate transporter (gltP) and a NADH peroxidase (npx), suggesting that PerR may be involved in regulating an oxidative stress response by B. burgdorferi. A PerR homolog identified from Bacillus subtilis mediates cellular responses to oxidative stress and metal starvation in that bacterium. To understand the role this regulatory protein plays in the survival response of B. burgdorferi and to identify other genes it regulated, the PI proposed to (1) characterize PerR and its putative target sequence using mobility shift DNA-binding, primer extension, DNase I footprinting, and methylation/uracil interference assays, (2) assess the role of PerR and Nox in the oxidative stress response in B. burgdorferi by examining the effects of O2-, peroxide, and metal starvation on the expression of Nox and (3) identify additional genes regulated by PerR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR ANALYSIS OF TREPONEMAL MOTILITY GENES Principal Investigator & Institution: Limberger, Ronald J.; Director; Wadsworth Center Empire State Plaza Albany, Ny 12237 Timing: Fiscal Year 2001; Project Start 01-JUL-1993; Project End 30-NOV-2002 Summary: (Adapted from the Applicant's Abstract): Spirochetes are a diverse group of helical and planar wave-shaped bacteria having a unique structure and mode of motility. Spirochetes are the causative agents of syphilis (Treponema pallidum) and Lyme disease (Borrelia burgdorferi) and are associated with periodontal disease (Treponema denticola). The periplasmic location of the flagellar filament, together with the cell shape, enables the spirochete to move through dense matrices that would inhibit most other bacteria and assists in pathogenesis. This proposal involves determining the function of motility-associated polypeptides, development and analysis of mutants altered in motility to determine gene regulatory mechanisms, and assessment of the virulence capabilities of motility mutants. Treponema denticola will be used as a model for treponemal motility because it possesses newly identified tools for genetic analysis. The first polypeptide encoded by the fla motility operon, Tap1, has no known homologs but the investigators hypothesize it is involved in motility. This hypothesis will be tested using targeted mutagenesis to inactivate tap1 to observe the effect on cell movement together with immune electron microscopy to determine cellular location. Analysis of transcription of a polar flgE mutant suggests that T. denticola also has a unique system for regulation of motility gene expression. To test this hypothesis, targeted non-polar mutations will be made in motility-associated genes of specific classes, including the flagellar switch (fliG), hook (flgE), and regulation (fliA). Cytoplasmic filaments are a major component of treponemal cells with unknown function. A T. denticola mutant that lacks cytoplasmic filaments was constructed by insertional inactivation and these cells possess altered motility in liquid media and reduced colony diameter on 0.5% agarose-NOS plates. They hypothesize that the treponemal cytoplasmic filaments play a role in motility either directly through interaction with the periplasmic flagellum or indirectly through maintenance of cell structure. Biochemical analysis and tomography, together with the analysis of the cfpA-interrupted mutants will ascertain the role of this major cellular polypeptide. Finally, the involvement of motility in the virulence capabilities of T. denticola will be assessed in a murine abscess model using the specific motility mutants. The broad long-term objective is to understand the structure, function and regulation of treponemal motility-associated polypeptides and to assess their role in pathogenesis. Understanding the relationship of motility and cell structure to spirochete pathogenesis will result in development of therapeutics targeted towards inhibition of spirochete motility for prevention of human disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR GENETIC MARKERS FOR TICK VECTORS Principal Investigator & Institution: Hutcheson, Harry J.; Microbiology, Immunology & Pathology; Colorado State University Fort Collins, Co 80523 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2003 Summary: (adapted from applicant's abstract): The long term goal of the proposed research is to identify and develop molecular genetic markers for the identification and assessment of vector competence of Ixodes spp. ticks. Ticks in the genus Ixodes (~240 spp), and especially those in the largest subgenus Ixodes (~75 spp), are becoming increasingly familiar to the public health community because of their ability to transmit multiple diseases to humans and animals, such as protozoa (e.g., Babesia), viruses (e.g.,

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tick-borne encephalitis), and bacteria (e.g., Erlichia and the Lyme disease agent, Borrelia burgdorferi). Although only about 10% of tick species are of public health importance, it is necessary to accurately identify all species because of their different abilities to transmit disease agents, as is the case with Ixodes spp. For example, it is difficult to distinguish members of this genus when individuals become damaged upon removal, which is too often true when ticks are submitted for identification. Therefore, the specific aims of this proposal are to (1) develop a pcr-based key to all 34 species of Ixodes found in the USA using the proven segment of nuclear ribosomal DNA, the second internal transcribed spacer (ITS-2), (2) develop new polymorphic molecular genetic markers from single copy nuclear genes and introns (e.g., beta tubulin and ef-1 alpha) and by using proven RAPD primers, single-strand polymorphisms, and other techniques for identifying multiple markers in the 300-500 bp range, optimal for SSCP. In this aim, tick cell cultures will be utilized as a source of consistent and high-quality DNA, and (3) compare the vector competence of the 18 mitochondrial haplotypes of Ixodes scapularis to I. (I.) pacificus and I. (Ixodiopsis) woodi using 3 B. burgdorferi strains from the northeastern, southeastern, and western regions of the USA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR GENETICS OF LYME ARTHRITIS SUSCEPTIBILITY Principal Investigator & Institution: Weis, Janis J.; Professor; Pathology; University of Utah 200 S University St Salt Lake City, Ut 84112 Timing: Fiscal Year 2001; Project Start 30-SEP-1994; Project End 31-MAY-2004 Summary: (Adapted from the Applicant's Abstract): Lyme disease is caused by infection with the tick transmitted spirochete Borrelia burgdorferi. A common manifestation of disease is arthritis, which occurs in 60% of individuals not treated at the time of the tick bite. The arthritis is characterized by edema, tendonitis, synovial hyperproliferation, and inflammatory cell infiltrate, and is associated with bacterial invasion of the affected joint. The finding that not all individuals infected with B. burgdorferi develop arthritis suggests that genetic elements of the host regulate the severity of disease. Strong support for genetic regulation of disease severity comes from studies in mice, where infected C3H/HeN mice develop severe arthritis 3-4 weeks following infection, while in BALB/c and C57BL/N mice the arthritis is mild. The histopathology of Lyme arthritis in mice is similar to that observed in humans, suggesting that common pathways regulate the severity and progression of disease in humans and mice. The genetic contribution to arthritis development is being characterized by the generation of intercross populations of mice, using the severely arthritic C3H/HeN and mildly arthritic C57BL/6N mice as parents. The F2 intercross of these strains allowed identification of four Quantitative Trait Loci that regulates arthritis severity. Two of these loci, termed Borrelia burgdorferi disease associated loci 1 and 2 (Bb1 and Bb2) were identified by measurement of swelling in rear ankles joints of infected mice. Bbl and Bb2 are located on chromosomes 4 and 5, respectively, Two other loci, Bb3 and Bb4, were identified by histopathological assessment, and map to chromosomes 5 and 11, respectively. These findings will be pursued by generation of congenic mice, in which each of the four arthritis associated Bb alleles will be introgressed onto the background of the reciprocal parent. The arthritis phenotype for each congenic mouse line will be determined by infecting with B. burgdorferi, and Bb alleles with highly penetrant phenotypes will be studied further. Recombinant congenic mice will be developed in order to narrow the physical region associated with the arthritis phenotype to 1-2 cM. The recombinant congenic mice will be used for assessment of biological functions related to arthritis development and to determine if arthritis phenotype can be

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transferred with hematopoietic cells. Positional cloning of arthritis regulatory genes will be initiated by developing a high resolution physical map of the 1-2 cM region associated with disease phenotype Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOUSE MODEL OF LYME BORRELIOSIS Principal Investigator & Institution: Barthold, Stephen W.; Professor and Director; Ctr for Comparative Medicine; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2002; Project Start 01-JUL-1988; Project End 31-JAN-2007 Summary: (Adapted from the Applicant's Abstract): Despite significant advances in understanding the biology of Borrelia burgdorferi, the agent of Lyme disease, the pathogenesis of Lyme disease remains poorly understood. The overall objective of this project is to use a mouse model of Lyme disease to investigate spirochete population kinetics and differential expression of specific Borrelia burgdorferi genes in selected target tissues during the dissemination/disease evolution phase, disease resolution (immune) phase, and persistent phases of B. burgdorferi infection. During the past project period, gene products were defined that are associated with antibody-mediated protective, but not arthritis- or carditis-resolving immunity (DbpA), and gene products that are associated with arthritis-, but not carditis- resolving or protective immunity (Arp and P37-42). In the current project period, the search will continue for other arthritis- and carditis-resolving antigen targets, as well as to characterize antigens expressed during persistent infection. Highly sensitive assays (real time PCR) have been optimized for quantitative analysis of spirochete population kinetics and for examining prototype gene expression in tissues at different stages of infection. Having optimized these assays, Specific Aim 1 will continue the search for B. burgdorferi antigens associated with biologically relevant antibody responses by screening a B. burgdorferi genomic expression library with sera from infected mice. Recombinant proteins and antisera will be tested for biologic activity (protective, disease-resolving, and dissemination-preventing activity) in the model. Specific Aim 2 will examine prototype gene expression during different phases of infection, and examine the effects of immunity or immune tolerance to biologically relevant antigens on these events. Specific Aim 3 will investigate mechanisms of persistent infection and disease quiescence by examining expression of prototype genes during this phase of infection, and define antigens that are involved in maintaining the host-agent equilibrium. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEUROBEHAVIORAL SYNDROMES OF CHRONIC LYME DISEASE Principal Investigator & Institution: Krupp, Lauren B.; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2001 Summary: Chronic neurologic Lyme disease has emerged as the major health care issue concerning B. burgdorferi infection, the most rapidly growing vector borne infection in the United States. Encephalopathy is the core syndrome of chronic neurologic Lyme disease. The primary goal of this project is to characterize Lyme encephalopathy. Chronic Lyme patients (n=100) will be assessed on neurobehavioral measures, as compared to controls drawn from the community (n=100) and CSF measures, as compared to an Other Neurologic Disease (OND) group (n=50). We will test specific hypotheses related to the major clinical features and pathogenesis of chronic neurologic

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Lyme Disease

Lyme disease. A longitudinal design over an 18 month period will allow the course and key risk factors of Lyme encephalopathy to be defined. Specific Aim 1. To define the neurobehavioral and psychological sequelae of chronic Lyme disease Specific Aim 2. To determine the pathogenesis for neurobehavioral deficits in chronic Lyme disease Specific Aim 3. To identify the clinical and laboratory factors which predict health outcome in chronic Lyme disease Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROLOGIC INVOLVEMENT IN PEDIATRIC LYME DISEASE Principal Investigator & Institution: Belman, Anita L.; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2001 Summary: Lyme disease, due to the tick borne spirochete Borrelia burgdorferI (Bb), is a major emerging infection. It was originally recognized in children, and children continue to have a high rate of infection. Major issues concerning neurologic aspects of the disease in children and adolescents remain unresolved. Failure to understand the full spectrum of neurologic features has led to health care practices which may be both costly and ineffective. The objective of this proposal is to characterize the neurologic, cognitive, and behavioral aspects of pediatric disseminated Lyme disease. Three groups of children will be evaluated in a prospective longitudinal 18 month study. Case Group 1 [N=50] will meet Centers for Disease Control and Prevention (CDC) surveillance criteria for neurologic Lyme disease. Case Group 2 [N=50] will meet the CDC surveillance criteria for extraneural Lyme disease [Lyme arthritis, carditis or multifocal erythema migrans. Control Group 3 [N=50] will be composed of an age- sex- and IQmatched group of healthy Bb seronegative controls. All three groups will have comprehensive neurologic, neuropsychologic, behavioral. and psychosocial evaluations at entry. Subjects with neurologic involvement will have cerebrospinal fluid [CSF] studies. Disseminated Lyme disease subjects will receive currently recommended antibiotic treatment. All three groups will be followed prospectively with full reevaluation at 18 months. SPECIFIC AIM 1: To delineate the neurologic and CSF features of disseminated Lyme disease in children. Hypothesis 1: Neurologic involvement is common in pediatric disseminated Lyme disease. SPECIFIC AIM 2: To delineate the behavioral and neurocognitive features of disseminated Lyme disease in children. Hypothesis 2: Behavioral changes [dysphoria, irritability, fatigue] and cognitive problems [deficits of attention and memory] are frequent in children with neurologic Lyme disease. These problems will have remitted by 18 month follow up. SPECIFIC AIM 3: To identify specific risk factors for persistent post treatment behavioral and neurocognitive complaints. Hypothesis 3: Persistent post-treatment complaints at the 18 month follow-up are more common in children with psychosomatic problems, and those with parents who reinforce illness-related behavior. This project will: (A) establish the relative frequency, severity, and progression of neurologic and neurobehavioral disturbances associated with pediatric Lyme disease; (B) provide needed data to optimize diagnosis, evaluation, and management of neurologic Lyme syndromes in children. thereby helping to standardize care and reduce medical costs; (C) increase our understanding of underlying pathophysiologic mechanisms of this disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NON-HUMAN PRIMATE ANIMAL MODELS FOR RSCH ON CHRONIC LYME Principal Investigator & Institution: Pachner, Andrew R.; Professor; None; Univ of Med/Dent Nj Newark Newark, Nj 07103 Timing: Fiscal Year 2000; Project Start 14-JUN-1999; Project End 13-JUN-2004 Summary: The objectives of this contract are to gain knowledge about infection of the nervous system with Borrelia burgdorferi in the Rhesus macaque animal model that would aid in the diagnosis and treatment of human Lyme neuroborreliosis (LNB). This includes: (a) optimizing the current experimental model of LNB in non-human primates; (b) learning more about neurotropism and neuropathogenicity in the expression of LNB, as well as the mechanisms involved; and (c) determining whether long-term infection with B. burgdorferi results in damage to the central and/or peripheral nervous system. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NOVEL ANTIGENS FOR THE SERODIAGNOSIS OF HUMAN BABESIOSIS Principal Investigator & Institution: Houghton, Raymond L.; Group Leader, Senior Scientist; Corixa Corporation 1124 Columbia St, Ste 200 Seattle, Wa 98104 Timing: Fiscal Year 2001; Project Start 01-MAR-1998; Project End 31-DEC-2002 Summary: Increase surveillance of tick-borne infections has shown that many individuals infected with Lyme disease have co-infections with Babesia microti (agent of human babesiosis) and Ehrlichia, both of which are potentially fatal in immunocompromised individuals and have been shown to impact blood transfusions. Since the treatment of B. microti infections (malaria-like intraerythrocytic parasite) is vastly different that Lyme disease there is a need for an accurate serology test to differentiate the two infections. The proposed studies will enable the development of an ELISA and Immunoblot test using B. microti recombinants in combination that will supplement the currently available Lyme disease test and eventually facilitate testing of blood donors. Development of such tests improves our ability to differentially diagnose tick-borne diseases and facilitates administration of the appropriate treatment. Advances have already been achieved at Corixa in identifying immunodominant recombinant antigens. This, in combination with collaborations with key investigators in the area of tick-borne diseases, blood banking and a leading reference laboratory for Lyme disease testing and access to their extensive serum bank should enable the goals and objectives of this proposal to be achieved. PROPOSED COMMERCIAL APPLICATION The proposed studies will lead to commercialization of diagnostic tests for use in the blood bank and reference laboratory. Such tests would provide for improved differential diagnosis of babesiosis in the presence of other tick-borne infections e.g. Lyme disease and Human Granulocytic Ehrlichiosis. The estimated market for such a test should be similar to that for Lyme disease testing both in the U.S. and worldwide. Current estimates for this market are 30-50 million dollars/year but could be greater if blood bank testing is mandated even on a regional basis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NUCLEIC ACID-BASED DIAGNOSTIC PROBES FOR LYME DISEASE Principal Investigator & Institution: Schwartz, Ira S.; Chairman; Biochem and Molecular Biology; New York Medical College Valhalla, Ny 10595 Timing: Fiscal Year 2001; Project Start 30-SEP-1991; Project End 30-JUN-2005

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Lyme Disease

Summary: (Adapted from the Applicant's Abstract): Lyme disease is the most common vector-borne disease in the United States. It is caused by the bite of a tick infected with the spirochete, Borrelia burgdorferi, the etiologic agent of the disease. Evaluation of the potential for development of disease from a tick bite is complicated by incomplete knowledge of the diversity of spirochete genotypes in nature and their pathogenic capacities. Furthermore, current laboratory diagnosis rests on a number of serologic tests of varying degrees of sensitivity and reliability, which limits the rapid and specific diagnosis of the disease immediately following a tick bite. During the previous grant period significant progress was made in the molecular typing of B. burgdorferi clinical isolates. In particular, the investigators observed an unequal distribution of genotypes between skin and blood; a particular genotype which is readily cultured from skin was significantly less frequently found in blood. This suggests that the capacity for hematogenous dissemination may vary among different B. burgdorferi genotypes. In addition, progress in the application of a polymerase chain reaction (PCR)-based assay for detection of B. burgdorferi in skin, blood, and synovial fluid was achieved. The investigators propose to extend these findings by pursuing the following specific aims: l) They hypothesize that there is significant genotypic diversity among B. burgdorferi in nature, with the greatest diversity in wildlife hosts and the least in human patients. Molecular typing of B. burgdorferi in ticks and various wildlife hosts will be carried out by PCR-RFLP analysis and DNA sequencing and the number and distribution of genotypes in reservoir hosts, ticks and patients will be compared. 2) Dissemination of different RFLP types will be tested directly in a murine model. I. scapularis colonies infected with single, clonal B. burgdorferi genotypes will be established and potential phenotypic variation will be explored with regard to dissemination, acquisition and transmission. 3) The potential of PCR as a modality for diagnosis of early Lyme disease and Lyme arthritis, particularly in patient blood and synovial fluid specimens, will be further explored. A number of variables will be systematically evaluated with the goal of designing a PCR-based approach which can be effectively employed for reliable diagnosis of Lyme disease. The proposed experiments will provide for a more complete understanding of the infection dynamics of B. burgdorferi. This will contribute to a better appreciation of the risk of contracting Lyme disease from a tick bite. In addition, a reliable PCR-based method for detection of B. burgdorferi in patient blood and synovial should improve accurate diagnosis of early Lyme disease and Lyme arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OSPA-MEDIATED BORRELIA ADHERENCE TO TICK GUT Principal Investigator & Institution: Pal, Utpal; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 15-APR-2002; Project End 31-MAR-2005 Summary: (provided by applicant): The present proposal aims to understand OspAmediated adherence of spirochete Borrelia burgdorferi during Lyme disease. B. burgdorferi cycles between an arthropod vector and a mammalian host in nature and transmitted to humans by the bite of an infected Ixodes scapularis tick. Outer surface protein A, a lipoprotein found on the surface of the bacterium, forms the basis of the recombinant human vaccine against Lyme disease. Differential expression of ospA during life cycle of the spirochete indicates the important temporal and tissue-specific function of the protein by B. burgdorferi in the tick gut. Our preliminary data now show that OspA mediates B. Burgdorferi attachment to tick gut via binding to a tick gut protein. In the present study we will characterize OspA binding to the tick gut, including the identification of OspA epitopes that facilitate this interaction. Then we will

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identify and clone the tick receptor for OspA. Since OspA is also expressed sometimes during late stages of arthritis, we will also seek to test whether OspA mediates B. Burgdorferi adherence in the joints. These studies should provide new knowledge that may be useful for developing an alternate OspA or OspA-receptor based Lyme disease vaccine and also to understand pathogenesis of Lyme disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OSPA-NEGATIVE ELISA FOR LYME DISEASE Principal Investigator & Institution: Koski, Raymond A.; L2 Diagnostics, Llc Box 8175 New Haven, Ct 94904 Timing: Fiscal Year 2001; Project Start 01-JUL-1999; Project End 31-MAR-2003 Summary: A significant public health need exists for a standardized serodiagnostic Lyme disease test that distinguishes infection from false positives due to outer surface protein A (OspA) vaccination. A new enzyme-linked immunosorbent assay (ELISA) will be developed using Borrelia burgdorferi antigen preparations that lack OspA antigen, the primary constituent of the Lyme disease vaccine recently approved by the FDA. Vaccine recipients generate OspA antibodies typically causing seropositive test results whether or not actual infection occurred; conventional Lyme disease ELISAs use wholecell lysates of B. burgdorferi including expressed OspA. Three different OspA-negative antigen candidate preparations initiated in Phase I using three different approaches -variant strain selection, plasmid gene disruption, and recombinant antigen expression -will be evaluated in ELISA formats. Sensitivity and specificity will be determined using serum panels representing early and late stages of Lyme disease, normal human sera, and sera from patients with other infectious or autoimmune diseases. The best performing ELISA will be further developed and evaluated extensively in a commercial reference laboratory setting. We anticipate that as the OspA vaccine becomes widely used, the new OspA-negative ELISA will supplant current ELISAs based on whole-cell lysates of standard B. burgdorferi strains. PROPOSED COMMERCIAL APPLICATIONS: This research will lead to a serologic ELISA diagnostic for human Lyme disease for use in commercial reference laboratories. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: OUTER BURGDORFERI

SURFACE

PROTEIN

GENE

EXPRESSION

IN

B.

Principal Investigator & Institution: Samuels, D. Scott.; Associate Professor; Div of Biological Sciences; University of Montana University Hall 202 Missoula, Mt 598124104 Timing: Fiscal Year 2003; Project Start 15-MAY-2003; Project End 14-MAY-2005 Summary: (provided by applicant): Lyme disease, the most common arthropod-borne disease in the United States, is caused by infection with the spirochete Borrelia burgdorferi. B. burgdorferi synthesizes several outer surface proteins (Osps), including OspA, OspB and OspC. OspA is the target in the Lyme disease vaccine and is thought to be involved in the binding of B. burgdorferi to the gut of its tick vector. OspC is thought to be a transmission or mammalian colonization factor and its synthesis is induced during tick feeding. The variation of OspA and OspB versus OspC is likely a means by which B. burgdorferi adapts to the different environments of the tick vector and mammalian host, and prepares for the environmental transition. Our hypothesis is that DNA supercoiling senses environmental signals and transduces them into an altered gene expression program in which ospC transcription is directly affected by DNA supercoiling. This project proposes to dissect, using molecular genetic and

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biochemical techniques, the regulation of outer surface protein gene expression. Gac and Hbb are two architectural DNA-binding proteins that alter DNA structure and supercoiling in B. burgdorferi. We will genetically assay the role of Gac and Hbb in ospC transcription by mutating the gac and hbb genes in B.burgdorferi. In addition, we will define cis-acting sequences by constructing ospC promoter mutants. We believe that we will be able to probe the mechanism of the variation in outer surface protein gene expression in B. burgdorferi, which will contribute to the understanding of the basic biology of this pathogen and can lead to improved diagnostic, prevention and treatment strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: P38 MAP KINASE ROLE IN THE GENESIS OF LYME ARTHRITIS Principal Investigator & Institution: Anguita, Juan; Assistant Professor; Biology; University of North Carolina Charlotte Office of Research Services Charlotte, Nc 282230001 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2006 Summary: (provided by applicant): Borrelia burgdorferi is the causative agent of Lyme disease, the most common vector-borne disease in the United States. Among the symptoms occurring as a result of infection with B. burgdorferi, Lyme arthritis is the most prevalent in patients infected with the spirochete. B. burgdorferi infection causes an upregulation of proinflammatory cytokines. Tumor necrosis factor (TNF) alpha, IL-12 and Interferon (IFN) gamma, followed by a CD4+ T cell helper (Th) type 1 cytokine production pattern have been reported in strains susceptible to develop more severe inflammatory symptoms. The molecular mechanisms by which the proinflammatory cytokine pattern is induced are not completely elucidated. p38 MAP kinase is involved in the genesis of several non-infectious arthritides, like rheumatoid arthritis, by regulating the expression of proinflammatory cytokines, p38 MAP kinase is also required for the production of IFNgamma, an important proinflammatory mediator, by T cells. The use of a specific inhibitor is considered a potential therapy in those processes that involve a proinflammatory response mediated by p38 MAP kinase. We hypothesize that B. burgdorferi activates the p38 MAP kinase pathway. The activation of this pathway is required for proinflammatory cytokine production by macrophages and neutrophils. The activation of this pathway is also required for IFNgamma production by CD4+ T cells and Thl differentiation during Lyme borreliosis. Thus, we propose that the p38 MAP kinase pathway is required for the development of murine Lyme arthritis. Understanding the contribution of this pathway to the development of murine Lyme arthritis, as a model of human disease, may open new therapeutic approaches that would take advantage of specific pharmacological inhibitors of p38 MAP kinase currently being tested in human clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PATHOGENESIS OF NEUROLOGIC LYME DISEASE Principal Investigator & Institution: Luft, Benjamin J.; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2001 Summary: The goal of this project is to identify Borrelial and host-specific factors involved in the invasion of and persistence within the central nervous system (CNS). This will be done by identifying those strains of B. burgdorferi which are neurotropic; by determining strain antigenic variation associated with neurotropism and persistence;

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by defining the relationship between neurotropism ,antigenic variability, and early and late neurologic Lyme syndromes; and by examining the role of host T-cell responses in dissemination and perpetuation-of disease. This project will use erythema migrans skin biopsy, cerebrospinal fluid, and blood samples from early Lyme disease patients (Project 2), and cerebrospinal fluid and blood samples from late Lyme disease patients (Project 3). Techniques to be used include polymerase chain reaction (PCR), singlestranded conformational polymorphism and cytokine assays. The following specific aims will be addressed. Specific Aim 1: To identify neurotropic strains of B. burgdorferi. Specific Aim 2: To test the hypothesis that T-cell cytokine production (Th1 vs Th2) in response to B. burgdorferi, correlates with clinical outcome. The following predictions will be tested: A. Early Lyme patients show a predominant Th2 T-cell response, while late/chronic Lyme patients show a predominant Th1 response. B. Early Lyme patients with a predominant Th1 T-cell response are more likely to develop chronic sequelae than early Lyme disease patients with a predominant Th2 response. This will be tested by correlating cytokine production of early Lyme disease patients with clinical outcome at 18 months. C. Early Lyme patients with neurologic symptoms have a predominant Th1 response, while early Lyme patients with a single lesion of erythema migrans and no systemic symptoms have a predominant Th2 response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOGENIC MECHANISMS IN LYME BORRELIOSIS Principal Investigator & Institution: Lovett, Michael A.; Professor of Genetics; Microbiology and Immunology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 01-JUN-1990; Project End 31-MAR-2006 Summary: (provided by the applicant): This proposal is centered on the molecular basis of host-adaptation by Borrelia burgdorferi in mice and on the phenotypic changes of host-adapted Borrelia (HAB) that relate to pathogenesis and immunity. The small numbers of B. burgdorferi (Bb) present in infected mice has been a hindrance to determination of their surface antigenic structure. The signals in the host environment that initiate the process of host-adaptation by Bb have not been reported. Several recent findings in our laboratory form the basis for this proposal. We have learned that the magnitude of spirochetemia in scid mice is orders of magnitude greater than previously appreciated, making possible direct study of HAB spirochetes. These HAB circulating in the blood of scid mice are bound to blood cells, and have an antigenic composition distinct from that of in vitro cultivated Bb. Further, we learned that contact of in vitro cultivated Bb with blood cells results in expression of proteins otherwise poorly expressed in vitro, but upregulated during infection. Three specific aims are proposed. The first is "proteomic analysis of Bb host-adaptation in the mouse model of Lyme disease." We have developed novel methods for efficient extraction of the surface proteins expressed by HAB in mouse skin, blood, heart, and joint. Using the tools of proteomics we will catalogue the full set of HAB surface proteins expressed in different tissues and the relative amounts in which they are expressed. The second specific aim is "molecular basis of host-adaptation." Contact with host cells in vitro triggers Bb to upregulate the expression of certain surface antigens. These events will be related to the findings of our proteomic analysis of host adaptation in the mouse. The Bb receptor(s) and host cell ligand(s) that mediate this process will be defined. The third specific aim is "relationship of surface antigenic structure of host-adapted Bb to protective immunity." HAB bound to circulating blood cells will be used to assess the relative representation of

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specific molecules on their surface. Novel HAB surface proteins will be tested as protective immunogens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PET ENCEPHALOPATHY

AND

MRI

IMAGING

OF

PERSISTENT

LYME

Principal Investigator & Institution: Fallon, Brian A.; Associate Professor of Clinical Psychiat; Psychiatry; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2001; Project Start 08-DEC-1999; Project End 30-NOV-2003 Summary: This project tests specific hypotheses about functional and structural brain abnormalities in patients with Persistent Lyme Encephalopathy (PLE) and it cvaluates the efficacy of 10 weeks of IV ceftriaxone among patients previously treated with shorter courses of Iv antibiotics. Prior planar rCBF and SPECT studies of PLE reveal diffuse deficits affecting cortical and subcortical areas, primarily the white matter. These scans are often interpreted as consistent with vasculitis, multi-infarct dementia, or Lyme Disease. MRI series demonstrate that between 20-400/o of patients have hyperintensities, suggestive of inadequate arteriolar perftision resulting in demyelination and gliosis. To understand better the significance of these imaging abnormalities, this project will employ MRI and PET imaging and cognitive testing: a) to examine whether the functional imaging deficits are primarily vascular or metabolic in nature; b) to evaluate whether time course of improvement in MRI and PET scans correlates with clinical cognitive improvement; c) to identify whether deficits in blood flow (CBF), cerebral metabolism (CMR), and extent of MRI hyperintensities have prognostic significance; and d) to determine whether a subgroup of patients with poor outcome PLE have impaired vascular reserve 60 patients with PLE and 20 matched controls will be studied over 4 years. A second major goal is to determine the efficacy of a 10 week placebo-controlled trial of IV ceftriaxone in PLE using objective behavioral and imaging measures. After treatment, patients will be monitored off antibiotics to week 24. Durability of response will be examined by cognitive retesting at wk 48. Imaging procedures include MRI (T1 sagittal, 3D volumetric, T2 spin echo, FLAIR, and magnetization transfer sequences), O15. H2O PET during rest and hypercapnia, and FDG PET assessment of resting rCMR. We will test specific hypotheses about reversible and fixed functional and structural abnormalities that may account for antibiotic responsive and -unresponsive PLE. These hypotheses derive from histopathological studies indicating that a subgroup of patients with PLE have evidence of a vasculitic process that may lead to a syphilis-like endarteritis obliterans, with impairment in hcmodynamic reserve. This study will enhance our understanding of the pathophysiology and treatment of patients suffering with the disabling effects of persistent Lyme encephalopathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHEROMONE/ACARICIDE MATRIX CONTROLS LYME DISEASE VECTOR Principal Investigator & Institution: Mclaughlin, John R.; Ipm Technologies, Inc. 4134 N Vancouver Ave, Ste 105 Portland, or 97217 Timing: Fiscal Year 2002; Project Start 15-JUN-2000; Project End 30-JUN-2004 Summary: (provided by applicant): IPM Technologies, Inc. will produce a formulation that will attract and kill nymphs and adults of the deer tick, Ixodes scapularis in the laboratory and in field trials. The target species, blacklegged tick transmits Lyme

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disease, two kinds of ehrlichiosis, and human babesiosis in the U.S. The project will identify specific active chemicals, optimize their formulation, screen for activity against additional target vectors, establish field trials, engineer application technology, and begin the process of EPA registration. The identity of the assembly pheromone of the tick will be confirmed and used to aggregate ticks that are attracted by host or tick related compounds formulated with an acaricide into a patented, EPA-registered bait matrix. Very low rates of insecticide will be required to achieve control, as the ticks will aggregate at the bait. Minimal toxicity enables bait application to areas of high human activity and sensitive ecosystems. This product shows great commercial potential due to the civilian and military medical importance of tick-borne disease and present limitations in tick management options. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROTEOMICS IN DIAGNOSTIC DISCOVERY: LYME DISEASE Principal Investigator & Institution: Fried, Victor A.; Diagnomics, Inc. Elmwood Hall (Ny Med Coll) Valhalla, Ny 10595 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2004 Summary: (provided by applicant): The mission of Diagnomics, Inc. is to discover specific ensembles of proteins/antigens that will serve as diagnostic markers and to provide recombinant clones to these markers for production of diagnostic kits in partnership or licensing with a third party. Using proteomics and post-genomic technologies, antigens, including strongly antigenic low expression proteins (SALEPs), will be identified and used as recombinant molecules to create sensitive and reliable markers for evaluating patient serum. Lyme disease is an excellent candidate for development of this new discovery paradigm. First, nearly 3 million seroassays for Lyme disease are performed per year and these assays are unreliable, generally lacking sensitivity, specificity and reproducibility. Second, the genome sequence of Borrelia burgdorferi, the etiologic agent of the disease, is known and thus identification of proteins can be performed using mass spectroscopy fingerprinting techniques. Finally, Diagnomics, Inc. has access to large collections of clinical isolates and patient and control sera. In Phase 1 development, we will: 1) Identify antigenic Borrelia burgdorferi proteins by screening 2D gel fractionated clinical isolates by Western blotting with patient and control sera, and identify these immunoreactive proteins by proteomics using MALDI-TOF mass spectroscopy peptide mapping and genomic database search; 2) Prepare recombinant antigens by PCR subcloning into expression vectors; 3) Validate an ensemble of diagnostic recombinant antigens by testing with sera from cultureconfirmed Lyme disease patients and control individuals. This validated ensemble will be developed in collaboration with a third party as a serological diagnostic kit for Lyme disease that will be reliable, specific and sensitive. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RAPID DETECTION AND IDENTIFICATION OF ZOONOTIC PATHOGENS Principal Investigator & Institution: Dunn, John J.; Senior Scientist; Brookhaven Science Assoc-Brookhaven Lab Brookhaven National Lab Upton, Ny 11973 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 29-FEB-2008 Summary: (provided by applicant): Zoonotic pathogens including those transmitted by insect vectors are some of the most deadly of all infectious diseases known to mankind. In the past, wars and natural disasters were the main catalysts that promoted epidemics

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of these ancient afflictions, which are normally transmitted by fleas, lice and ticks. Many of these diseases remain endemic in various regions of the world and therefore pose serious threats to U.S. armed forces troops and civilians who might enter endemic disease zones. A number of these agents have been further weaponized and are widely recognized as being the most significant biothreat agents. Study of disease agents and development of rapid means for their detection take on added importance in light of the use of anthrax for a bioterror attack on the U.S.A. The aim of this proposal is to modify a novel DNA-based methodology we have developed for profiling genomic DNAs to permit rapid, cultivation-free differential detection and identification of biothreat infectious agents in their natural environments, including intermediate infected hosts, and clinical specimens from humans or infected animals. We plan to use Borrelia burgdorferi, the arthropod-borne etiologic agent of Lyme disease and Yersinia pestis, the etiologic agent of plague, as our principle test agents to work through the systems. We will begin with B. burgdorferi since although it has a complicated life-cycle involving both arthropod and animal intermediates, it is easy to grow and we have extensive experience in working with it in different complex environments including ticks, rodents and human samples. Thus it gives us the opportunity of detecting this pathogen in a variety of complex environments. We also have significant experience with characterizing and identifying subtle changes in the genome of Y. pestis utilizing genomic signature tags. We will use these methods as the foundation of new, highthroughput sequence-based systems to detect zoonotic and/or vector-borne biothreat agents such as Yersinia pestis, Francisella tularensis, Rickettsia ricketsii and other human pathogens such as Ehrlichia and Babesia species. This technology can ultimately be adapted as a sensitive method to detect specific DNA signature sequences from both known and unknown pathogens in a wide variety of complex environments and since it is PCR-based it has the advantage that only minimal quantities of starting material are needed for analysis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REAGENTS FOR IMPROVED DIAGNOSTIC SEROLOGY OF LYME DISEASE Principal Investigator & Institution: Philipp, Mario T.; Chairman; Tulane University of Louisiana New Orleans, La New Orleans, La 70112 Timing: Fiscal Year 2001; Project Start 01-MAY-2001; Project End 30-APR-2002 Summary: Objectives To develop reagents for the improved diagnostic serology of Lyme disease. Results A segment (P7-1) of the variable domain of VlsE, the variant surface antigen of the spirochete Borrelia burgdorferi sensu lato was cloned and sequenced. and a conserved, immunodominant region of 26 amino acids (IR6) was identified. A 26-mer peptide (C6) was synthesized on the basis of the IR6 sequence and a peptide ELISA was developed for serodiagnosis of Lyme disease. Ten rhesus monkeys were infected with Borrelia burgdorferi strains JD1 or B31 by either tick or needle inoculation. Blood samples were periodically collected for up to 3 years post-infection (PI) until the animals were sacrificed, and serum samples were assessed for antibody responses to C6. Anti-C6 antibody was detectable in 6 monkeys as early as week 2 and in the remaining animals between weeks 3 and 5 PI. Antibody persisted at high levels for as long as serum samples were monitored. Forty-one serum samples from patients the majority of which had culture-confirmed, acute Lyme borreliosis, were obtained from the Centers for Disease Control and Prevention (CDC) and assessed with the C6 ELISA. Sensitivity was 85% (35/41), whereas with a commercially available Lyme disease ELISA it was 78% (32/41), and 49% (20/41) with a commercially available IgG

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Lyme immunoblot, 51% (21/41) with an IgM immunoblot, and 78% (32/41) by the combination of both IgG and IgM immunoblots. Of a group of 99 randomly collected serum samples from hospital patients in Louisiana, where Lyme disease is not endemic, only 2 were positive with the C6 ELISA. In addition, serum samples from 9/9 relapsing fever patients and 12/12 syphilitic patients also had no detectable anti-C6 antibodies. On the basis of the small number of serum samples tested thus far, the C6 peptide-based ELISA permits sensitive, specific and simple serodiagnosis of Lyme disease. Future directions To extend our survey of crossreactivity; samples from patients with autoim mune diseases will be tested. FUNDING PUBLICATIONS None Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF EXPRESSION OF BORRELIA BURGDORFERI BMPC Principal Investigator & Institution: Cabello, Felipe C.; Professor; Microbiology and Immunology; New York Medical College Valhalla, Ny 10595 Timing: Fiscal Year 2001; Project Start 01-JUL-1998; Project End 31-AUG-2002 Summary: Lyme disease is a multisystem, tick-borne chronic infection caused by the persistence of the spirochete Borrelia burgdorferi. B. burgdorferi has the ability to proliferate in a variety of niches in reservoir and human hosts as well as in the vector lxodes scapularis. Preliminary evidence indicates that differential gene expression resulting from environmental stimuli in one of the mechanisms that allows bacterial to adapt rapidly to fast changing environments found during infection and disease of vectors and hosts. We and others have described a family of chromosomal genes (bmpA-D) encoding homologous 36.9-39.8 kDa lipoproteins of the p39 family. The tandem chromosomal location of the bmp genes, their homology and overlapping regulatory signals together with the potential surface location of the proteins they encode in addition to their apparent up regulation by environmental stimuli suggests the hypothesis that these proteins may be important for B. burgdorferi survival in different environments. In this project, we propose to study the effects environmental stimuli have on bmpC, a member of this gene family first described by us, both in vitro and in vivo in mice and ticks, in an effort to improve our understanding of the mechanisms employed by B. burgdorferi to enable it to persist and thrive in vectors and hosts. The long-range goal of our efforts is to improve understanding of B. burgdorferi gene expression despite the lack of genetic systems that would facilitate this work. The specific aims of the current project are: 1) identify anti-BmpC Mab and polyclonal antibodies not cross-reactive with BmpD, BmpA and BmpB and use them to characterize BmpC protein and confirm its localization and lipidation in B. burgdorferi 297; 2) Determine levels of expression and mechanisms of regulation of bmpC under different in vitro and in vivo conditions; and 3) Determine genetic organization and DNA structural and regulatory sequences of bmpC in B. burgdorferi, B. afzelii and B. garinii genospecies and in B. burgdorferi 297 grown under different conditions in vitro and in vivo. The latter studies will indicate whether different levels of transcription are secondary to changes in the regulatory and structural DNA sequences of the bmpC gene. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REGULATION OF P66 EXPRESSION IN BORRELIA BURGDORFERI. Principal Investigator & Institution: Medrano, Melisa S.; Molecular Biol & Microbiology; Tufts University Boston Boston, Ma 02111

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Timing: Fiscal Year 2002; Project Start 01-SEP-2002 Summary: (provided by applicant): Lyme disease, caused by the tick-borne spirochete Borrelia burgdorferi, results in a persistent, multisystemic infection. Little is known about the virulence and immune evasion of B. burgdorferi, but it has been shown to bind certain cell-surface receptors termed integrins. Integrins are divalent cationdependent heterodimers that normally mediate cell to cell and cell to extracellular matrix interactions. P66 is a B. burgdorferi outer surface protein that was identified as an integrin ligand, and so is likely to participate in the ability of the bacterium to infect its mammalian host. Aim I of this proposal includes the analysis of site-directed mutants in a region of p66 thought to be important for binding to integrins. These mutants will be compared with wild-type protein and intact B. burgdorferi to identify the specific amino acid residues important for integrin binding. In Aims 2 and 3, biochemical and genetic approaches will be taken to identify B. burgdorferi proteins that regulate p66 expression. The pattern of p66 expression in different environments is unique among the B. burgdorferi proteins studied to date. Two aspects of B. burgdorferi virulence, namely integrin-ligand interaction and regulation of gene expression, will therefore be illuminated by this work. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF TICK SALIVA IN LYME DISEASE AND VACCINE STRATEGY Principal Investigator & Institution: Mather, Thomas N.; Professor; None; University of Rhode Island 70 Lower College Road, Suite 2 Kingston, Ri 028810811 Timing: Fiscal Year 2002; Project Start 30-SEP-1994; Project End 31-MAR-2007 Summary: (Provided by Applicant) Interactions at the vector-host interface are likely to be most critical to transmission of arthropod transmitted infections. Our studies have demonstrated that through the action of their saliva, black-legged ticks (Ixodes scapularis) manipulate the host immune response in a manner that both assures bloodfeeding success, and favors survival and transmission of Lyme disease spirochetes (Borrelia burgdorferi). We have learned that these bacteria receive cues from tick saliva to regulate their protein expression, perhaps leading to enhanced invasiveness or survival in the host. We have discovered several novel molecules, including I. scapularis' salivary anti-complement protein (Isac) and a Factor Xa-inhibiting anticoagulant (Ixolaris), and recombinant proteins are in production. Taken together, this progress now allows us to test our hypothesis, that an effective prevention strategy for Lyme disease, and other I. scapularis-transmitted infections, can be developed by manipulating host immune responses to components of vector saliva or saliva-induced microbial products. In continuing this project, we will identify and isolate molecules from the saliva of vector ticks and from B. burgdorferi that provide protection against Lyme disease and other infections transmitted by I. scapularis. A comprehensive protocol integrating vector salivary gland genomics and proteomics is expected to accelerate both discovery and recovery of potentially important protective molecules. Massive cDNA sequencing of an I. scapularis salivary gland cDNA library containing full-length clones has revealed nearly 1,200 sequences and at least 476 genes. We will begin cloning these into plasmids using high-throughput technology to generate candidate DNA vaccines. In addition, recent advances in B. burgdorferi genomics will allow rapid progress on studies examining B. burgdorferi gene and protein expression in the presence and absence of tick saliva, or under other starvation-stress conditions. We will test whether whole genome analysis by DNA arrays and 2-D gel electrophoresis can facilitate discovery of potential protective molecules. Candidate vaccines will be

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screened for their ability to interrupt tick feeding or block pathogen transmission in a white-footed mouse (Peromyscus leucopus) model. We expect these studies to lead to new vaccination strategies that combine tick and bacterial elements for preventing Lyme disease, and possibly a broader range of tick-transmitted infections. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RPOS AND GENE EXPRESSION IN BORRELIA BURGDORFERI Principal Investigator & Institution: Ramamoorthy, Ramesh; None; Tulane University of Louisiana New Orleans, La New Orleans, La 70112 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2007 Summary: (provided by applicant): Borrelia burgdorferi, the etiologic agent of Lyme disease, cycles in nature between two evolutionarily diverse hosts, an invertebrate tick vector and a vertebrate host. The proliferation and maintenance of the spirochete in the two hosts is guided by several adaptive strategies involving the shuffling of proteins in response to changing environmental conditions. In this respect, molecular changes in the spirochete associated with tick feeding is of particular significance as they precede vertebrate infection. Tick feeding results in a dramatic burst in the spirochetal population, with accompanying changes in protein composition. These changes can be duplicated in vitro by shifting a spirochetal culture to a higher temperature and lower pH environment. One of the key proteins induced under these conditions is the transcription factor RpoS. Our long-term goal is to investigate the molecular events triggered in B. burgdorferi in response to changes in environmental temperature and pH. Our short-term objective is to exploit the in vitro model to develop a better understanding of this phenomenon. Specifically, the goals of this proposal are to (1) investigate the mechanism of regulation of RpoS, (2) identify chromosomal RpoSregulated genes, (3) characterize the role of RpoS in the regulation of the chromosomal RpoS-regulated genes in vivo. The regulation of RpoS expression will be examined, as we and others have determined that its own expression is responsive to changes in temperature and pH. We have identified a putative DNA-binding protein by electromobility shift assay that specifically binds to the rpoS 5' sequence. Initially, a response regulator protein RRP-2 will be examined as a putative candidate, failing which the unknown protein will be screened for and identified. The role of this DNAbinding protein in the expression of RpoS will be defined in vitro. We will also identify new chromosomal RpoS-regulated proteins by an in vitro screening assay. This assay will involve in vitro transcription using recombinant B. burgdorferi RNA polymerases loaded with sigma D or sigma S. Finally, the regulation of expression of these newly identified genes by RpoS will be partially characterized in vivo. These studies will shed light on the mechanism guiding the flow of genetic information, and identify new effector proteins, in Lyme disease spirochetes poised to infect the vertebrate host. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SAND FLY AND TICK SALIVA AND DISEASE Principal Investigator & Institution: Titus, Richard G.; Professor; Colorado State University Fort Collins, Co 80523 Timing: Fiscal Year 2001; Project Start 01-JUL-1989; Project End 31-JAN-2003 Summary: (Adapted from investigator's abstract) The saliva of every blood-sucking arthropod vector for disease that has been examined contains molecules that have either potent pharmacological or immunosuppressive effects. These molecules aid the vectors also inadvertently enhance the infectivity of the pathogens that these vectors transmit

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(arthropods probe in the skin for a blood meal and deliver pathogens to the skin without their saliva). The saliva of the sand flay (the vector for leishmaniasis) dramatically augments infection with Leishmania in mice and can determine whether Leishmania is able to successfully establish infection in the host. These observations suggest that it may be possible to vaccinate humans against vector-borne disease by vaccinating against the molecules in vector saliva that allow the pathogen to establish infection in the host. In the previous granting period, the sand fly salivary gene was cloned that encodes the protein (Maxadilan or MAX) that augments infection with Leishmania. Immunization with MAX blocks disease-exacerbating effects of MAX in mice. In this proposal the effects of MAX on relevant cell types involved in the response to infection with Leishmania, and the mechanism by which MAX has these effects will be examined. Furthermore, vaccine protocols will be optimized in mice so that they block transmission of leishmaniasis by sand flies. Lyme disease in a serious health problem in the United States. There are at least 3 different immunosuppressive proteins in the saliva of the tick vector for Lyme disease, Ixodes scapularis. The investigator wishes to clone the genes for these proteins and characterize their protein products as was done for the sand fly protein. In addition, he will determine whether these proteins enhance infection with the etiological agent of Lyme disease, Borrelia burgdorferi, and whether these proteins can be used to develop a transmission blocking vaccine for Lyme disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SINGLE STEP PEPTIDE ELISA FOR LYME SERODIAGONOSIS Principal Investigator & Institution: Levin, Andrew E.; Immunetics, Inc. 63 Rogers St Cambridge, Ma 02142 Timing: Fiscal Year 2002; Project Start 15-MAR-2002; Project End 14-MAR-2004 Summary: (Provided by applicant): The proposed project aims to provide a peptide ELISA as a single step serodiagnostic assay for Lyme disease, to replace the current twotier testing protocol recommended by CDC in 1994. This single step test will eliminate the deficiencies in cost efficiency, reproducibility and objectivity, throughput and accuracy associated with the use of the Lyme Western Blot as the second step in the twotier protocol. An ELISA based on peptides including the C6 peptide of the antigenic Borrelia protein VlsE and a peptide derived from the OspC protein will be developed. The sensitivity of the peptide ELISA in detection of early Lyme disease will be determined precisely as a function of time after infection through an analysis of longitudinal serum samples from infected rhesus monkeys, which provide a model for human disease. The peptide ELISA will be compared directly with the two-tier method in a clinical evaluation of well-characterized human sera from patients with Lyme disease in different stages, confirmed by culture, and in a prospective study of new patients followed over time. This will be the first study of its kind aimed at simplifying and improving the diagnostic approach to Lyme disease using an accurate and costefficient peptide ELISA. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SOUTHERN SIERRA TELEHEALTH NETWORK (SSTN) Principal Investigator & Institution: Mechtenberg, David A.; Ridgecrest Regional Hospital 1081 N China Lake Blvd Ridgecrest, Ca 93555 Timing: Fiscal Year 2003; Project Start 20-DEC-2002; Project End 19-DEC-2003

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Summary: (provided by applicant): Ridgecrest Regional Hospital (RRH) is a community-based organization that provides and promotes comprehensive, quality health care for the population of the Southeastern Sierra region of California. In order to provide a dynamic link to relevant health resources and access to NLM databases for the surrounding rural communities, RRH proposes to expand their existing web page and develop a Web-enabled Portal. This portal will provide internet access to Digital libraries to providers, patients, and the public. It will provide access to hih quality health-related information and education, with emphasis on the top health related illness in the region, including heart disease, malignant neoplasms, pneumonia, influenza, and cerebrovascular diseases. In addition, particular emphasis will be placed on regional issues such as rattlesnake bite treatment, Lyme Disease, Valley Fever, and the development of a data base of local resources of all facilities that carry critical needs medications and services for diseases throughout the Southeastern Sierra region. The long-term objective of this project, Southeastern Sierra Telehealth Network (SSTN) is to organize heath related information systems and provide access to it. Goals and activities proposed in this grant include: 1. To meet pre-established medical/health needs identified by previous needs assessment studies and include as clinical tools in the development of the portal. 2. To increase awareness and use of NLM services to health care facilities that have limited or no libraries. 3. To provide training to end users at participating sites so they can access current scientific and health related information resources provided by SSTN. RRH Clinicians and librarians will create and decide upon the content for the portal. Grant funds will be used to hire a web master to build the portal, upgrade computer technologies at participating sites and provide training. RRH will provide ongoing upgrades of the web page by their Information System Dept. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STUDY OF PERSISTENT INFECTION IN SSC SKIN AND VESSELS Principal Investigator & Institution: Mayes, Maureen D.; Professor; Internal Medicine; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2001; Project Start 26-SEP-2001; Project End 14-JAN-2002 Summary: (provided by applicant): The overall objective of this proposal is to study the possibility that in some systemic sclerosis patients, a persistent bacterial infection involving dermal microvascular endothelium or other cells that are resident in skin results in the obliterative microvasculopathy and/or the fibrosing features of this disease. As a first step in addressing this issue, we will test the following hypothesis: persistent bacterial infection of skin or microvasculature occurs more commonly in systemic sclerosis cases than in matched controls and participates in the disease process. Specific aims are: (1) to test skin biopsies from 60 systemic scleroderma patients and 30 matched normal controls for evidence of bacterial persistence by pan-bacterial and chlamydia-specific molecular screening; (2) to microdissect dermal vessels from these same cases and controls and test this tissue by panbacterial and chlamydia-specific molecular probes; (3) to prepare PBMC'S from these individuals and screen with these probes; and (4) depending on positive results, to perform immunohistochemistry studies for these organisms on skin biopsies/vessels from selected patients and appropriate controls. Scleroderma small vessel vasculopathy shares some key features with large vessel atherosclerosis, a condition also characterized by intimal proliferation and luminal narrowing among multiple other abnormalities. Inflammation may play an important role in the pathogenesis of atherosclerosis raising the possibility of infectious agents as mediators in this process. There are several examples of infection resulting in chronic inflammatory autoimmune diseases including Lyme disease (Borrelia

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burgdorferii), and reactive arthritis (ReA), an inflammatory joint disease associated with prior infection by a number of specific bacterial pathogens, including Chlamydia trachomatis and various species of the Genera Salmonella, Yersinia, Campylobacter, and others. This research team is comprised of individuals with expertise in clinical scleroderma, the vascular abnormalities of primary and secondary Raynaud's disease, and autoimmunity related to persistent bacterial infections with relevant pathogens. If positive results are obtained in at least a subset of scleroderma cases, intervention trials could be devised with therapy targeted to specific organisms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE 2.9 LIPOPROTEIN FAMILY OF BORRELIA BURGDORFERI Principal Investigator & Institution: Norgard, Michael V.; Professor; Microbiology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2001; Project Start 01-SEP-1999; Project End 31-AUG-2004 Summary: (Adapted from the Applicant's Abstract): Lyme disease, caused by the pathogenic spirochete Borrelia burgdorferi (Bb) is a major public health problem which warrants further efforts towards the development of improved vaccines and new diagnostics. The investigators have discovered a new family of lipoproteins (termed "2.9" lipoproteins) that appear to be "differentially expressed" by Bb; i.e., some of these lipoproteins are expressed as Bb replicates in vitro (analogous to the arthropod phase of Bb's life cycle) whereas others are expressed as Bb replicates "in vivo" (i.e., during the mammalian phase of infection). Compelling preliminary data already support the expectation that those 2.9 lipoproteins expressed "in vivo" may serve as effective vaccines and serodiagnostic reagents. The Specific Aims of this proposal are: (1) To determine and compare the "in vitro" versus "in vivo" expression patterns for the 2.9 lipoproteins of Bb strain 297; (2) To assess whether the 2.9 lipoproteins (particularly those express by Bb under "in vivo" conditions) are surface-exposed in Bb and thus targets for protective antibodies (i.e., vaccine candidates); (3) To investigate the 2.9 lipoproteins as new antigens for the serodiagnosis of Lyme disease; and (4) To examine the presence of homologous 2.9 lipoproteins (particularly those with vaccinogenic and diagnostic importance ) in all three sensu lato genospecies of B. burgdorferi. A particularly novel aspect of this proposal is its reliance upon a new animal model system in which virulent, "mammalian host-adapted" Bb can be obtained from rat or rabbit peritoneal chambers in quantities sufficient to identify 2.9 lipoproteins of Bb expressed "in vivo." The power of utilizing these new animal model systems for sorting out the "in vitro" versus "in vivo" expression patterns for 2.9 lipoproteins lies in the fact that antigens expressed during each or both phases of the zoonotic life cycle of Bb can be selectively chosen to address contemporary issues in Lyme disease vaccine development and serodiagnosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE EFFECTIVENESS OF VACCINES IN CLINICAL PRACTICE Principal Investigator & Institution: Shapiro, Eugene D.; Pediatrics; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: The goals of Dr. Eugene Shapiro, the principal investigator, are: 1) to conduct high quality research to answer important questions about a) the effectiveness of licensed vaccines as they are used in clinical practice and b) the clinical epidemiology and outcomes of patients with Lyme disease, and 2) to mentor young physicians so that

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they can become successful independent investigators. Dr. Shapiro completed separate fellowships in pediatric infectious diseases and in clinical epidemiology and research methods. He has been on the faculty at the Yale School of Medicine since 1983. During that time he has developed a large network of collaborators at the university, in the community, and throughout the state for his patient-oriented research projects; he also collaborates with the Connecticut Sate Department of Public Health. Because many important questions about vaccines (e.g., the duration of protection or the vaccine's efficacy in subgroups of patients or for specific manifestations of an infection) cannot be answered by randomized clinical trials, Dr. Shapiro has been especially interested in observational (case-control) studies of the efficacy of licensed vaccines. He is particularly well-known for developing methods (and incorporating them into his studies) to minimize bias and to assess the validity of the results of the large-scale casecontrol studies that he has conducted of the effectiveness of vaccines in clinical practice. If this proposal is funded, it will allow Dr. Shapiro to spend 75% of his time conducting research and serving as a mentor. Dr. Shapiro is currently conducting a case-control study of the clinical effectiveness of varicella vaccine in children. In future years he plans to conduct a case- control study of the effectiveness of the recently-licensed Lyme vaccine and, eventually, a case-control study of the effectiveness of conjugate pneumococcal vaccine (which is expected to be licensed within the next 12-24 months) in children. Dr. Shapiro is also conducting studies of the long-term outcomes of children and adults who were diagnosed as having Lyme disease from 1 to 15 years ago. Dr. Shapiro will serve as a mentor for 1-2 fellows (or young faculty members) each year. The fellows will learn to conduct high-quality clinical studies by working with Clinical Epidemiology Unit. They also will participate in regular research conferences and journal clubs and will meet regularly with Dr. Shapiro to review their progress and to help them develop their own studies as well as to develop strategies for the development of their careers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE ROLE OF CO-MORBID MENTAL DISORDERS IN LYME DISEASE Principal Investigator & Institution: Hassett, Afton L.; Medicine; Univ of Med/Dent NjR W Johnson Med Sch Robert Wood Johnson Medical Sch Piscataway, Nj 08854 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2007 Summary: (provided by investigator): Committed to a career in behavioral science research, the candidate's immediate goals are to obtain high quality didactic training and additional mentored experience related to interdisciplinary research. Long term career goals include exploring the role of co-morbid mental disorders and related psychological processes in rheumatologic illness and eventually becoming an expert on medically unexplained symptom syndromes across specialties. Current research is based on the candidate's stress-diathesis theoretical model for the "psychopathogenesis" of unexplained symptom syndromes present in rheumatology, i.e., Post Lyme Disease and fibromyalgia. The K08 Award would allow the candidate to devote 80 percent of her time to research and training. UMDNJ-Robert Wood Johnson Medical School is an outstanding environment in which to conduct this type of research. In addition to traditional biomedical research, many faculty members are actively exploring the role of psychological processes in health and illness. Mentorship would be provided by two such exceptional faculty, Javier I. Escobar, MD, Chairman of Psychiatry and Leonard H. Sigal MD, Chief of Rheumatology and Director of the Lyme Disease Center at UMDNJRWJMS. In addition to superior mentored clinical research experience, the candidate

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will receive advanced training in research methodology, statistical analysis, the responsible conduct of research, and neuroscience. Training highlights include statistical analyses through the Department of Statistics at Rutgers University and Neuroscience coursework at Princeton University. Mentored experience in research will consist of two studies. Study 1 will assess the co-morbid clinical disorders (Axis I) and pathological personality traits (Axis II) of patients who attribute chronic symptoms to Lyme disease. Study 2 prospectively examines newly diagnosed Lyme disease patients for co-morbid mental disorders and related cognitive/behavioral processes at baseline and follows them for one year. Our goal is to identify risk factors for the development of chronic symptoms ascribed to Lyme disease after adequate antibiotic treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TICK VACCINE PREVENTION OF LYME BORRELIOSIS Principal Investigator & Institution: Kantor, Fred S.; Associate Professor; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2003; Project Start 15-MAR-2003; Project End 28-FEB-2007 Summary: (provided by applicant): Our strategy is to prevent transmission of Lyme borreliosis by interfering with the tick's ability to feed to repletion. The proposed project attempts to identify and characterize a family of anticoagulants used by Ixodes ticks needed to permit feeding on their mammalian hosts. Such anticoagulants are vital to the success of tick feeding and in the transmission on tick borne pathogens. We shall explore the family of Ixodes tick anticoagulants by biochemical separation from tick salivary gland and saliva, and by probing cDNA and genomic libraries with appropriate primer fragments. Previous attempts in our laboratories to isolate tick salivary proteins by probing cDNA libraries with antibodies from animals made tick immune resulted in 40 clones; 22 of which were represented by an anticoagulant that we have called SALP14. In the present proposal we will probe libraries with primers derived from homologous portions of the clones previously identified in order to characterize what we now recognize as a family of anticoagulants vital to tick feeding and transmission of Lyme borreliosis. We will express and purify the recombinant anticoagulants and characterize their activities. To determine active sites, we will generate deletion mutants of these anticoagulants and identify the smallest region essential for effective catalytic activity, as well as antigenicity. The goal is to interfere with feeding by the immune response directed against the functional epitope(s) of the anticoagulant molecules. Feeding to repletion is essential for ticks to complete their life cycle and for the transmission of the pathogens they harbor. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: TISSUE SPECIFIC BORRELIA GENE EXPESSION Principal Investigator & Institution: Fikrig, Erol; Professor; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2001; Project Start 01-MAY-2001; Project End 31-MAR-2006 Summary: (provided by the applicant): This project seeks to understand how microbial antigens that are selectively expressed in vivo, and in specific tissues, contribute to the genesis of protective host immune responses and can serve as rational targets for vaccines. Borrelia burgdorferi has been shown to preferentially express different genes during infection of the mammalian host and within distinct host tissues. Moreover, B. burgdorferi has a tropism for the skin, joints, heart and nervous system, and these organs/tissues are associated with particular clinical manifestations of Lyme disease,

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such as erythema migrans or Lyme arthritis. B. burgdorferi genes that are selectively expressed in vivo and in precise host tissues will be identified using 2 strategies. First, differential immunoscreening, a technique developed in our laboratory, will be used. In this approach, a B. burgdorferi expression library is probed with 2 sets of sera (for example, [a] sera from an infected host, and [b] sera from a host hyperimmunized with killed B. burgdorferi) to identify antigens that only react with [a], and may therefore be selectively expressed in vivo. Secondly, DECAL (Differential Expression analysis using a Custom Amplified Library), will be adapted to identify B. burgdorferi genes expressed in the host. In this strategy, prokaryotic ribosomal RNA is removed for a bacterial expression library, which can then be used for subtractive analysis of gene expression in host tissues. Then the immune responses to the host-specific B. burgdorferi antigens will be characterized. We will directly assess tissue-specific gene expression, by RT-PCR using patient specimens and also in an experimental murine model of Lyme borreliosis. Then we will correlate antigen-specific immune responses with the course of Lyme disease in patients and determine whether immune responses to tissue-specific antigens influence the course of infection and/or prevent specific clinical manifestations of disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VACCINATION AGAINST IXODES SCAPULARIS TICK BITES Principal Investigator & Institution: Ledizet, Michel; L2 Diagnostics, Llc Box 8175 New Haven, Ct 94904 Timing: Fiscal Year 2002; Project Start 15-SEP-2001; Project End 31-AUG-2004 Summary: (provided by applicant): Lyme disease is a multi-systemic infection caused by the pathogen Borrelia burgdorjeri. The black-legged tick, Ixodes scapularis, is the common vector for B. burgdorferi. This tick also transmits the agents of human granulocytic ehrlichiosis and babesiosis. The purpose of this project is to develop an anti-I. scapiilaris vaccine to block tick attachment and tick-mediated disease transmission. Rabbits or guinea pigs infested with I. scapularis acquire antibodymediated resistance to tick bites, a phenomenon known as "tick-immunity.'' Phase I experiments evaluated Salp13 and Salp25D, two recombinant proteins expressed from I. scapularis salivary gland cDNAs, as candidate vaccines. Guinea pigs immunized with a combination of the two recombinant proteins demonstrated host resistance to tick bites. Phase II specific aims are to: (a) produce prototype Salp 13 and Salp25D vaccines suitable for extensive testing in animal models; (b) investigate Salp 13 and Salp25D contributions to the tick bite-induced tick immunity; and (c) determine if immunization with an optimized Salp13/Salp25D vaccine blocks pathogen transmission from ticks. These experiments will lead to Phase III development of a new vaccine designed to protect against multiple tick-borne pathogens. PROPOSED COMMERCIAL APPLICATION: A vaccine against Ixodes scapiilaris tick bites would potentially protect against several pathogens, including B. burgdorferi, Babesia microti, and the agent of human granulocytic ehrlichiosis. The commercial market would overlap with the market for LYMErix, a Glaxo SmithKline human Lyme disease vaccine, and the currently approved canine Lyme disease vaccines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: VACCINE RESPONSIVENESS TO BORRELIA BURGDORFERI OSPA Principal Investigator & Institution: Flavell, Richard A.; Professor and Chairman; Immunobiology; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047

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Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-DEC-2007 Summary: (provided by applicant): The Lyme disease vaccine is based on OspA, a Borrelia burgdorferi lipoprotein, and immunity is contingent upon high levels of OspA antibodies. Toll-like receptors (TLRs) are important for the initiation of immune responses to pathogens and TLR2 recognizes bacterial lipoproteins, including OspA. Our preliminary data now demonstrate that TLR1 is also involved in recognizing OspA. Therefore defects in TLR-mediated signaling could result in ineffective lipoproteinrecognition and influence responsiveness to OspA-vaccination. In this proposal we will explore the association between TLR1, TLR2, and responsiveness to vaccination with OspA in mice and humans. We have now identified 7 persons with very low OspA antibody titers after vaccination. Macrophages from these individuals produced less TNF-a after stimulation with OspA - but not peptidoglycan - than controls; suggesting a defect in signaling that is partially associated with TLR2 (because peptidoglycan is also recognized by TLR2). In vitro transfection studies then demonstrated that dominantnegative TLR1 could inhibit TLR2-mediated OspA responsiveness, implying that TLR1 and TLR2 cooperate for lipoprotein recognition. This was further examined in Tlr2-/mice, and Tlr1-/-mice that we have created. Tlr1-/- or Tlr2-/- mice made lower levels of OspA antibodies, after immunization with OspA, than controls. Macrophages from Tlr2/- mice responded poorly to both OspA and peptidoglycan whereas cells from Tlr1-/mice responded to peptidoglycan - but not OspA. These preliminary data suggest that TLR1 and TLR2 are required for OspA recognition, that the absence of TLR1 or TLR2 results in impair antibody responses to OspA immunization in mice, and that defects in the TLR1/2 signaling pathway may account for human hyporesponsiveness to OspA vaccination. We will now fully characterize the response to OspA in Tlr1-/- or Tlr2-/mice, and in humans that do not develop significant OspA antibodies following vaccination. These studies may provide an understanding of the molecular mechanisms for variability in antibody responses to the OspA vaccine, a first glimpse into TLR deficiencies in humans, and lead to new approaches to augment immune responses to OspA and other vaccines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VIRULENCE BURGDORFERI

ASSOCIATED

PROTEINS

OF

BORRELIA

Principal Investigator & Institution: Skare, Jonathan T.; Associate Professor; Medical Microbiol & Immunology; Texas A&M University Health Science Ctr College Station, Tx 778433578 Timing: Fiscal Year 2001; Project Start 01-APR-1999; Project End 31-MAR-2003 Summary: (Adapted from the Applicant's Abstract): Borrelia burgdorferi sensu lato, the etiologic agent of Lyme disease, causes a multi-system disorder that may progress into a persistent infection characterized by significant morbidity. The overall goal of this proposal is to identify and characterize virulent strain associated (VSA) outer membrane (OM) proteins, both those that are outer membrane- spanning (Oms) and lipoproteins, that function as protective immunogens. The investigators' long-term goal is to link protective immunity elicited by these proteins to pathogenic mechanisms. Specifically, this study proposes to: (1) Purify and characterize a 28 and 35 kilodalton (kDa) virulent strain associated (VSA) OM proteins of B. burgdorferi that are specific to infectious isolates. The native forms of the 28 and 35 kDa OM proteins will be purified from OM vesicles derived from B. burgdorferi and their amino terminal or internal peptide sequences determined. These sequences will then be used to identify the genes encoding these proteins by screening the B. burgdorferi genomic database; (2) Characterize four

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virulent strain associated (VSA) antigens of B. burgdorferi identified from a phage lambda expression library. We will determine the extent of differential expression of the VSA antigen in virulent versus avirulent B. burgdorferi and evaluate whether these antigens are either expressed in infected animals or temperature regulated; and (3) Test these OM VSA antigens identified for their ability to confer protective immunity. Recombinant VSA proteins will be overproduced, purified, and used to immunize mice. The native VSA OM 28 and 35 kDa proteins will be incorporated into liposomes and the resulting proteoliposomes used to immunize mice. Immunized animals will then be challenged with infectious B. burgdorferi. Serum specific for protective immunogens will be tested to determine whether these antibodies confer passive protection and whether antibodies mediate adherence inhibition or preferentially kill in vitro cultivated virulent B. burgdorferi in a complement dependent manner. Determination of the protective abilities of different B. burgdorferi antigens expressed in the host relative to those expressed during in vitro cultivation, will facilitate in the development of a vaccine cocktail to protect against non-clonal, environmental isolates of B. burgdorferi. Furthermore, these studies will provide insight into pathogenic mechanisms mediated by VSA antigens of B. burgdorferi. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VIRULENCE-ASSOCIATED PROTEINS IN LYME DISEASE Principal Investigator & Institution: Norris, Steven J.; Professor and Vice Chair for Research; Pathology and Lab Medicine; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2001; Project Start 01-SEP-1994; Project End 30-JUN-2005 Summary: (Adapted from Applicant's Abstract): Lyme disease, which is caused by infection with Borrelia burgdorferi and related spirochetes, is transmitted by ticks, and is characterized by dematologic, neurologic, cardiovascular, and arthritic manifestations. B. burgdorferi is an invasive organism that causes disease through persistent infection and chronic stimulation of host inflammatory responses. Understanding how the organism can evade the host immune response and cause persistent infection is important for understanding its pathogenesis, and improving diagnosis, treatment, and prevention. In the previous period of the award, Dr. Norris and colleagues discovered that B. burgdorferi possesses an elaborate system of antigenic variation, called the VMP-like Sequence (vls) locus, because of its similarity to the Variable Major Protein system of relapsing fever Borrelia. A central cassette region of the vlsE gene has been identified which undergoes extensive segmental recombination with a series of vls silent cassettes located adjacent of vlsE on the linear plasmid lp28-1. VlsE protein is highly immunogenic, and immunization with it confers protection against infection with B. burgdorferi expressing the homologous protein, but is only partially protective against isogenic strains expressing variants of VlsE, generated by recombination in the vls locus. Additionally, a strong antibody response can be detected in animals and in humans infected with B. burgdorferi, indicating VlsE is immunogenic and expressed during infection. These findings indicate the discovery of a highly immunogenic protein whose ability for genetic and immunologic variation could provide the bacteria with a powerful mechanism for immune evasion. The investigator plans to build on these initial important findings to further characterize the vls system in related spirochetes that cause Lyme disease, B. garinii, B. afzellii, and other isolates of B. burgdorferi. The immune response to VlsE epitopes will be investigated, and the potential of a multi-valent vaccine based on variant epitopes of VlsE will be tested. The location of invariant and variant epitopes of VlsE will be determined by structural

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analysis, employing recombinant VlsE and making use of monoclonal antibodies to be generated against VlsE variants. The correlation of particular plasmids with infectivity will be further analyzed to help identify additional gene products important in persistence, invasion, and pathological development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: WADSWORTH CTR: INFECTIOUS DIS, WEST NILE, AIDS, MALARIA, TB, BIOTERRORISM, LYME Principal Investigator & Institution: Galivan, John H.; Research Scientist Vi & Director; Wadsworth Center Empire State Plaza Albany, Ny 12237 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 14-SEP-2003 Summary: (provided by applicant): The WC is establishing a nationally recognized center in arthropod-borne disease research. Since 1999, five exceptional scientists have been recruited who will lead the program. The program is being consolidated into four adjacent buildings on the GL campus (a complex of nine buildings constructed in the 1930's). Approximately 10,000 sq. ft. of space has been rehabilitated in two of these buildings, at a cost of $7.5 million, to create dedicated research laboratories for arthropod-borne diseases. Funds are being sought to create a biocontainment insectary with adjacent animal and laboratory space; this is a necessity to achieve excellence in broad research programs on arthropod-borne viral, bacterial and parasitic diseases. Among the proposed renovations are Biosafety Level 2 (BSL2) and BSL3 insectaries totaling 2,750 sq. ft. The proposed facility will be the largest research-oriented BSL3 insectary in the Northeast, capable of extensive collaborative programs regionally and nationally. External funding to support arthropod-related research for the WC investigators and their collaborators has reached approximately $6.9 million and is expected to expand significantly upon the development of individual and collaborative programs that are possible only with the proposed facility. Specific Aims include: 1) creation of a BSL2 insectary and adjacent animal facilities for maintenance of arthropod colonies, and a BSL3 insectary and animal facilities for work with infected arthropods; 2) construction of two adjacent research laboratories for WC and collaborating investigators to conduct insectary-related research; and 3) installation of a new heating, ventilation, and air-conditioning (HVAC) system for control of temperature and humidity throughout the facility. 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 “Lyme disease” (or synonyms) into the search box. This search gives you access to 3 4

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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full-text articles. The following is a sample of items found for Lyme disease in the PubMed Central database: •

A 55-kilodalton antigen encoded by a gene on a Borrelia burgdorferi 49-kilobase plasmid is recognized by antibodies in sera from patients with Lyme disease. by Feng S, Das S, Lam T, Flavell RA, Fikrig E.; 1995 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173477

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A European Multicenter Study of Immunoblotting in Serodiagnosis of Lyme Borreliosis. by Robertson J, Guy E, Andrews N, Wilske B, Anda P, Granstrom M, Hauser U, Moosmann Y, Sambri V, Schellekens J, Stanek G, Gray J.; 2000 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86736

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A molecular marker for the identification of the zoonotic reservoirs of Lyme borreliosis by analysis of the blood meal in its European vector Ixodes ricinus. by Kirstein F, Gray JS.; 1996 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=168227

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A monoclonal antibody to Borrelia burgdorferi flagellin modifies neuroblastoma cell neuritogenesis in vitro: a possible role for autoimmunity in the neuropathy of Lyme disease. by Sigal LH, Williams S.; 1997 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=175205

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Ability of the Borreliacidal Antibody Test To Confirm Lyme Disease in Clinical Practice. by Callister SM, Jobe DA, Agger WA, Schell RF, Kowalski TJ, Lovrich SD, Marks JA.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=120016

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Ablation of interleukin-12 exacerbates Lyme arthritis in SCID mice. by Anguita J, Samanta S, Barthold SW, Fikrig E.; 1997 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=175621

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Accelerated infectivity of tick-transmitted Lyme disease spirochetes to vector ticks. by Shih CM, Liu LP.; 1996 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229237

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An optimized PCR leads to rapid and highly sensitive detection of Borrelia burgdorferi in patients with Lyme borreliosis. by Priem S, Rittig MG, Kamradt T, Burmester GR, Krause A.; 1997 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229651

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Analysis of the Cellular Localization of Bdr Paralogs in Borrelia burgdorferi, a Causative Agent of Lyme Disease: Evidence for Functional Diversity. by Roberts DM, Theisen M, Marconi RT.; 2000 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101917

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Analysis of the distribution and molecular heterogeneity of the ospD gene among the Lyme disease spirochetes: evidence for lateral gene exchange. by Marconi RT, Samuels DS, Landry RK, Garon CF.; 1994 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=196277

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Antibodies against whole sonicated Borrelia burgdorferi spirochetes, 41-kilodalton flagellin, and P39 protein in patients with PCR- or culture-proven late Lyme borreliosis. by Oksi J, Uksila J, Marjamaki M, Nikoskelainen J, Viljanen MK.; 1995 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228390

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Archaeal-type lysyl-tRNA synthetase in the Lyme disease spirochete Borrelia burgdorferi. by Ibba M, Bono JL, Rosa PA, Soll D.; 1997 Dec 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24988

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Arthritis severity and spirochete burden are determined by serotype in the Borrelia turicatae-mouse model of Lyme disease. by Pennington PM, Allred CD, West CS, Alvarez R, Barbour AG.; 1997 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=174589

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B7-1 and B7-2 monoclonal antibodies modulate the severity of murine Lyme arthritis. by Anguita J, Roth R, Samanta S, Gee RJ, Barthold SW, Mamula M, Fikrig E.; 1997 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=175428

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Biased T-Cell Antigen Receptor Repertoire in Lyme Arthritis. by Roessner K, Trivedi H, Gaur L, Howard D, Aversa J, Cooper SM, Sigal LH, Budd RC.; 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108020

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Borrelia burgdorferi B31 Erp Proteins That Are Dominant Immunoblot Antigens of Animals Infected with Isolate B31 Are Recognized by Only a Subset of Human Lyme Disease Patient Sera. by Miller JC, El-Hage N, Babb K, Stevenson B.; 2000 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86492

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Borrelia burgdorferi-specific T lymphocytes induce severe destructive Lyme arthritis. by Lim LC, England DM, DuChateau BK, Glowacki NJ, Schell RF.; 1995 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173166

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CD8+ T cells are activated during the early Th1 and Th2 immune responses in a murine Lyme disease model. by Dong Z, Edelstein MD, Glickstein LJ.; 1997 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=175768

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Cellular and Humoral Immune Responses to Borrelia burgdorferi Antigens in Patients with Culture-Positive Early Lyme Disease. by Vaz A, Glickstein L, Field JA, McHugh G, Sikand VK, Damle N, Steere AC.; 2001 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98832

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Changes in Temporal and Spatial Patterns of Outer Surface Lipoprotein Expression Generate Population Heterogeneity and Antigenic Diversity in the Lyme Disease Spirochete, Borrelia burgdorferi. by Hefty PS, Jolliff SE, Caimano MJ, Wikel SK, Akins DR.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128081

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Characteristics of Garden Dormice That Contribute to Their Capacity as Reservoirs for Lyme Disease Spirochetes. by Matuschka FR, Allgower R, Spielman A, Richter D.; 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=91083

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•

Characterization of a Borrelia burgdorferi VlsE Invariable Region Useful in Canine Lyme Disease Serodiagnosis by Enzyme-Linked Immunosorbent Assay. by Liang FT, Jacobson RH, Straubinger RK, Grooters A, Philipp MT.; 2000 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87557

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Characterization of Lyme Borreliosis Isolates from Patients with Erythema Migrans and Neuroborreliosis in Southern Sweden. by Ornstein K, Berglund J, Nilsson I, Norrby R, Bergstrom S.; 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87927

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Characterization of outer membranes isolated from Borrelia burgdorferi, the Lyme disease spirochete. by Radolf JD, Goldberg MS, Bourell K, Baker SI, Jones JD, Norgard MV.; 1995 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173280

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Circular and linear plasmids of Lyme disease spirochetes have extensive homology: characterization of a repeated DNA element. by Zuckert WR, Meyer J.; 1996 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=177937

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Clarithromycin in treatment of early Lyme disease: a pilot study. by Dattwyler RJ, Grunwaldt E, Luft BJ.; 1996 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163136

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Clearance of Borrelia burgdorferi May Not Be Required for Resistance to Experimental Lyme Arthritis. by Brown CR, Reiner SL.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108164

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Coexistence of antibodies to tick-borne pathogens of babesiosis, ehrlichiosis, and Lyme borreliosis in human sera. by Magnarelli LA, Dumler JS, Anderson JF, Johnson RC, Fikrig E.; 1995 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228637

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Coinfection with Borrelia burgdorferi and the Agent of Human Granulocytic Ehrlichiosis Alters Murine Immune Responses, Pathogen Burden, and Severity of Lyme Arthritis. by Thomas V, Anguita J, Barthold SW, Fikrig E.; 2001 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98295

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Comparative in vitro and in vivo susceptibilities of the Lyme disease spirochete Borrelia burgdorferi to cefuroxime and other antimicrobial agents. by Johnson RC, Kodner CB, Jurkovich PJ, Collins JJ.; 1990 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=172012

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Comparison of cefuroxime axetil and doxycycline in treatment of patients with early Lyme disease associated with erythema migrans. by Luger SW, Paparone P, Wormser GP, Nadelman RB, Grunwaldt E, Gomez G, Wisniewski M, Collins JJ.; 1995 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=162601

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Comparison of Immunodot and Western Blot Assays for Diagnosing Lyme Borreliosis. by Fawcett PT, Rose CD, Gibney KM, Doughty RA.; 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95608

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Comparison of the Yields of Blood Cultures Using Serum or Plasma from Patients with Early Lyme Disease. by Wormser GP, Bittker S, Cooper D, Nowakowski J, Nadelman RB, Pavia C.; 2000 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86513

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Complement-mediated serum sensitivity among spirochetes that cause Lyme disease. by van Dam AP, Oei A, Jaspars R, Fijen C, Wilske B, Spanjaard L, Dankert J.; 1997 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=175122

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Comprehensive Analysis of the Factor H Binding Capabilities of Borrelia Species Associated with Lyme Disease: Delineation of Two Distinct Classes of Factor H Binding Proteins. by McDowell JV, Wolfgang J, Tran E, Metts MS, Hamilton D, Marconi RT.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155754

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Correlation of seroreactivity with response to antibiotics in pediatric Lyme borreliosis. by Fawcett PT, Rose CD, Gibney KM, Doughty RA.; 1997 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=170481

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Coumermycin A1 inhibits growth and induces relaxation of supercoiled plasmids in Borrelia burgdorferi, the Lyme disease agent. by Samuels DS, Garon CF.; 1993 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=187602

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Crystal structure of Lyme disease antigen outer surface protein A complexed with an Fab. by Li H, Dunn JJ, Luft BJ, Lawson CL.; 1997 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20483

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Crystal structure of outer surface proteinC (OspC) from the Lyme disease spirochete, Borrelia burgdorferi. by Kumaran D, Eswaramoorthy S, Luft BJ, Koide S, Dunn JJ, Lawson CL, Swaminathan S.; 2001 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=145497

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C-Terminal Invariable Domain of VlsE Is Immunodominant but Its Antigenicity Is Scarcely Conserved among Strains of Lyme Disease Spirochetes. by Liang FT, Bowers LC, Philipp MT.; 2001 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98280

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Decorin-Binding Protein of Borrelia burgdorferi Is Encoded within a Two-Gene Operon and Is Protective in the Murine Model of Lyme Borreliosis. by Hagman KE, Lahdenne P, Popova TG, Porcella SF, Akins DR, Radolf JD, Norgard MV.; 1998 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108255

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Decreased interleukin-4 and increased gamma interferon production by peripheral blood mononuclear cells of patients with Lyme borreliosis. by Oksi J, Savolainen J, Pene J, Bousquet J, Laippala P, Viljanen MK.; 1996 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=174272

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Demonstration of the Genetic Stability and Temporal Expression of Select Members of the Lyme Disease Spirochete OspF Protein Family during Infection in Mice. by McDowell JV, Sung SY, Price G, Marconi RT.; 2001 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98571

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Detection of Borreliacidal Antibodies in Lyme Borreliosis Patient Sera Containing Antimicrobial Agents. by Jobe DA, Rawal N, Schell RF, Callister SM.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95800

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Detection of Lyme disease spirochetes in the skin of naturally infected wild sika deer (Cervus nippon yesoensis) by PCR. by Kimura K, Isogai E, Isogai H, Kamewaka Y, Nishikawa T, Ishii N, Fujii N.; 1995 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=167423

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Diagnosis of Lyme Borreliosis by a Whole-Blood Gamma Interferon Assay for CellMediated Immune Responses. by Sikand VK.; 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=103742

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Diagnostic Value of Proteins of Three Borrelia Species (Borrelia burgdorferi Sensu Lato) and Implications for Development and Use of Recombinant Antigens for Serodiagnosis of Lyme Borreliosis in Europe. by Hauser U, Lehnert G, Wilske B.; 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95599

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Differential Binding of Host Complement Inhibitor Factor H by Borrelia burgdorferi Erp Surface Proteins: a Possible Mechanism Underlying the Expansive Host Range of Lyme Disease Spirochetes. by Stevenson B, El-Hage N, Hines MA, Miller JC, Babb K.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127719

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Differential Immune Response to the Variable Surface Loop Antigen of P66 of Borrelia burgdorferi Sensu Lato Species in Geographically Diverse Populations of Lyme Borreliosis Patients. by Ornstein K, Ostberg Y, Bunikis J, Noppa L, Berglund J, Norrby R, Bergstrom S.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130129

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Differential spirochetal infectivities to vector ticks of mice chronically infected by the agent of Lyme disease. by Shih CM, Liu LP, Spielman A.; 1995 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228665

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Differential Survival of Lyme Borreliosis Spirochetes in Ticks That Feed on Birds. by Kurtenbach K, Schafer SM, Sewell HS, Peacey M, Hoodless A, Nuttall PA, Randolph SE.; 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128348

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Direct Molecular Typing of Borrelia burgdorferi Sensu Lato Species in Synovial Samples from Patients with Lyme Arthritis. by Jaulhac B, Heller R, Limbach FX, Hansmann Y, Lipsker D, Monteil H, Sibilia J, Piemont Y.; 2000 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86617

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Distribution of Twelve Linear Extrachromosomal DNAs in Natural Isolates of Lyme Disease Spirochetes. by Palmer N, Fraser C, Casjens S.; 2000 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111310

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Diversity of European Lyme Disease Spirochetes at the Southern Margin of Their Range. by Matuschka FR, Klug B, Schinkel TW, Spielman A, Richter D.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=106265

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DNA microarray analysis of differential gene expression in Borrelia burgdorferi, the Lyme disease spirochete. by Revel AT, Talaat AM, Norgard MV.; 2002 Feb 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122230

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DNA Vaccines Expressing a Fusion Product of Outer Surface Proteins A and C from Borrelia burgdorferi Induce Protective Antibodies Suitable for Prophylaxis but Not for Resolution of Lyme Disease. by Wallich R, Siebers A, Jahraus O, Brenner C, Stehle T, Simon MM.; 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98139

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Dogs as Sentinels for Human Lyme Borreliosis in The Netherlands. by Goossens HA, van den Bogaard AE, Nohlmans MK.; 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87839

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Dominant recognition of a Borrelia burgdorferi outer surface protein A peptide by T helper cells in patients with treatment-resistant Lyme arthritis. by Kamradt T, LenglJanssen B, Strauss AF, Bansal G, Steere AC.; 1996 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173916

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Dual Role of Interleukin-10 in Murine Lyme Disease: Regulation of Arthritis Severity and Host Defense. by Brown JP, Zachary JF, Teuscher C, Weis JJ, Wooten RM.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96863

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Early and late antibody responses to full-length and truncated constructs of outer surface protein A of Borrelia burgdorferi in Lyme disease. by Kalish RA, Leong JM, Steere AC.; 1995 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173290

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Effect of ambient temperature on competence of deer ticks as hosts for Lyme disease spirochetes. by Shih CM, Telford SR 3rd, Spielman A.; 1995 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228075

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Effect of Immunization with Recombinant OspA on Serologic Tests for Lyme Borreliosis. by Fawcett PT, Rose CD, Budd SM, Gibney KM.; 2001 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96014

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Effect of Prior Exposure to Noninfected Ticks on Susceptibility of Mice to Lyme Disease Spirochetes. by Richter D, Spielman A, Matuschka FR.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=106690

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Effects of Ixodes scapularis and Borrelia burgdorferi on modulation of the host immune response: induction of a TH2 cytokine response in Lyme disease-susceptible (C3H/HeJ) mice but not in disease-resistant (BALB/c) mice. by Zeidner N, Mbow ML, Dolan M, Massung R, Baca E, Piesman J.; 1997 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=175437

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Effects of OspA Vaccination on Lyme Disease Serologic Testing. by Aguero-Rosenfeld ME, Roberge J, Carbonaro CA, Nowakowski J, Nadelman RB, Wormser GP.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85737

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Efficacy of an Evernimicin (SCH27899) In Vitro and in an Animal Model of Lyme Disease. by Pavia CS, Wormser GP, Nowakowski J, Cacciapuoti A.; 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90397

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Enzyme-Linked Immunosorbent Assay Using Recombinant OspC and the Internal 14-kDa Flagellin Fragment for Serodiagnosis of Early Lyme Disease. by Rauer S, Spohn N, Rasiah C, Neubert U, Vogt A.; 1998 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104650

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Establishment of enzyme-linked immunosorbent assay using purified recombinant 83-kilodalton antigen of Borrelia burgdorferi sensu stricto and Borrelia afzelii for serodiagnosis of Lyme disease. by Rauer S, Kayser M, Neubert U, Rasiah C, Vogt A.; 1995 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228536

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Evaluation of Whole-Cell and OspC Enzyme-Linked Immunosorbent Assays for Discrimination of Early Lyme Borreliosis from OspA Vaccination. by Wieneke CA, Lovrich SD, Callister SM, Jobe DA, Marks JA, Schell RF.; 2000 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88715

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Evidence for the Contribution of Point Mutations to vlsE Variation and for Apparent Constraints on the Net Accumulation of Sequence Changes in vlsE during Infection with Lyme Disease Spirochetes. by Sung SY, McDowell JV, Marconi RT.; 2001 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=99662

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Evidence for Vaccine Synergy between Borrelia burgdorferi Decorin Binding Protein A and Outer Surface Protein A in the Mouse Model of Lyme Borreliosis. by Hanson MS, Patel NK, Cassatt DR, Ulbrandt ND.; 2000 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97733

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Evidence That the Variable Regions of the Central Domain of VlsE Are Antigenic during Infection with Lyme Disease Spirochetes. by McDowell JV, Sung SY, Hu LT, Marconi RT.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128138

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Experimental Lyme Arthritis in the Absence of Interleukin-4 or Gamma Interferon. by Brown CR, Reiner SL.; 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116514

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Expression of Adhesion Molecules in Synovia of Patients with Treatment-Resistant Lyme Arthritis. by Akin E, Aversa J, Steere AC.; 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98084

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Fetal outcome in murine Lyme disease. by Silver RM, Yang L, Daynes RA, Branch DW, Salafia CM, Weis JJ.; 1995 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=172958

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FlaA, a putative flagellar outer sheath protein, is not an immunodominant antigen associated with Lyme disease. by Ge Y, Charon NW.; 1997 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=175421

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Gamma Interferon Is Not Required for Arthritis Resistance in the Murine Lyme Disease Model. by Glickstein L, Edelstein M, Dong JZ.; 2001 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98381

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Genetic Control of Experimental Lyme Arthritis in the Absence of Specific Immunity. by Brown CR, Reiner SL.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96554

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Genetic Diversity of Borrelia burgdorferi in Lyme Disease Patients as Determined by Culture versus Direct PCR with Clinical Specimens. by Liveris D, Varde S, Iyer R, Koenig S, Bittker S, Cooper D, McKenna D, Nowakowski J, Nadelman RB, Wormser GP, Schwartz I.; 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84470

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Genetic transformation of the Lyme disease agent Borrelia burgdorferi with coumarin-resistant gyrB. by Samuels DS, Mach KE, Garon CF.; 1994 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=196823

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Genospecies Identification and Characterization of Lyme Disease Spirochetes of Genospecies Borrelia burgdorferi Sensu Lato Isolated from Rodents in Taiwan. by Shih CM, Chang HM, Chen SL, Chao LL.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105287

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Geographic Risk for Lyme Disease and Human Granulocytic Ehrlichiosis in Southern New York State. by Daniels TJ, Boccia TM, Varde S, Marcus J, Le J, Bucher DJ, Falco RC, Schwartz I.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90906

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GlpQ: an antigen for serological discrimination between relapsing fever and Lyme borreliosis. by Schwan TG, Schrumpf ME, Hinnebusch BJ, Anderson DE Jr, Konkel ME.; 1996 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229300

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Granulocytic Ehrlichiae in Ixodes persulcatus Ticks from an Area in China Where Lyme Disease Is Endemic. by Cao WC, Zhao QM, Zhang PH, Dumler JS, Zhang XT, Fang LQ, Yang H.; 2000 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87564

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Hemagglutination and proteoglycan binding by the Lyme disease spirochete, Borrelia burgdorferi. by Leong JM, Morrissey PE, Ortega-Barria E, Pereira ME, Coburn J.; 1995 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173084

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Homology throughout the multiple 32-kilobase circular plasmids present in Lyme disease spirochetes. by Casjens S, van Vugt R, Tilly K, Rosa PA, Stevenson B.; 1997 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=178682

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Humoral Immune Response Associated with Lyme Borreliosis in Nonhuman Primates: Analysis by Immunoblotting and Enzyme-Linked Immunosorbent Assay with Sonicates or Recombinant Proteins. by Pachner AR, Dail D, Li L, Gurey L, Feng S, Hodzic E, Barthold S.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130097

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Identification of novel insertion elements, restriction fragment length polymorphism patterns, and discontinuous 23S rRNA in Lyme disease spirochetes: phylogenetic analyses of rRNA genes and their intergenic spacers in Borrelia japonica sp. nov. and genomic group 21038 (Borrelia andersonii sp. nov.) isolates. by Marconi RT, Liveris D, Schwartz I.; 1995 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228430

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Identifying Diagnostic Peptides for Lyme Disease through Epitope Discovery. by Kouzmitcheva GA, Petrenko VA, Smith GP.; 2001 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96025

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IFN[gamma] production in peripheral blood of early Lyme disease patients to hLFA[alpha]L (aa326-345). by Gomes-Solecki MJ, Wormser GP, Dattwyler RJ.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=134469

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Immunoblot interpretation criteria for serodiagnosis of early Lyme disease. by Engstrom SM, Shoop E, Johnson RC.; 1995 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=227960

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Immunoglobulin M Capture Assay for Serologic Confirmation of Early Lyme Disease: Analysis of Immune Complexes with Biotinylated Borrelia burgdorferi Sonicate Enhanced with Flagellin Peptide Epitope. by Brunner M, Stein S, Mitchell PD, Sigal LH.; 1998 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104692

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Immunohistochemical Analysis of Lyme Disease in the Skin of Naive and InfectionImmune Rabbits following Challenge. by Chong-Cerrillo C, Shang ES, Blanco DR, Lovett MA, Miller JN.; 2001 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98474

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Impact of Strain Heterogeneity on Lyme Disease Serology in Europe: Comparison of Enzyme-Linked Immunosorbent Assays Using Different Species of Borrelia burgdorferi Sensu Lato. by Hauser U, Krahl H, Peters H, Fingerle V, Wilske B.; 1998 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104554

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Importance of Sample Preparation for Molecular Diagnosis of Lyme Borreliosis from Urine. by Bergmann AR, Schmidt BL, Derler AM, Aberer E.; 2002 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154646

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Improving the Specificity of Recombinant Immunoassays for Lyme Disease. by Porwancher R.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156488

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Improving the Yield of Blood Cultures for Patients with Early Lyme Disease. by Wormser GP, Nowakowski J, Nadelman RB, Bittker S, Cooper D, Pavia C.; 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124859

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Infection with Agents of Human Granulocytic Ehrlichiosis, Lyme Disease, and Babesiosis in Wild White-Footed Mice (Peromyscus leucopus) in Connecticut. by Stafford KC III, Massung RF, Magnarelli LA, Ijdo JW, Anderson JF.; 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85405

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Integrin [alpha]IIb[beta]3 Mediates Binding of the Lyme Disease Agent Borrelia burgdorferi to Human Platelets. by Coburn J, Leong JM, Erban JK.; 1993 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47075

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Integrins [alpha]v[beta]3 and [alpha]5[beta]1 Mediate Attachment of Lyme Disease Spirochetes to Human Cells. by Coburn J, Magoun L, Bodary SC, Leong JM.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108148

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Interlaboratory comparison of test results for detection of Lyme disease by 516 participants in the Wisconsin State Laboratory of Hygiene/College of American Pathologists Proficiency Testing Program. by Bakken LL, Callister SM, Wand PJ, Schell RF.; 1997 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229622

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Involvement of CD4+ T lymphocytes in induction of severe destructive Lyme arthritis in inbred LSH hamsters. by Lim LC, England DM, Glowacki NJ, DuChateau BK, Schell RF.; 1995 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173690

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Isolation and Characterization of Borrelia burgdorferi Sensu Lato Strains in an Area of Italy Where Lyme Borreliosis Is Endemic. by Ciceroni L, Ciarrochi S, Ciervo A, Mondarini V, Guzzo F, Caruso G, Murgia R, Cinco M.; 2001 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88120

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Isolation and Transmission of the Lyme Disease Spirochete from the Southeastern United States. by Oliver JH Jr, Chandler FW Jr, Luttrell MP, James AM, Stallknecht DE, McGuire BS, Hutcheson HJ, Cummins GA, Lane RS.; 1993 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47139

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Isolation of Lyme Disease Borrelia from Puffins (Fratercula arctica) and Seabird Ticks (Ixodes uriae) on the Faeroe Islands. by Gylfe A, Olsen B, Strasevicius D, Marti Ras N, Weihe P, Noppa L, Ostberg Y, Baranton G, Bergstrom S.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84640

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Laboratory Testing for Lyme Disease: Possibilities and Practicalities. by Reed KD.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153420

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Linear chromosomes of Lyme disease agent spirochetes: genetic diversity and conservation of gene order. by Casjens S, Delange M, Ley HL 3rd, Rosa P, Huang WM.; 1995 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=176948

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LuxS-Mediated Quorum Sensing in Borrelia burgdorferi, the Lyme Disease Spirochete. by Stevenson B, Babb K.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128172

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Lyme Arthritis Resolution with Antiserum to a 37-Kilodalton Borrelia burgdorferi Protein. by Feng S, Hodzic E, Barthold SW.; 2000 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101718

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Lyme Borreliosis in Rhesus Macaques: Effects of Corticosteroids on Spirochetal Load and Isotype Switching of Anti-Borrelia burgdorferi Antibody. by Pachner AR, Amemiya K, Bartlett M, Schaefer H, Reddy K, Zhang WF.; 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96041

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Lyme disease and current aspects of immunization. by Kamradt T.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128914

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Lyme Disease Borrelia Species in Northeastern China Resemble Those Isolated from Far Eastern Russia and Japan. by Li M, Masuzawa T, Takada N, Ishiguro F, Fujita H, Iwaki A, Wang H, Wang J, Kawabata M, Yanagihara Y.; 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=106449

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Lyme Disease Borrelia spp. in Ticks and Rodents from Northwestern China. by Takada N, Masuzawa T, Ishiguro F, Fujita H, Kudeken M, Mitani H, Fukunaga M, Tsuchiya K, Yano Y, Ma XH.; 2001 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=93285

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Lyme Disease in Taiwan: First Human Patient with Characteristic Erythema Chronicum Migrans Skin Lesion. by Shih CM, Wang JC, Chao LL, Wu TN.; 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104630

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Lyme Disease: A Growing Threat to Urban Populations. by Steere AC.; 1994 Mar 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43375

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Lyme Disease-Causing Borrelia Species Encode Multiple Lipoproteins Homologous to Peptide-Binding Proteins of ABC-Type Transporters. by Kornacki JA, Oliver DB.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108494

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Macrophages and enriched populations of T lymphocytes interact synergistically for the induction of severe, destructive Lyme arthritis. by DuChateau BK, Jensen JR, England DM, Callister SM, Lovrich SD, Schell RF.; 1997 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=175398

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Macrophages exposed to Borrelia burgdorferi induce Lyme arthritis in hamsters. by Du Chateau BK, England DM, Callister SM, Lim LC, Lovrich SD, Schell RF.; 1996 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=174108

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Modulation of Murine Lyme Borreliosis by Interruption of the B7/CD28 T-Cell Costimulatory Pathway. by Shanafelt MC, Kang I, Barthold SW, Bockenstedt LK.; 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107886

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Molecular characterization of a 35-kilodalton protein of Borrelia burgdorferi, an antigen of diagnostic importance in early Lyme disease. by Gilmore RD Jr, Kappel KJ, Johnson BJ.; 1997 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229516

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Molecular polymorphism of the lyme disease agent Borrelia garinii in northern Europe is influenced by a novel enzootic Borrelia focus in the North Atlantic. by Bunikis J, Olsen B, Fingerle V, Bonnedahl J, Wilske B, Bergstrom S.; 1996 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228799

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Molecular typing of Borrelia burgdorferi from Lyme disease patients by PCRrestriction fragment length polymorphism analysis. by Liveris D, Wormser GP, Nowakowski J, Nadelman R, Bittker S, Cooper D, Varde S, Moy FH, Forseter G, Pavia CS, Schwartz I.; 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229006

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Monoclonal Antibodies Specific for the Outer Surface Protein A (OspA) of Borrelia burgdorferi Prevent Lyme Borreliosis in Severe Combined Immunodeficiency (Scid) Mice. by Schaible UE, Kramer MD, Eichmann K, Modolell M, Museteanu C, Simon MM.; 1990 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=53984

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Mutation and Recombination in the Upstream Homology Box-Flanked ospE-Related Genes of the Lyme Disease Spirochetes Result in the Development of New Antigenic

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Variants during Infection. by Sung SY, McDowell JV, Carlyon JA, Marconi RT.; 2000 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97285 •

New laboratory guidelines for serologic diagnosis of Lyme disease: evaluation of the two-test protocol. by Ledue TB, Collins MF, Craig WY.; 1996 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229265

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Nitric oxide production during murine Lyme disease: lack of involvement in host resistance or pathology. by Seiler KP, Vavrin Z, Eichwald E, Hibbs JB Jr, Weis JJ.; 1995 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173547

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Occurrence of Severe Destructive Lyme Arthritis in Hamsters Vaccinated with Outer Surface Protein A and Challenged with Borrelia burgdorferi. by Croke CL, Munson EL, Lovrich SD, Christopherson JA, Remington MC, England DM, Callister SM, Schell RF.; 2000 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97189

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One-Step Reverse Transcriptase PCR Method for Detection of Borrelia burgdorferi mRNA in Mouse Lyme Arthritis Tissue Samples. by Limbach FX, Jaulhac B, Piemont Y, Kuntz JL, Monteil H, Sibilia J.; 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85022

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Oral vaccination with an attenuated Salmonella typhimurium strain expressing Borrelia burgdorferi OspA prevents murine Lyme borreliosis. by Dunne M, al-Ramadi BK, Barthold SW, Flavell RA, Fikrig E.; 1995 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173199

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OspE-Related, OspF-Related, and Elp Lipoproteins Are Immunogenic in Baboons Experimentally Infected with Borrelia burgdorferi and in Human Lyme Disease Patients. by Hefty PS, Brooks CS, Jett AM, White GL, Wikel SK, Kennedy RC, Akins DR.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139709

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P55, an immunogenic but nonprotective 55-kilodalton Borrelia burgdorferi protein in murine Lyme disease. by Feng S, Barthold SW, Telford SR 3rd, Fikrig E.; 1996 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173770

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Peptide-Based OspC Enzyme-Linked Immunosorbent Assay for Serodiagnosis of Lyme Borreliosis. by Mathiesen MJ, Christiansen M, Hansen K, Holm A, Asbrink E, Theisen M.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105224

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Phenotypic and Genetic Characterization of a Novel Borrelia burgdorferi Sensu Lato Isolate from a Patient with Lyme Borreliosis. by Wang G, van Dam AP, Dankert J.; 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85444

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Platelet-activating-factor-mediated pathogenesis in Lyme disease. by Isogai E, Kimura K, Fujii N, Nishikawa T, Ishii N, Postic D, Baranton G, Isogai H.; 1996 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173874

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Prevalence of antibodies against Borrelia species in patients with unclassified uveitis in regions in which Lyme disease is endemic and nonendemic. by Kimura K, Isogai E, Isogai H, Nishikawa T, Masuzawa T, Yoshikawa K, Kotake S, Ohno S, Fujii N.; 1995 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=170100

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Prevalence of Lyme Disease Borrelia spp. in Ticks from Migratory Birds on the Japanese Mainland. by Ishiguro F, Takada N, Masuzawa T, Fukui T.; 2000 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=91932

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Prevalence of Lyme disease spirochetes in Ixodes persulcatus and wild rodents in far eastern Russia. by Sato Y, Miyamoto K, Iwaki A, Masuzawa T, Yanagihara Y, Korenberg EI, Gorelova NB, Volkov VI, Ivanov LI, Liberova RN.; 1996 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=168201

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Quantitative Approach for the Serodiagnosis of Canine Lyme Disease by the Immunoblot Procedure. by Guerra MA, Walker ED, Kitron U.; 2000 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86982

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Rapid Typing of Borrelia burgdorferi Sensu Lato Species in Specimens from Patients with Different Manifestations of Lyme Borreliosis. by Lunemann JD, Zarmas S, Priem S, Franz J, Zschenderlein R, Aberer E, Klein R, Schouls L, Burmester GR, Krause A.; 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87886

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Reactivity with a specific epitope of outer surface protein A predicts protection from infection with the Lyme disease spirochete, Borrelia burgdorferi. by Golde WT, Piesman J, Dolan MC, Kramer M, Hauser P, Lobet Y, Capiau C, Desmons P, Voet P, Dearwester D, Frantz JC.; 1997 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=175064

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Reassessment of a Midwestern Lyme Disease Focus for Borrelia burgdorferi and the Human Granulocytic Ehrlichiosis Agent. by Jackson CA, Lovrich SD, Agger WA, Callister SM.; 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130725

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Recognition of Multiple Antibody Epitopes throughout Borrelia burgdorferi p66, a Candidate Adhesin, in Patients with Early or Late Manifestations of Lyme Disease. by Ntchobo H, Rothermel H, Chege W, Steere AC, Coburn J.; 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98111

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Recombinant Assay for Serodiagnosis of Lyme Disease Regardless of OspA Vaccination Status. by Gomes-Solecki MJ, Wormser GP, Schriefer M, Neuman G, Hannafey L, Glass JD, Dattwyler RJ.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=120112

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Recombinant BBK32 Protein in Serodiagnosis of Early and Late Lyme Borreliosis. by Heikkila T, Seppala I, Saxen H, Panelius J, Peltomaa M, Julin T, Carlsson SA, Lahdenne P.; 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140353

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Recombinant Chimeric Borrelia Proteins for Diagnosis of Lyme Disease. by GomesSolecki MJ, Dunn JJ, Luft BJ, Castillo J, Dykhuizen DE, Yang X, Glass JD, Dattwyler RJ.; 2000 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86960

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Recombinant Flagellin A Proteins from Borrelia burgdorferi Sensu Stricto, B. afzelii, and B. garinii in Serodiagnosis of Lyme Borreliosis. by Panelius J, Lahdenne P, Saxen H, Heikkila T, Seppala I.; 2001 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88480

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Recommendation to include OspA and OspB in the new immunoblotting criteria for serodiagnosis of Lyme disease. by Hilton E, Devoti J, Sood S.; 1996 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229023

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Role of Osteopontin in Murine Lyme Arthritis and Host Defense against Borrelia burgdorferi. by Potter MR, Rittling SR, Denhardt DT, Roper RJ, Weis JH, Teuscher C, Weis JJ.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127811

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Seasonal correlation of sporadic schizophrenia to Ixodes ticks and Lyme borreliosis. by Fritzsche M.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149397

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Sensitive and Specific Serodiagnosis of Lyme Disease by Enzyme-Linked Immunosorbent Assay with a Peptide Based on an Immunodominant Conserved Region of Borrelia burgdorferi VlsE. by Liang FT, Steere AC, Marques AR, Johnson BJ, Miller JN, Philipp MT.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85863

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Sensitivity and specificity of the borreliacidal-antibody test during early Lyme disease: a "gold standard"? by Callister SM, Jobe DA, Schell RF, Pavia CS, Lovrich SD.; 1996 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=170357

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Serodiagnosis of Lyme borreliosis by Borrelia burgdorferi sensu stricto, B. garinii, and B. afzelii western blots (immunoblots). by Norman GL, Antig JM, Bigaignon G, Hogrefe WR.; 1996 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229104

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Serologic Diagnosis of Lyme Borreliosis by Using Enzyme-Linked Immunosorbent Assays with Recombinant Antigens. by Magnarelli LA, Ijdo JW, Padula SJ, Flavell RA, Fikrig E.; 2000 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86574

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Serum Complement Sensitivity as a Key Factor in Lyme Disease Ecology. by Kurtenbach K, Sewell HS, Ogden NH, Randolph SE, Nuttall PA.; 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108041

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Simultaneous presence of different Borrelia burgdorferi genospecies in biological fluids of Lyme disease patients. by Demaerschalck I, Ben Messaoud A, De Kesel M, Hoyois B, Lobet Y, Hoet P, Bigaignon G, Bollen A, Godfroid E.; 1995 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=227997

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Species-Specific Plasmid Sequences for PCR Identification of the Three Species of Borrelia burgdorferi Sensu Lato Involved in Lyme Disease. by Misonne MC, Hoet PP.; 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124850

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Species-Specific Serodiagnosis of Lyme Arthritis and Neuroborreliosis Due to Borrelia burgdorferi Sensu Stricto, B. afzelii, and B. garinii by Using Decorin Binding Protein A. by Heikkila T, Seppala I, Saxen H, Panelius J, Yrjanainen H, Lahdenne P.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153353

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Strain Variation in Glycosaminoglycan Recognition Influences Cell-Type-Specific Binding by Lyme Disease Spirochetes. by Parveen N, Robbins D, Leong JM.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96523

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Structural Requirements for Glycosaminoglycan Recognition by the Lyme Disease Spirochete, Borrelia burgdorferi. by Leong JM, Robbins D, Rosenfeld L, Lahiri B, Parveen N.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108771

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Surface exposure and species specificity of an immunoreactive domain of a 66kilodalton outer membrane protein (P66) of the Borrelia spp. that cause Lyme disease. by Bunikis J, Noppa L, Ostberg Y, Barbour AG, Bergstrom S.; 1996 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=174496

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T-Cell-Independent Responses to Borrelia burgdorferi Are Critical for Protective Immunity and Resolution of Lyme Disease. by McKisic MD, Barthold SW.; 2000 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101777

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Telomere resolution in the Lyme disease spirochete. by Chaconas G, Stewart PE, Tilly K, Bono JL, Rosa P.; 2001 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150187

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Temperature-related differential expression of antigens in the Lyme disease spirochete, Borrelia burgdorferi. by Stevenson B, Schwan TG, Rosa PA.; 1995 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173648

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Temporal Changes in Outer Surface Proteins A and C of the Lyme DiseaseAssociated Spirochete, Borrelia burgdorferi, during the Chain of Infection in Ticks and Mice. by Schwan TG, Piesman J.; 2000 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88728

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Temporal Correlations between Tick Abundance and Prevalence of Ticks Infected with Borrelia burgdorferi and Increasing Incidence of Lyme Disease. by Stafford KC III, Cartter ML, Magnarelli LA, Ertel SH, Mshar PA.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104807

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Temporal study of immunoglobin M seroreactivity to Borrelia burgdorferi in patients treated for Lyme borreliosis. by Hilton E, Tramontano A, DeVoti J, Sood SK.; 1997 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229671

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The Borrelia burgdorferi 37-Kilodalton Immunoblot Band (P37) Used in Serodiagnosis of Early Lyme Disease Is the flaA Gene Product. by Gilmore RD Jr, Murphree RL, James AM, Sullivan SA, Johnson BJ.; 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84463

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The ecology of infectious disease: Effects of host diversity and community composition on Lyme disease risk. by LoGiudice K, Ostfeld RS, Schmidt KA, Keesing F.; 2003 Jan 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=141036

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The hook protein of Borrelia burgdorferi, encoded by the flgE gene, is serologically recognized in Lyme disease. by Jwang B, Dewing P, Fikrig E, Flavell RA.; 1995 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=170207

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The Immunoglobulin (IgG) Antibody Response to OspA and OspB Correlates with Severe and Prolonged Lyme Arthritis and the IgG Response to P35 Correlates with Mild and Brief Arthritis. by Akin E, McHugh GL, Flavell RA, Fikrig E, Steere AC.; 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96293

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The Relapsing Fever Spirochete Borrelia hermsii Contains Multiple, AntigenEncoding Circular Plasmids That Are Homologous to the cp32 Plasmids of Lyme Disease Spirochetes. by Stevenson B, Porcella SF, Oie KL, Fitzpatrick CA, Raffel SJ, Lubke L, Schrumpf ME, Schwan TG.; 2000 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101665

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T-helper-cell cytokines in the early evolution of murine Lyme arthritis. by Kang I, Barthold SW, Persing DH, Bockenstedt LK.; 1997 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=175438

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Therapeutic passive vaccination against chronic Lyme disease in mice. by Zhong W, Stehle T, Museteanu C, Siebers A, Gern L, Kramer M, Wallich R, Simon MM.; 1997 Nov 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25028

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Transcriptional analyses and mapping of the ospC gene in Lyme disease spirochetes. by Marconi RT, Samuels DS, Garon CF.; 1993 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=193003

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Transformation of the Lyme Disease Spirochete Borrelia burgdorferi with Heterologous DNA. by Stevenson B, Bono JL, Elias A, Tilly K, Rosa P.; 1998 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107509

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Transhemispheric exchange of Lyme disease spirochetes by seabirds. by Olsen B, Duffy DC, Jaenson TG, Gylfe A, Bonnedahl J, Bergstrom S.; 1995 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228686

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Uptake and killing of Lyme disease and relapsing fever borreliae in the perfused rat liver and by isolated Kupffer cells. by Sambri V, Aldini R, Massaria F, Montagnani M, Casanova S, Cevenini R.; 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=174005

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Use of recombinant antigens of Borrelia burgdorferi in serologic tests for diagnosis of lyme borreliosis. by Magnarelli LA, Fikrig E, Padula SJ, Anderson JF, Flavell RA.; 1996 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228775

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Use of Serum Immune Complexes in a New Test That Accurately Confirms Early Lyme Disease and Active Infection with Borrelia burgdorferi. by Brunner M, Sigal LH.; 2001 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88321

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Utilization of tests for Lyme disease antibody at a university hospital. by Nachamkin I, Riddle DL, Feldman M, Edelstein PH.; 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=170332

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Validity of Interpretation Criteria for Standardized Western Blots (Immunoblots) for Serodiagnosis of Lyme Borreliosis Based on Sera Collected throughout Europe. by Hauser U, Lehnert G, Wilske B.; 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85128

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Variable serum immunoglobulin responses against different Borrelia burgdorferi sensu lato species in a population at risk for and patients with Lyme disease. by Bunikis J, Olsen B, Westman G, Bergstroom S.; 1995 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228199

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VraA (BBI16) Protein of Borrelia burgdorferi Is a Surface-Exposed Antigen with a Repetitive Motif That Confers Partial Protection against Experimental Lyme Borreliosis. by Labandeira-Rey M, Baker EA, Skare JT.; 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98035

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

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A 58-year-old man with a diagnosis of chronic lyme disease. Author(s): Steere AC. Source: Jama : the Journal of the American Medical Association. 2002 August 28; 288(8): 1002-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12190371&dopt=Abstract

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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A climate-based model predicts the spatial distribution of the Lyme disease vector Ixodes scapularis in the United States. Author(s): Brownstein JS, Holford TR, Fish D. Source: Environmental Health Perspectives. 2003 July; 111(9): 1152-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12842766&dopt=Abstract

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A comparative study of mammalian and reptilian alternative pathway of complement-mediated killing of the Lyme disease spirochete (Borrelia burgdorferi). Author(s): Kuo MM, Lane RS, Giclas PC. Source: J Parasitol. 2000 December; 86(6): 1223-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11191895&dopt=Abstract

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A controlled study of cognitive deficits in children with chronic Lyme disease. Author(s): Tager FA, Fallon BA, Keilp J, Rissenberg M, Jones CR, Liebowitz MR. Source: The Journal of Neuropsychiatry and Clinical Neurosciences. 2001 Fall; 13(4): 500-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11748319&dopt=Abstract

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A Lyme disease case study and individualized healthcare plan. Author(s): Cavendish R. Source: J Sch Nurs. 2003 April; 19(2): 81-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12653619&dopt=Abstract

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A role for peripheral blood fibrocytes in Lyme disease? Author(s): Grab DJ, Salim M, Chesney J, Bucala R, Lanners HN. Source: Medical Hypotheses. 2002 July; 59(1): 1-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12160674&dopt=Abstract

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Ability of the borreliacidal antibody test to confirm lyme disease in clinical practice. Author(s): Callister SM, Jobe DA, Agger WA, Schell RF, Kowalski TJ, Lovrich SD, Marks JA. Source: Clinical and Diagnostic Laboratory Immunology. 2002 July; 9(4): 908-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12093694&dopt=Abstract

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ACIP issues recommendations for Lyme disease vaccine. Advisory Committee on Immunization Practices. Author(s): Morey SS. Source: American Family Physician. 1999 November 1; 60(7): 2171-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10569515&dopt=Abstract

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Acute onset of facial nerve palsy associated with Lyme disease in a 6 year-old child. Author(s): Siwula JM, Mathieu G. Source: Pediatr Dent. 2002 November-December; 24(6): 572-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12528951&dopt=Abstract

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Adhesion mechanisms of the Lyme disease spirochete, Borrelia burgdorferi. Author(s): Coburn J. Source: Current Drug Targets. Infectious Disorders. 2001 August; 1(2): 171-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12455413&dopt=Abstract

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Adverse event reports following vaccination for Lyme disease: December 1998-July 2000. Author(s): Lathrop SL, Ball R, Haber P, Mootrey GT, Braun MM, Shadomy SV, Ellenberg SS, Chen RT, Hayes EB. Source: Vaccine. 2002 February 22; 20(11-12): 1603-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11858868&dopt=Abstract

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An open-label, nonrandomized, single-center, prospective extension, clinical trial of booster dose schedules to assess the safety profile and immunogenicity of recombinant outer-surface protein A (OspA) Lyme disease vaccine. Author(s): Schoen RT, Deshefy-Longhi T, Van-Hoecke C, Buscarino C, Fikrig E. Source: Clinical Therapeutics. 2003 January; 25(1): 210-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12637121&dopt=Abstract

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An OspA-based genospecies identification of Lyme disease spirochetes (Borrelia burgdorferi) isolated in Taiwan. Author(s): Shih CM, Chao LL. Source: The American Journal of Tropical Medicine and Hygiene. 2002 May; 66(5): 611-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12201600&dopt=Abstract

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An unusual case of bilaterally symmetrical neuropathic osteoarthropathy of the midfoot as a result of lyme disease-induced peripheral neuropathy: a case report. Author(s): Adams HB, Blasko GA, DiDomenico LA. Source: Foot & Ankle International / American Orthopaedic Foot and Ankle Society [and] Swiss Foot and Ankle Society. 2002 February; 23(2): 155-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11858337&dopt=Abstract

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Analysis of some peripheral blood lymphocyte subsets in relation to Borrelia burgdorferi antibodies in patients with Lyme disease. Author(s): Zajkowska JM, Hermanowska-Szpakowicz T, Wysocka J, Kondrusik M, Pancewicz SA, Grygorczuk S. Source: Rocz Akad Med Bialymst. 2000; 45: 184-98. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11712430&dopt=Abstract

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Anetoderma: another facet of Lyme disease? Author(s): Bauer J, Leitz G, Palmedo G, Hugel H. Source: Journal of the American Academy of Dermatology. 2003 May; 48(5 Suppl): S868. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12734487&dopt=Abstract

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Antibiotic prophylaxis for Lyme disease: how the way of reporting a clinical trial can alter the perception of effectiveness. Author(s): Gonzalez U. Source: Archives of Dermatology. 2003 March; 139(3): 373-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12622635&dopt=Abstract

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Arthritis following recombinant outer surface protein A vaccination for Lyme disease. Author(s): Rose CD, Fawcett PT, Gibney KM. Source: The Journal of Rheumatology. 2001 November; 28(11): 2555-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11708435&dopt=Abstract

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Artificial-infection protocols allow immunodetection of novel Borrelia burgdorferi antigens suitable as vaccine candidates against Lyme disease. Author(s): Wallich R, Jahraus O, Stehle T, Tran TT, Brenner C, Hofmann H, Gern L, Simon MM. Source: European Journal of Immunology. 2003 March; 33(3): 708-19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12616491&dopt=Abstract

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Avidity determination of Borrelia burgdorferi-specific IgG antibodies in Lyme disease. Author(s): Rauer S, Beitlich P, Neubert U, Rasiah C, Kaiser R. Source: Scandinavian Journal of Infectious Diseases. 2001; 33(11): 809-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11760158&dopt=Abstract

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Bacterial pathogenesis: a variation on variation in Lyme disease. Author(s): Koomey M. Source: Current Biology : Cb. 1997 September 1; 7(9): R538-40. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9285701&dopt=Abstract

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Bilateral follicular conjunctivitis as a manifestation of Lyme disease. Author(s): Mombaerts IM, Maudgal PC, Knockaert DC. Source: American Journal of Ophthalmology. 1991 July 15; 112(1): 96-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1882933&dopt=Abstract

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Bilateral keratitis in Lyme disease. Author(s): Kornmehl EW, Lesser RL, Jaros P, Rocco E, Steere AC. Source: Ophthalmology. 1989 August; 96(8): 1194-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2477779&dopt=Abstract

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Bilateral papilloedema with concomitant neuroretinitis in a 7-year-old girl with Lyme disease. Author(s): Lochhead J, Thompson GM. Source: Eye (London, England). 2001 December; 15(Pt 6): 799-801. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11827011&dopt=Abstract

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Bilateral sensorineural hearing loss and spastic paraparesis in Lyme disease. Author(s): Bertholon P, Damon G, Antoine J, Richard O, Aubert G, Icunnoamlak Z, Martin C. Source: Otolaryngology and Head and Neck Surgery. 2000 March; 122(3): 458-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10699828&dopt=Abstract

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Biliary complications in the treatment of unsubstantiated Lyme disease. Author(s): Ettestad PJ, Campbell GL, Welbel SF, Genese CA, Spitalny KC, Marchetti CM, Dennis DT. Source: The Journal of Infectious Diseases. 1995 February; 171(2): 356-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7844372&dopt=Abstract

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Binding of human plasminogen and urokinase-type plasminogen activator to the Lyme disease spirochete, Borrelia burgdorferi. Author(s): Klempner MS, Noring R, Epstein MP, McCloud B, Hu R, Limentani SA, Rogers RA. Source: The Journal of Infectious Diseases. 1995 May; 171(5): 1258-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7751701&dopt=Abstract

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Biological and social determinants of the Lyme disease problem. Author(s): Barbour AG. Source: Infect Agents Dis. 1992 February; 1(1): 50-61. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1365529&dopt=Abstract

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Biopsy-confirmed CNS Lyme disease: MR appearance at 1.5 T. Author(s): Rafto SE, Milton WJ, Galetta SL, Grossman RI. Source: Ajnr. American Journal of Neuroradiology. 1990 May; 11(3): 482-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2112311&dopt=Abstract

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Bloodstream invasion in early Lyme disease: results from a prospective, controlled, blinded study using the polymerase chain reaction. Author(s): Goodman JL, Bradley JF, Ross AE, Goellner P, Lagus A, Vitale B, Berger BW, Luger S, Johnson RC. Source: The American Journal of Medicine. 1995 July; 99(1): 6-12. Erratum In: http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7598144&dopt=Abstract

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Bone marrow manifestation of Lyme disease (Lyme Borreliosis). Author(s): Kvasnicka HM, Thiele J, Ahmadi T. Source: British Journal of Haematology. 2003 March; 120(5): 723. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12614200&dopt=Abstract

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Bone scan abnormalities in a child with Lyme disease. Author(s): De Nef JJ, van der Vis-Melsen M. Source: Clinical Nuclear Medicine. 1990 October; 15(10): 727-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2225679&dopt=Abstract

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Borrelia burgdorferi B31 Erp proteins that are dominant immunoblot antigens of animals infected with isolate B31 are recognized by only a subset of human lyme disease patient sera. Author(s): Miller JC, El-Hage N, Babb K, Stevenson B. Source: Journal of Clinical Microbiology. 2000 April; 38(4): 1569-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10747145&dopt=Abstract

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Borrelia burgdorferi DNA in the urine of treated patients with chronic Lyme disease symptoms. A PCR study of 97 cases. Author(s): Bayer ME, Zhang L, Bayer MH. Source: Infection. 1996 September-October; 24(5): 347-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8923044&dopt=Abstract

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Borrelia burgdorferi reactivity in patients with severe persistent fatigue who are from a region in which Lyme disease is endemic. Author(s): Coyle PK, Krupp LB, Doscher C, Amin K. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 1994 January; 18 Suppl 1: S24-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8148448&dopt=Abstract

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Borrelia burgdorferi: a protagonist in Lyme disease, a bystander in morphoea? Author(s): Hercogova J. Source: Journal of the European Academy of Dermatology and Venereology : Jeadv. 2002 March; 16(2): 98-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12046842&dopt=Abstract

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Borrelia burgdorferi-specific immune complexes in acute Lyme disease. Author(s): Schutzer SE, Coyle PK, Reid P, Holland B. Source: Jama : the Journal of the American Medical Association. 1999 November 24; 282(20): 1942-6. Erratum In: Jama 2000 October 25; 284(16): 2059. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10580460&dopt=Abstract

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Borrelia seropositive with no symptoms of Lyme disease. Author(s): Lutwick LI. Source: Lancet. 1994 June 4; 343(8910): 1442. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7910925&dopt=Abstract

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Borreliacidal activity of early Lyme disease sera against complement-resistant Borrelia afzelii FEM1 wild-type and an OspC-lacking FEM1 variant. Author(s): Kraiczy P, Hunfeld KP, Peters S, Wurzner R, Ackert G, Wilske B, Brade V. Source: Journal of Medical Microbiology. 2000 October; 49(10): 917-28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11023189&dopt=Abstract

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Branch retinal artery occlusion associated with Lyme disease. Author(s): Lightman DA, Brod RD. Source: Archives of Ophthalmology. 1991 September; 109(9): 1198-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1929948&dopt=Abstract

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Cardiac conduction disturbances in Lyme disease. Author(s): Swinnen J, Moerenhout C, Cools FJ. Source: Acta Cardiol. 2003 June; 58(3): 211-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12846512&dopt=Abstract

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Cardiac manifestations of Lyme disease. Author(s): Pinto DS. Source: The Medical Clinics of North America. 2002 March; 86(2): 285-96. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11982302&dopt=Abstract

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Case 1: enlarging lesion on right inner thigh. Diagnosis: erythema chronicum migrans caused by Lyme disease. Author(s): Karim A, Robson A, Calonje E. Source: Clinical and Experimental Dermatology. 2003 May; 28(3): 335-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12780734&dopt=Abstract

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Case and discussion of Lyme disease. Author(s): Montiel NJ, Li CY, Zaw KM, Sinha AA. Source: J Drugs Dermatol. 2003 August; 2(4): 415-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12884467&dopt=Abstract

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Central nervous system Lyme disease. Author(s): Nachman SA, Pontrelli L. Source: Seminars in Pediatric Infectious Diseases. 2003 April; 14(2): 123-30. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12881800&dopt=Abstract

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Cerebellar ataxia as the presenting manifestation of Lyme disease. Author(s): Arav-Boger R, Crawford T, Steere AC, Halsey NA. Source: The Pediatric Infectious Disease Journal. 2002 April; 21(4): 353-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12075773&dopt=Abstract

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Cerebral metabolic changes associated with Lyme disease. Author(s): Newberg A, Hassan A, Alavi A. Source: Nuclear Medicine Communications. 2002 August; 23(8): 773-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12124483&dopt=Abstract

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Changes in temporal and spatial patterns of outer surface lipoprotein expression generate population heterogeneity and antigenic diversity in the Lyme disease spirochete, Borrelia burgdorferi. Author(s): Hefty PS, Jolliff SE, Caimano MJ, Wikel SK, Akins DR. Source: Infection and Immunity. 2002 July; 70(7): 3468-78. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12065486&dopt=Abstract

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Characterization of the vls antigenic variation loci of the Lyme disease spirochaetes Borrelia garinii Ip90 and Borrelia afzelii ACAI. Author(s): Wang D, Botkin DJ, Norris SJ. Source: Molecular Microbiology. 2003 March; 47(5): 1407-17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12603744&dopt=Abstract

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Chemotactic migration of the Lyme disease spirochete (Borrelia burgdorferi) to salivary gland extracts of vector ticks. Author(s): Shih CM, Chao LL, Yu CP. Source: The American Journal of Tropical Medicine and Hygiene. 2002 May; 66(5): 61621. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12201601&dopt=Abstract

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Chronic Lyme disease: it's not all in our heads. Author(s): Morgenstern RG. Source: Environmental Health Perspectives. 2003 February; 111(2): A77; Author Reply A77. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12573918&dopt=Abstract

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Chronic lyme disease: psychogenic fantasy or somatic infection? Author(s): Mervine P. Source: Environmental Health Perspectives. 2003 February; 111(2): A76; Author Reply A77. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12573917&dopt=Abstract

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Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans. Author(s): Smith RP, Schoen RT, Rahn DW, Sikand VK, Nowakowski J, Parenti DL, Holman MS, Persing DH, Steere AC. Source: Annals of Internal Medicine. 2002 March 19; 136(6): 421-8. Summary for Patients In: http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11900494&dopt=Abstract

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Coinfection in patients with lyme disease: how big a risk? Author(s): Stricker RB, Gaito A, Harris NS, Burrascano JJ. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 November 1; 37(9): 1277-8; Author Reply 1278-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14557980&dopt=Abstract

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Comparative study of cefuroxime axetil versus amoxicillin in children with early Lyme disease. Author(s): Eppes SC, Childs JA. Source: Pediatrics. 2002 June; 109(6): 1173-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12042561&dopt=Abstract

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Complement inhibitor factor H binding to Lyme disease spirochetes is mediated by inducible expression of multiple plasmid-encoded outer surface protein E paralogs. Author(s): Alitalo A, Meri T, Lankinen H, Seppala I, Lahdenne P, Hefty PS, Akins D, Meri S. Source: Journal of Immunology (Baltimore, Md. : 1950). 2002 October 1; 169(7): 3847-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12244181&dopt=Abstract

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Comprehensive analysis of the factor h binding capabilities of borrelia species associated with lyme disease: delineation of two distinct classes of factor h binding proteins. Author(s): McDowell JV, Wolfgang J, Tran E, Metts MS, Hamilton D, Marconi RT. Source: Infection and Immunity. 2003 June; 71(6): 3597-602. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12761145&dopt=Abstract

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Contributions of societal and geographical environments to “chronic Lyme disease”: the psychopathogenesis and aporology of a new “medically unexplained symptoms” syndrome. Author(s): Sigal LH, Hassett AL. Source: Environmental Health Perspectives. 2002 August; 110 Suppl 4: 607-11. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12194894&dopt=Abstract

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Cost-effectiveness analysis of the Lyme disease vaccine. Author(s): Hsia EC, Chung JB, Schwartz JS, Albert DA. Source: Arthritis and Rheumatism. 2002 June; 46(6): 1651-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12115198&dopt=Abstract

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Current and novel therapies for Lyme disease. Author(s): Pavia CS. Source: Expert Opinion on Investigational Drugs. 2003 June; 12(6): 1003-16. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12783604&dopt=Abstract

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Death from inappropriate therapy for Lyme disease. Author(s): Patel R, Grogg KL, Edwards WD, Wright AJ, Schwenk NM. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2000 October; 31(4): 1107-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11049799&dopt=Abstract

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Decorin-binding proteins A and B confer distinct mammalian cell type-specific attachment by Borrelia burgdorferi, the Lyme disease spirochete. Author(s): Fischer JR, Parveen N, Magoun L, Leong JM. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 June 10; 100(12): 7307-12. Epub 2003 May 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12773620&dopt=Abstract

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Decreased CD57 lymphocyte subset in patients with chronic Lyme disease. Author(s): Stricker RB, Winger EE. Source: Immunology Letters. 2001 February 1; 76(1): 43-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11222912&dopt=Abstract

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Detection of Borrelia burgdorferi-specific antigen in antibody-negative cerebrospinal fluid in neurologic Lyme disease. Author(s): Coyle PK, Schutzer SE, Deng Z, Krupp LB, Belman AL, Benach JL, Luft BJ. Source: Neurology. 1995 November; 45(11): 2010-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7501150&dopt=Abstract

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Detection of multiple reactive protein species by immunoblotting after recombinant outer surface protein A lyme disease vaccination. Author(s): Molloy PJ, Berardi VP, Persing DH, Sigal LH. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2000 July; 31(1): 42-7. Epub 2000 July 17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10913394&dopt=Abstract

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Development and laboratory evaluation of a new recombinant ELISA for the serodiagnosis of Lyme disease. Author(s): Hunfeld KP, Ernst M, Zachary P, Jaulhac B, Sonneborn HH, Brade V. Source: Wiener Klinische Wochenschrift. 2002 July 31; 114(13-14): 580-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12422605&dopt=Abstract

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Diagnosing Lyme disease. Patients have to learn to help themselves. Author(s): Mervine P. Source: Bmj (Clinical Research Ed.). 2000 January 8; 320(7227): 121. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10671055&dopt=Abstract

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Diagnosing Lyme disease. Support group is needed in the United Kingdom. Author(s): Wright P. Source: Bmj (Clinical Research Ed.). 2000 January 8; 320(7227): 121. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10625277&dopt=Abstract

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Diagnosis of Lyme disease. Author(s): Sigal LH. Source: Jama : the Journal of the American Medical Association. 1995 November 8; 274(18): 1427-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7474186&dopt=Abstract

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Diagnosis, treatment, and prevention of Lyme disease in children. Author(s): Eppes SC. Source: Paediatric Drugs. 2003; 5(6): 363-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12765486&dopt=Abstract

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Diaphragmatic paralysis due to Lyme disease. Author(s): Faul JL, Ruoss S, Doyle RL, Kao PN. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1999 March; 13(3): 700-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10232450&dopt=Abstract

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Differences are voiced by two Lyme camps at a Connecticut public hearing on insurance coverage of Lyme disease. Author(s): Feder HM Jr. Source: Pediatrics. 2000 April; 105(4 Pt 1): 855-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10742331&dopt=Abstract

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Differential binding of host complement inhibitor factor H by Borrelia burgdorferi Erp surface proteins: a possible mechanism underlying the expansive host range of Lyme disease spirochetes. Author(s): Stevenson B, El-Hage N, Hines MA, Miller JC, Babb K. Source: Infection and Immunity. 2002 February; 70(2): 491-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11796574&dopt=Abstract

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Disease-specific diagnosis of coinfecting tickborne zoonoses: babesiosis, human granulocytic ehrlichiosis, and Lyme disease. Author(s): Krause PJ, McKay K, Thompson CA, Sikand VK, Lentz R, Lepore T, Closter L, Christianson D, Telford SR, Persing D, Radolf JD, Spielman A; Deer-Associated Infection Study Group. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 May 1; 34(9): 1184-91. Epub 2002 April 04. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11941544&dopt=Abstract

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Diversionary role of hoofed game in the transmission of Lyme disease spirochetes. Author(s): Matuschka FR, Heiler M, Eiffert H, Fischer P, Lotter H, Spielman A. Source: The American Journal of Tropical Medicine and Hygiene. 1993 May; 48(5): 693-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8517488&dopt=Abstract

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DNA microarray analysis of differential gene expression in Borrelia burgdorferi, the Lyme disease spirochete. Author(s): Revel AT, Talaat AM, Norgard MV. Source: Proceedings of the National Academy of Sciences of the United States of America. 2002 February 5; 99(3): 1562-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11830671&dopt=Abstract

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DNA vaccines expressing a fusion product of outer surface proteins A and C from Borrelia burgdorferi induce protective antibodies suitable for prophylaxis but Not for resolution of Lyme disease. Author(s): Wallich R, Siebers A, Jahraus O, Brenner C, Stehle T, Simon MM. Source: Infection and Immunity. 2001 April; 69(4): 2130-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11254567&dopt=Abstract

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Does process-specific slowing account for cognitive deficits in Lyme disease? Author(s): Pollina DA, Elkins LE, Squires NK, Scheffer SR, Krupp LB. Source: Applied Neuropsychology. 1999; 6(1): 27-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10382568&dopt=Abstract

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Duration of antibiotic therapy for early Lyme disease. A randomized, double-blind, placebo-controlled trial. Author(s): Wormser GP, Ramanathan R, Nowakowski J, McKenna D, Holmgren D, Visintainer P, Dornbush R, Singh B, Nadelman RB. Source: Annals of Internal Medicine. 2003 May 6; 138(9): 697-704. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12729423&dopt=Abstract

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Duration of antibiotic therapy for Lyme disease. Author(s): Steere AC. Source: Annals of Internal Medicine. 2003 May 6; 138(9): 761-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12729432&dopt=Abstract

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Ear, nose and throat manifestations of Lyme disease. Author(s): Lesser TH, Dort JC, Simmen DP. Source: The Journal of Laryngology and Otology. 1990 April; 104(4): 301-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2370450&dopt=Abstract

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Early and early disseminated phases of Lyme disease in the rhesus monkey: a model for infection in humans. Author(s): Philipp MT, Aydintug MK, Bohm RP Jr, Cogswell FB, Dennis VA, Lanners HN, Lowrie RC Jr, Roberts ED, Conway MD, Karacorlu M, et al. Source: Infection and Immunity. 1993 July; 61(7): 3047-59. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8514412&dopt=Abstract

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Early OspA immune complex formation in animal models of Lyme disease. Author(s): Schutzer SE, Luan J. Source: Journal of Molecular Microbiology and Biotechnology. 2003; 5(3): 167-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12766346&dopt=Abstract

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Effective retrieval of Lyme disease information on the Web. Author(s): Sood SK. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 August 15; 35(4): 451-64. Epub 2002 July 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12145731&dopt=Abstract

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Effects of climate on variability in Lyme disease incidence in the northeastern United States. Author(s): Subak S. Source: American Journal of Epidemiology. 2003 March 15; 157(6): 531-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12631543&dopt=Abstract

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Effects of OspA vaccination on Lyme disease serologic testing. Author(s): Aguero-Rosenfeld ME, Roberge J, Carbonaro CA, Nowakowski J, Nadelman RB, Wormser GP. Source: Journal of Clinical Microbiology. 1999 November; 37(11): 3718-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10523583&dopt=Abstract

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Efficacy of clarithromycin for treatment of experimental Lyme disease in vivo. Author(s): Alder J, Mitten M, Jarvis K, Gupta P, Clement J. Source: Antimicrobial Agents and Chemotherapy. 1993 June; 37(6): 1329-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8328782&dopt=Abstract

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Epizootiology of Lyme disease-causing borreliae. Author(s): Anderson JF, Magnarelli LA. Source: Clinics in Dermatology. 1993 July-September; 11(3): 339-51. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8221515&dopt=Abstract

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Erythema chronica migrans (ECM). Ticks and Lyme disease in Missouri. Author(s): Swinfard RW, Anderson PC. Source: Mo Med. 1999 May; 96(5): 159-61. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10333681&dopt=Abstract

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Erythema chronica migrans, ticks and Lyme disease in Missouri. Author(s): Donnell HD Jr. Source: Mo Med. 1999 October; 96(10): 476. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10528494&dopt=Abstract

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Erythema migrans. Rash as key to early diagnosis of Lyme disease. Author(s): Masters EJ. Source: Postgraduate Medicine. 1993 July; 94(1): 133-4, 137-42. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8321768&dopt=Abstract

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Establishment of enzyme-linked immunosorbent assay using purified recombinant 83-kilodalton antigen of Borrelia burgdorferi sensu stricto and Borrelia afzelii for serodiagnosis of Lyme disease. Author(s): Rauer S, Kayser M, Neubert U, Rasiah C, Vogt A. Source: Journal of Clinical Microbiology. 1995 October; 33(10): 2596-600. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8567889&dopt=Abstract

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Evaluation of a two-test serodiagnostic method for community assessment of Lyme disease in an endemic area. Author(s): Trevejo RT, Krause PJ, Schriefer ME, Dennis DT. Source: The American Journal of Tropical Medicine and Hygiene. 2001 November; 65(5): 563-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11716115&dopt=Abstract

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Evaluation of study patients with Lyme disease, 10-20-year follow-up. Author(s): Kalish RA, Kaplan RF, Taylor E, Jones-Woodward L, Workman K, Steere AC. Source: The Journal of Infectious Diseases. 2001 February 1; 183(3): 453-60. Epub 2000 December 27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11133377&dopt=Abstract

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Evaluation of two-test serodiagnostic method for early Lyme disease in clinical practice. Author(s): Trevejo RT, Krause PJ, Sikand VK, Schriefer ME, Ryan R, Lepore T, Porter W, Dennis DT. Source: The Journal of Infectious Diseases. 1999 April; 179(4): 931-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10068589&dopt=Abstract

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Evidence that the variable regions of the central domain of VlsE are antigenic during infection with lyme disease spirochetes. Author(s): McDowell JV, Sung SY, Hu LT, Marconi RT. Source: Infection and Immunity. 2002 August; 70(8): 4196-203. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12117928&dopt=Abstract

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Evidence-based diagnosis of Lyme disease. Author(s): Davidson MM, Ling CL, Chisholm SM, Wiseman AD, Joss AW, Ho-Yen DO. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 1999 July; 18(7): 484-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10482025&dopt=Abstract

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Exploratory study on natural focus and its causative agent of genotype of Lyme disease by polymerase chain reaction in the forest areas of Beijing. Author(s): Li J, Cao W, Zhang X, Wu X, Zhang P, Zhao Q, Yang H, Dong Z, Cai S. Source: Zhonghua Liu Xing Bing Xue Za Zhi. 2002 June; 23(3): 209-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12411092&dopt=Abstract

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Exploring the causes of cutaneous B-cell lymphoma: we should learn from the Lyme disease experience. Author(s): Naldi L, Minelli C. Source: Dermatology (Basel, Switzerland). 2000; 201(4): 353-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11146350&dopt=Abstract

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Expression of the CD2 activation epitope T11-3 (CD2R) on T cells in rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, and Lyme disease: phenotypic and functional analysis. Author(s): Potocnik AJ, Menninger H, Yang SY, Pirner K, Krause A, Burmester GR, Broker BM, Hept P, Weseloh G, Michels H, et al. Source: Scandinavian Journal of Immunology. 1991 September; 34(3): 351-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1715605&dopt=Abstract

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Facial nerve palsy associated with lyme disease. Author(s): Halperin JJ. Source: Muscle & Nerve. 2003 October; 28(4): 516-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14506728&dopt=Abstract

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Facial nerve palsy in Lyme disease: evaluation of clinical diagnostic criteria. Author(s): Smouha EE, Coyle PK, Shukri S. Source: The American Journal of Otology. 1997 March; 18(2): 257-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9093686&dopt=Abstract

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Facial palsy in Lyme disease. Author(s): Eggenberger ER. Source: The New England Journal of Medicine. 1993 May 27; 328(21): 1571. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8479507&dopt=Abstract

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Facial palsy in Lyme disease. Author(s): Sood SK. Source: Archives of Pediatrics & Adolescent Medicine. 1998 September; 152(9): 928-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9743044&dopt=Abstract

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Facial palsy with elevated protein in otherwise normal CSF in a child with Lyme disease. Author(s): Heininger U, Ries M, Harms D, Brade V. Source: Infection. 1991 July-August; 19(4): 245-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1917037&dopt=Abstract

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Facilitation of complement-dependent killing of the Lyme disease spirochete, Borrelia burgdorferi, by specific immunoglobulin G Fab antibody fragments. Author(s): Kochi SK, Johnson RC, Dalmasso AP. Source: Infection and Immunity. 1993 June; 61(6): 2532-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8500889&dopt=Abstract

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Failure of treatment with cephalexin for Lyme disease. Author(s): Nowakowski J, McKenna D, Nadelman RB, Cooper D, Bittker S, Holmgren D, Pavia C, Johnson RC, Wormser GP. Source: Archives of Family Medicine. 2000 June; 9(6): 563-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10862221&dopt=Abstract

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Fall and rise of Lyme disease and other Ixodes tick-borne infections in North America and Europe. Author(s): Barbour AG. Source: British Medical Bulletin. 1998; 54(3): 647-58. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10326291&dopt=Abstract

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False-positive Lyme disease serology in human granulocytic ehrlichiosis. Author(s): Wormser GP, Horowitz HW, Dumler JS, Schwartz I, Aguero-Rosenfeld M. Source: Lancet. 1996 April 6; 347(9006): 981-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8598802&dopt=Abstract

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False-positive results of PCR testing for Lyme disease. Author(s): Molloy PJ, Persing DH, Berardi VP. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2001 August 1; 33(3): 412-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11438915&dopt=Abstract

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False-positive serological tests for Lyme disease in facial palsy and varicella zoster meningo-encephalitis. Author(s): Woelfle J, Wilske B, Haverkamp F, Bialek R. Source: European Journal of Pediatrics. 1998 November; 157(11): 953-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9835449&dopt=Abstract

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Field ecology of Lyme disease in Kansas. Author(s): Mock DE, Brillhart DB, Upton SJ. Source: Kans Med. 1992 September; 93(9): 246-9. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1447862&dopt=Abstract

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First human vaccine for Lyme disease. Author(s): Ramani A. Source: Mayo Clinic Proceedings. 1999 August; 74(8): 846-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10473370&dopt=Abstract

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First isolation of Lyme disease spirochete, Borrelia burgdorferi from blacklegged tick, Ixodes scapularis, collected at Rondeau Provincial Park, Ontario. Author(s): Morshed MG, Scott JD, Banerjee SN, Fernando K, Mann R, Isaac-Renton J. Source: Can Commun Dis Rep. 2000 March 15; 26(6): 42-4. English, French. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10763556&dopt=Abstract

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First isolation of Lyme disease spirochete, Borrelia burgdorferi, from blacklegged tick, Ixodes scapularis, removed from a bird in nova Scotia, Canada. Author(s): Morshed MG, Scott JD, Banerjee SN, Banerjee M, Fitzgerald T, Fernando K, Mann R, Isaac-Renton J. Source: Can Commun Dis Rep. 1999 September 15; 25(18): 153-5. English, French. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10726372&dopt=Abstract

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FlaA, a putative flagellar outer sheath protein, is not an immunodominant antigen associated with Lyme disease. Author(s): Ge Y, Charon NW. Source: Infection and Immunity. 1997 July; 65(7): 2992-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9199479&dopt=Abstract

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FLAIR and magnetization transfer imaging of patients with post-treatment Lyme disease syndrome. Author(s): Morgen K, Martin R, Stone RD, Grafman J, Kadom N, McFarland HF, Marques A. Source: Neurology. 2001 December 11; 57(11): 1980-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11739813&dopt=Abstract

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Frightening dreams and spells: a case of ventricular asystole from Lyme disease. Author(s): Weissman K, Jagminas L, Shapiro MJ. Source: European Journal of Emergency Medicine : Official Journal of the European Society for Emergency Medicine. 1999 December; 6(4): 397-401. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10646930&dopt=Abstract

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Functional brain imaging and neuropsychological testing in Lyme disease. Author(s): Fallon BA, Das S, Plutchok JJ, Tager F, Liegner K, Van Heertum R. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 1997 July; 25 Suppl 1: S57-63. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9233666&dopt=Abstract

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Fundus autofluorescence in APMPPE in association with lyme disease. Author(s): Framme C, Sachs HG, Gabler B, Roider J. Source: Retina (Philadelphia, Pa.). 2002 October; 22(5): 653-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12441738&dopt=Abstract

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Gamma interferon is not required for arthritis resistance in the murine Lyme disease model. Author(s): Glickstein L, Edelstein M, Dong JZ. Source: Infection and Immunity. 2001 June; 69(6): 3737-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11349038&dopt=Abstract

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Genetic analysis of the outer surface protein C gene of Lyme disease spirochaetes (Borrelia burgdorferi sensu lato) isolated from rodents in Taiwan. Author(s): Shih CM, Chao LL. Source: Journal of Medical Microbiology. 2002 April; 51(4): 318-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11926737&dopt=Abstract

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Genetic diversity of Borrelia burgdorferi in lyme disease patients as determined by culture versus direct PCR with clinical specimens. Author(s): Liveris D, Varde S, Iyer R, Koenig S, Bittker S, Cooper D, McKenna D, Nowakowski J, Nadelman RB, Wormser GP, Schwartz I. Source: Journal of Clinical Microbiology. 1999 March; 37(3): 565-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9986813&dopt=Abstract

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Genospecies identification and characterization of Lyme disease spirochetes of genospecies Borrelia burgdorferi sensu lato isolated from rodents in Taiwan. Author(s): Shih CM, Chang HM, Chen SL, Chao LL. Source: Journal of Clinical Microbiology. 1998 November; 36(11): 3127-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9774551&dopt=Abstract

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Geographic clustering of an outer surface protein A mutant of Borrelia burgdorferi. Possible implications of multiple variants for Lyme disease persistence. Author(s): Malawista SE, Montgomery RR, Wang XM, Fu LL, Giles SS. Source: Rheumatology (Oxford, England). 2000 May; 39(5): 537-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10852986&dopt=Abstract

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Geographic risk for lyme disease and human granulocytic ehrlichiosis in southern New York state. Author(s): Daniels TJ, Boccia TM, Varde S, Marcus J, Le J, Bucher DJ, Falco RC, Schwartz I. Source: Applied and Environmental Microbiology. 1998 December; 64(12): 4663-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9835546&dopt=Abstract

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Gonarthritis in the course of Lyme disease in a one-and-a-half-year-old child. Author(s): Zajadacz B, Juszkiewicz A. Source: Wiad Lek. 2002; 55(3-4): 243-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12182012&dopt=Abstract

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Granulocytic Ehrlichiae in Ixodes persulcatus ticks from an area in China where Lyme disease is endemic. Author(s): Cao WC, Zhao QM, Zhang PH, Dumler JS, Zhang XT, Fang LQ, Yang H. Source: Journal of Clinical Microbiology. 2000 November; 38(11): 4208-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11060091&dopt=Abstract

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Guarded endorsement for Lyme disease vaccine. Author(s): Marwick C. Source: Jama : the Journal of the American Medical Association. 1998 June 24; 279(24): 1937-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9643844&dopt=Abstract

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Guidelines for the clinical diagnosis of Lyme disease. Author(s): Blaauw AA, van der Linden S. Source: Annals of Internal Medicine. 1998 September 1; 129(5): 423. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9735075&dopt=Abstract

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Guidelines for the clinical diagnosis of Lyme disease. Author(s): McCaulley ME. Source: Annals of Internal Medicine. 1998 September 1; 129(5): 422-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9735074&dopt=Abstract

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Guidelines for the clinical diagnosis of Lyme disease. Author(s): Liegner KB, Kochevar J. Source: Annals of Internal Medicine. 1998 September 1; 129(5): 422; Author Reply 423. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9735073&dopt=Abstract

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H9724, a monoclonal antibody to Borrelia burgdorferi's flagellin, binds to heat shock protein 60 (HSP60) within live neuroblastoma cells: a potential role for HSP60 in peptide hormone signaling and in an autoimmune pathogenesis of the neuropathy of Lyme disease. Author(s): Sigal LH, Williams S, Soltys B, Gupta R. Source: Cellular and Molecular Neurobiology. 2001 October; 21(5): 477-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11860186&dopt=Abstract

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Headache characteristics in hospitalized patients with Lyme disease. Author(s): Scelsa SN, Lipton RB, Sander H, Herskovitz S. Source: Headache. 1995 March; 35(3): 125-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7721571&dopt=Abstract

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Health-care reform and Lyme disease. Author(s): Reske SD. Source: Journal of the National Medical Association. 1994 August; 86(8): 567, 579. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7932832&dopt=Abstract

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Hepatitis associated with Lyme disease. Author(s): Sinusas K, Kazakoff MA, Macchia C. Source: The Journal of the American Board of Family Practice / American Board of Family Practice. 1992 November-December; 5(6): 635-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1462798&dopt=Abstract

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Histopathology of clinical phases of human Lyme disease. Author(s): Duray PH. Source: Rheumatic Diseases Clinics of North America. 1989 November; 15(4): 691-710. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2685926&dopt=Abstract

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HLA and Lyme disease. Author(s): Dostal C. Source: Scand J Rheumatol Suppl. 1990; 87: 149-50. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2259886&dopt=Abstract

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Holmes-Adie syndrome and Lyme disease. Author(s): Stricker RB, Winger EE. Source: Lancet. 2001 March 10; 357(9258): 805. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11254002&dopt=Abstract

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Host-pathogen interactions in the immunopathogenesis of Lyme disease. Author(s): Hu LT, Klempner MS. Source: Journal of Clinical Immunology. 1997 September; 17(5): 354-65. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9327334&dopt=Abstract

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How can i avoid lyme disease? What to say to the patient who asks. Author(s): Hamilton DR. Source: Postgraduate Medicine. 1990 May 1; 87(6): 167-8, 173-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2336417&dopt=Abstract

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How can we prevent Lyme disease? Author(s): Hayes EB, Piesman J. Source: The New England Journal of Medicine. 2003 June 12; 348(24): 2424-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12802029&dopt=Abstract

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How to diagnose and treat Lyme disease in children. Author(s): Scott JD. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 1993 January 15; 148(2): 132. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8489576&dopt=Abstract

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How to diagnose and treat Lyme disease in children. Author(s): Kindree D. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 1993 January 15; 148(2): 132. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8420648&dopt=Abstract

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Humoral immune response to outer surface protein C of Borrelia burgdorferi in Lyme disease: role of the immunoglobulin M response in the serodiagnosis of early infection. Author(s): Fung BP, McHugh GL, Leong JM, Steere AC. Source: Infection and Immunity. 1994 August; 62(8): 3213-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8039891&dopt=Abstract

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Hypothyroidism with concurrent Lyme disease. Author(s): Paparone PW. Source: J Am Osteopath Assoc. 1995 July; 95(7): 435-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7642407&dopt=Abstract

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Identification of an IL-2 binding protein in the saliva of the Lyme disease vector tick, Ixodes scapularis. Author(s): Gillespie RD, Dolan MC, Piesman J, Titus RG. Source: Journal of Immunology (Baltimore, Md. : 1950). 2001 April 1; 166(7): 4319-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11254684&dopt=Abstract

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Identification of candidate T-cell epitopes and molecular mimics in chronic Lyme disease. Author(s): Hemmer B, Gran B, Zhao Y, Marques A, Pascal J, Tzou A, Kondo T, Cortese I, Bielekova B, Straus SE, McFarland HF, Houghten R, Simon R, Pinilla C, Martin R. Source: Nature Medicine. 1999 December; 5(12): 1375-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10581079&dopt=Abstract

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Identifying diagnostic peptides for lyme disease through epitope discovery. Author(s): Kouzmitcheva GA, Petrenko VA, Smith GP. Source: Clinical and Diagnostic Laboratory Immunology. 2001 January; 8(1): 150-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11139210&dopt=Abstract

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IDSA issues guidelines on the treatment of Lyme disease. Infectious Diseases Society of America. Author(s): Preboth M. Source: American Family Physician. 2001 May 15; 63(10): 2065, 2067. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11388720&dopt=Abstract

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Immune complexes from serum of patients with lyme disease contain Borrelia burgdorferi antigen and antigen-specific antibodies: potential use for improved testing. Author(s): Brunner M, Sigal LH. Source: The Journal of Infectious Diseases. 2000 August; 182(2): 534-9. Epub 2000 July 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10915085&dopt=Abstract

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Immunohistochemical analysis of Lyme disease in the skin of naive and infectionimmune rabbits following challenge. Author(s): Chong-Cerrillo C, Shang ES, Blanco DR, Lovett MA, Miller JN. Source: Infection and Immunity. 2001 June; 69(6): 4094-102. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11349081&dopt=Abstract

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Improving the specificity of recombinant immunoassays for lyme disease. Author(s): Porwancher R. Source: Journal of Clinical Microbiology. 2003 June; 41(6): 2791. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791934&dopt=Abstract

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Incidence patterns of lyme disease and cutaneous B-cell non-Hodgkin's lymphoma in the United States. Author(s): Munksgaard L, Frisch M, Melbye M, Hjalgrim H. Source: Dermatology (Basel, Switzerland). 2000; 201(4): 351-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11146349&dopt=Abstract

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Index of suspicion. Case 4. Diagnosis: Lyme disease. Author(s): Gimino V, Kamat D. Source: Pediatrics in Review / American Academy of Pediatrics. 2001 January; 22(1): 2231. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11229325&dopt=Abstract

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Induced maternal response to the Lyme disease spirochaete Borrelia burgdorferi sensu lato in a colonial seabird, the kittiwake Rissa tridactyla. Author(s): Gasparini J, McCoy KD, Haussy C, Tveraa T, Boulinier T. Source: Proceedings of the Royal Society of London. Series B. Biological Sciences. 2001 March 22; 268(1467): 647-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11297183&dopt=Abstract

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Infection with multiple strains of Borrelia burgdorferi sensu stricto in patients with Lyme disease. Author(s): Seinost G, Golde WT, Berger BW, Dunn JJ, Qiu D, Dunkin DS, Dykhuizen DE, Luft BJ, Dattwyler RJ. Source: Archives of Dermatology. 1999 November; 135(11): 1329-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10566830&dopt=Abstract

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Inflammatory cytokine production predominates in early Lyme disease in patients with erythema migrans. Author(s): Glickstein L, Moore B, Bledsoe T, Damle N, Sikand V, Steere AC. Source: Infection and Immunity. 2003 October; 71(10): 6051-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14500528&dopt=Abstract

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Into the woods. New weapons against Lyme disease. Author(s): Peters S. Source: Adv Nurse Pract. 1999 October; 7(10): 53-4, 82. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10808773&dopt=Abstract

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Intralaboratory reliability of serologic and urine testing for Lyme disease. Author(s): Stephens BG, Harris NS. Source: The American Journal of Medicine. 2001 October 15; 111(6): 502-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11690582&dopt=Abstract

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Intralaboratory reliability of serologic and urine testing for Lyme disease. Author(s): Klempner MS, Schmid CH, Hu L, Steere AC, Johnson G, McCloud B, Noring R, Weinstein A. Source: The American Journal of Medicine. 2001 February 15; 110(3): 217-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11182109&dopt=Abstract

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In-vitro and in-vivo antibiotic susceptibilities of Lyme disease Borrelia isolated in China. Author(s): Li M, Masuzawa T, Wang J, Kawabata M, Yanagihara Y. Source: Journal of Infection and Chemotherapy : Official Journal of the Japan Society of Chemotherapy. 2000 March; 6(1): 65-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11810535&dopt=Abstract

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Is anthrax the next Lyme disease? Author(s): Rocca PV. Source: Del Med J. 2001 December; 73(12): 483-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11771484&dopt=Abstract

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Is it thee or me?--autoimmunity in Lyme disease. Author(s): Klempner MS, Huber BT. Source: Nature Medicine. 1999 December; 5(12): 1346-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10581067&dopt=Abstract

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Isolated neuritis of the sciatic nerve in a case of Lyme disease. Author(s): Avanzi S, Messa G, Marbini A, Pavesi G, Granella F. Source: Italian Journal of Neurological Sciences. 1998 April; 19(2): 81-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10935841&dopt=Abstract

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Isolation and morphological characterization of mosquito spirochetes from a Lyme disease endemic area. Author(s): Sanogo YO, Reipert S, Halouzka J, Hubalek Z, Nemec M. Source: Annals of the New York Academy of Sciences. 2000; 916: 672-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11193698&dopt=Abstract

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Joint manifestations of Lyme disease in Spain. Author(s): Guerrero A, Quereda C, Corres J, Escudero R, Marti Belda P, Serrano M. Source: British Journal of Rheumatology. 1991 February; 30(1): 71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1991226&dopt=Abstract

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Keeping Lyme disease at bay. An integrated approach to prevention. Author(s): Wade CF. Source: The American Journal of Nursing. 2000 July; 100(7): 26-31; Quiz 32. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10914066&dopt=Abstract

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Language, logic, and Lyme disease. Author(s): Melski JW. Source: Archives of Dermatology. 1999 November; 135(11): 1398-400. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10566841&dopt=Abstract

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Longitudinal evaluation of an educational intervention for preventing tick bites in an area with endemic lyme disease in Baltimore County, Maryland. Author(s): Malouin R, Winch P, Leontsini E, Glass G, Simon D, Hayes EB, Schwartz BS. Source: American Journal of Epidemiology. 2003 June 1; 157(11): 1039-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12777368&dopt=Abstract

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Long-term follow-up of patients with culture-confirmed Lyme disease. Author(s): Nowakowski J, Nadelman RB, Sell R, McKenna D, Cavaliere LF, Holmgren D, Gaidici A, Wormser GP. Source: The American Journal of Medicine. 2003 August 1; 115(2): 91-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12893393&dopt=Abstract

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Long-term neuropsychologic and health outcomes of children with facial nerve palsy attributable to Lyme disease. Author(s): Vazquez M, Sparrow SS, Shapiro ED. Source: Pediatrics. 2003 August; 112(2): E93-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12897313&dopt=Abstract

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Lyme disease (Lyme borreliosis). Author(s): Franz JK, Krause A. Source: Best Practice & Research. Clinical Rheumatology. 2003 April; 17(2): 241-64. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12787524&dopt=Abstract

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Lyme disease and the heart. Author(s): Haddad FA, Nadelman RB. Source: Frontiers in Bioscience : a Journal and Virtual Library. 2003 September 1; 8: S76982. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957829&dopt=Abstract

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Lyme disease and the peripheral nervous system. Author(s): Halperin JJ. Source: Muscle & Nerve. 2003 August; 28(2): 133-43. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12872317&dopt=Abstract

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Lyme disease complicated with pseudotumor cerebri. Author(s): Nord JA, Karter D. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 July 15; 37(2): E25-6. Epub 2003 Jul 09. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12856231&dopt=Abstract

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Lyme disease controversy: use and misuse of language. Author(s): Liegner KB. Source: Annals of Internal Medicine. 2002 November 5; 137(9): 775-7; Author Reply 7757. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12416968&dopt=Abstract

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Lyme disease controversy: use and misuse of language. Author(s): Stricker RB. Source: Annals of Internal Medicine. 2002 November 5; 137(9): 775-7; Author Reply 7757. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12416967&dopt=Abstract

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Lyme disease in children. Author(s): Belani K, Regelmann WE. Source: Rheumatic Diseases Clinics of North America. 1989 November; 15(4): 679-90. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2685925&dopt=Abstract

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Lyme disease in children. An overview. Author(s): Rudd-Arieta MP. Source: Adv Nurse Pract. 2003 June; 11(6): 77-8. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12807061&dopt=Abstract

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Lyme disease presenting as an influenza-like illness. Author(s): Porwancher R. Source: The American Journal of Medicine. 2003 July; 115(1): 73; Author Reply 73-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12867242&dopt=Abstract

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Lyme disease trends--Dutchess County, New York, 1992-2000. Author(s): Chow CC, Evans AS Jr, Noonan-Toly CM, White D, Johnson GS, Marks SJ, Caldwell MC, Hayes EB. Source: The Mount Sinai Journal of Medicine, New York. 2003 May; 70(3): 207-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12764540&dopt=Abstract

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Lyme disease without erythema migrans: cause for concern? Author(s): Stricker RB, Phillips SE. Source: The American Journal of Medicine. 2003 July; 115(1): 72-3; Author Reply 73-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12867241&dopt=Abstract

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Lyme disease: devastation by deer tick. Author(s): Jossi KL. Source: Nurs Spectr (Wash D C). 1998 July 13; 8(14): 9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10562146&dopt=Abstract

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Lyme disease: gold for Scotland and bronze for USA. Author(s): Davidson MM, Evans R, Ho-Yen DO. Source: Scott Med J. 2003 February; 48(1): 6-9. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12669494&dopt=Abstract

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Lyme disease: musculoskeletal manifestations. Author(s): Kolstoe J, Messner RP. Source: Rheumatic Diseases Clinics of North America. 1989 November; 15(4): 649-56. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2685923&dopt=Abstract

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Lyme disease: summary notes. Author(s): Katz AM. Source: Journal of Cutaneous Medicine and Surgery. 1999 October; 3(6): 306-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10575160&dopt=Abstract

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Lyme disease--what is the cost for Scotland? Author(s): Joss AW, Davidson MM, Ho-Yen DO, Ludbrook A. Source: Public Health. 2003 July; 117(4): 264-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12966749&dopt=Abstract

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Magnetic resonance imaging of meningoradiculomyelitis in early disseminated Lyme disease. Author(s): Tullman MJ, Delman BN, Lublin FD, Weinberger J. Source: Journal of Neuroimaging : Official Journal of the American Society of Neuroimaging. 2003 July; 13(3): 264-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12889175&dopt=Abstract

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Management of Lyme disease. Author(s): Goodwin SD, Sproat TT, Russell WL. Source: Clin Pharm. 1990 March; 9(3): 192-205. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2180624&dopt=Abstract

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Management of tick bites and early Lyme disease: a survey of Connecticut physicians. Author(s): Murray T, Feder HM Jr. Source: Pediatrics. 2001 December; 108(6): 1367-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11731662&dopt=Abstract

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Mapping Lyme disease incidence for diagnostic and preventive decisions, Maryland. Author(s): Frank C, Fix AD, Pena CA, Strickland GT. Source: Emerging Infectious Diseases. 2002 April; 8(4): 427-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11971779&dopt=Abstract

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Maternal Lyme disease and congenital heart disease: A case-control study in an endemic area. Author(s): Strobino B, Abid S, Gewitz M. Source: American Journal of Obstetrics and Gynecology. 1999 March; 180(3 Pt 1): 711-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10076152&dopt=Abstract

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Meningovascular form of neuroborreliosis: similarities between neuropathological findings in a case of Lyme disease and those occurring in tertiary neurosyphilis. Author(s): Miklossy J, Kuntzer T, Bogousslavsky J, Regli F, Janzer RC. Source: Acta Neuropathologica. 1990; 80(5): 568-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2251916&dopt=Abstract

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Mental nerve neuropathy in Lyme disease. Author(s): Maillefert JF, Dardel P, Piroth C, Tavernier C. Source: Rev Rhum Engl Ed. 1997 December; 64(12): 855. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9476279&dopt=Abstract

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Microbiologically confirmed early Lyme disease. Author(s): Masters EJ. Source: Annals of Internal Medicine. 2002 October 15; 137(8): 698; Author Reply 698. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12379074&dopt=Abstract

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Misconceptions about Lyme disease: confusions hiding behind ill-chosen terminology. Author(s): Sigal LH. Source: Annals of Internal Medicine. 2002 March 5; 136(5): 413-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11874324&dopt=Abstract

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Modulation of lymphocyte proliferative responses by a canine Lyme disease vaccine of recombinant outer surface protein A (OspA). Author(s): Chiao JW, Villalon P, Schwartz I, Wormser GP. Source: Fems Immunology and Medical Microbiology. 2000 July; 28(3): 193-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10865170&dopt=Abstract

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Molecular characterization of Lyme disease spirochetes (Borrelia burgdorferi sensu lato) isolated in Taiwan by restriction fragment length polymorphism analysis of 5S(rrf)-23S(rrl) intergenic spacer amplicons. Author(s): Chao LL, Shih CM. Source: The American Journal of Tropical Medicine and Hygiene. 2002 November; 67(5): 504-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12479552&dopt=Abstract

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Molecular diagnosis of Lyme disease: review and meta-analysis. Author(s): Dumler JS. Source: Molecular Diagnosis : a Journal Devoted to the Understanding of Human Disease Through the Clinical Application of Molecular Biology. 2001 March; 6(1): 1-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11257206&dopt=Abstract

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Molecular mimicry and antigen-specific T cell responses in multiple sclerosis and chronic CNS Lyme disease. Author(s): Martin R, Gran B, Zhao Y, Markovic-Plese S, Bielekova B, Marques A, Sung MH, Hemmer B, Simon R, McFarland HF, Pinilla C. Source: Journal of Autoimmunity. 2001 May; 16(3): 187-92. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11334482&dopt=Abstract

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Monolateral chorioretinitis with multiple foci in one case of Lyme disease. Author(s): Niutta A, Barcaroli I, Palombi E. Source: Ann Ophthalmol. 1993 July; 25(7): 257-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8363293&dopt=Abstract

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MR findings in acute Lyme disease affecting the knee. A case report. Author(s): Cavallaro A, Harrer T, Richter H, Bautz W, Fellner FA. Source: Rontgenpraxis. 2002; 54(6): 210-3. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12174443&dopt=Abstract

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MRI in Lyme disease of the spinal cord. Author(s): Mantienne C, Albucher JF, Catalaa I, Sevely A, Cognard C, Manelfe C. Source: Neuroradiology. 2001 June; 43(6): 485-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11465762&dopt=Abstract

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Multiple sclerosis vs Lyme disease: a case presentation to a discussant and a review of the literature. Author(s): Karussis D, Weiner HL, Abramsky O. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 1999 December; 5(6): 395-402. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10618695&dopt=Abstract

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Musculoskeletal and neurologic outcomes in patients with previously treated Lyme disease. Author(s): Shadick NA, Phillips CB, Sangha O, Logigian EL, Kaplan RF, Wright EA, Fossel AH, Fossel K, Berardi V, Lew RA, Liang MH. Source: Annals of Internal Medicine. 1999 December 21; 131(12): 919-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10610642&dopt=Abstract

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Musical hallucinations in patients with Lyme disease. Author(s): Stricker RB, Winger EE. Source: Southern Medical Journal. 2003 July; 96(7): 711-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12940329&dopt=Abstract

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Myths and facts about Lyme disease. Author(s): Sigal LH. Source: Cleve Clin J Med. 1997 April; 64(4): 203-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9105116&dopt=Abstract

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Nervous system manifestations of Lyme disease. Author(s): Halperin JJ. Source: Rheumatic Diseases Clinics of North America. 1989 November; 15(4): 635-47. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2555847&dopt=Abstract

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Neurologic aspects of Lyme disease. Author(s): Coyle PK, Schutzer SE. Source: The Medical Clinics of North America. 2002 March; 86(2): 261-84. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11982301&dopt=Abstract

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Neurologic manifestations in children with Lyme disease. Author(s): Bingham PM, Galetta SL, Athreya B, Sladky J. Source: Pediatrics. 1995 December; 96(6): 1053-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7491220&dopt=Abstract

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Neuropsychiatric manifestations of Lyme disease. Author(s): Paparone PW. Source: J Am Osteopath Assoc. 1998 July; 98(7): 373-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9695456&dopt=Abstract

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Neuropsychological aspects of Lyme disease. Author(s): Kaplan RF. Source: Applied Neuropsychology. 1999; 6(1): 1-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10382564&dopt=Abstract

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Neuropsychological deficits in Lyme disease patients with and without other evidence of central nervous system pathology. Author(s): Kaplan RF, Jones-Woodward L, Workman K, Steere AC, Logigian EL, Meadows ME. Source: Applied Neuropsychology. 1999; 6(1): 3-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10382565&dopt=Abstract

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Neuropsychological functioning in chronic Lyme disease. Author(s): Westervel HJ, McCaffrey RJ. Source: Neuropsychology Review. 2002 September; 12(3): 153-77. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12428915&dopt=Abstract

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Neutrophil chemotactic factors in synovial fluids of patients with Lyme disease. Author(s): Georgilis K, Noring R, Steere AC, Klempner MS. Source: Arthritis and Rheumatism. 1991 June; 34(6): 770-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2053924&dopt=Abstract

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New method for detection of Borrelia burgdorferi antigen complexed to antibody in seronegative Lyme disease. Author(s): Brunner M. Source: Journal of Immunological Methods. 2001 March 1; 249(1-2): 185-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11226475&dopt=Abstract

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New vaccine targets Lyme disease. New hope for diminishing the 'great masquerader'. Author(s): Lewis C. Source: Fda Consumer. 1999 May-June; 33(3): 12-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10443184&dopt=Abstract

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NMR identification of epitopes of Lyme disease antigen OspA to monoclonal antibodies. Author(s): Huang X, Yang X, Luft BJ, Koide S. Source: Journal of Molecular Biology. 1998 August 7; 281(1): 61-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9680475&dopt=Abstract

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Non-Lyme disease. Author(s): Bryan CS. Source: J S C Med Assoc. 1991 August; 87(8): 433-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1943031&dopt=Abstract

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Occupational risk of Lyme disease: an epidemiological review. Author(s): Piacentino JD, Schwartz BS. Source: Occupational and Environmental Medicine. 2002 February; 59(2): 75-84. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11850549&dopt=Abstract

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Optic neuropathy in children with Lyme disease. Author(s): Rothermel H, Hedges TR 3rd, Steere AC. Source: Pediatrics. 2001 August; 108(2): 477-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11483820&dopt=Abstract

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Oral concerns in Lyme disease. Author(s): Rhodus NL, Falace DA. Source: Northwest Dent. 2002 March-April; 81(2): 17-8. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11989326&dopt=Abstract

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Orbital Lyme disease: MR imaging before and after treatment: case report. Author(s): Fatterpekar GM, Gottesman RI, Sacher M, Som PM. Source: Ajnr. American Journal of Neuroradiology. 2002 April; 23(4): 657-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11950661&dopt=Abstract

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Orbital myositis with Lyme disease. Author(s): Seidenberg KB, Leib ML. Source: American Journal of Ophthalmology. 1990 January 15; 109(1): 13-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2297027&dopt=Abstract

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OspE-related, OspF-related, and Elp lipoproteins are immunogenic in baboons experimentally infected with Borrelia burgdorferi and in human lyme disease patients. Author(s): Hefty PS, Brooks CS, Jett AM, White GL, Wikel SK, Kennedy RC, Akins DR. Source: Journal of Clinical Microbiology. 2002 November; 40(11): 4256-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12409407&dopt=Abstract

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Outcomes of lyme disease. Author(s): Prybylski D. Source: Annals of Internal Medicine. 2000 November 7; 133(9): 746-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11074913&dopt=Abstract

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Overdiagnosis and overtreatment of Lyme disease in children. Author(s): Qureshi MZ, New D, Zulqarni NJ, Nachman S. Source: The Pediatric Infectious Disease Journal. 2002 January; 21(1): 12-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11791091&dopt=Abstract

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Overdiagnosis and overtreatment of Lyme disease leads to inappropriate health service use. Author(s): Sigal LH. Source: Clin Exp Rheumatol. 1999 January-February; 17(1): 41. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10084029&dopt=Abstract

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Overdiagnosis of Lyme disease. Author(s): Ferguson H. Source: Annals of Internal Medicine. 1998 November 1; 129(9): 752; Author Reply 752-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9841621&dopt=Abstract

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Patterns of Lyme disease diagnosis and treatment by family physicians in a southeastern state. Author(s): Boltri JM, Hash RB, Vogel RL. Source: Journal of Community Health. 2002 December; 27(6): 395-402. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458782&dopt=Abstract

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PCR-reverse line blot typing method underscores the genomic heterogeneity of Borrelia valaisiana species and suggests its potential involvement in Lyme disease. Author(s): Godfroid E, Min Hu C, Humair PF, Bollen A, Gern L. Source: Journal of Clinical Microbiology. 2003 August; 41(8): 3690-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12904377&dopt=Abstract

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Persistence of immunoglobulin M or immunoglobulin G antibody responses to Borrelia burgdorferi 10-20 years after active Lyme disease. Author(s): Kalish RA, McHugh G, Granquist J, Shea B, Ruthazer R, Steere AC. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2001 September 15; 33(6): 780-5. Epub 2001 August 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11512082&dopt=Abstract

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Persistence of the antibody response to the VlsE sixth invariant region (IR6) peptide of Borrelia burgdorferi after successful antibiotic treatment of Lyme disease. Author(s): Peltomaa M, McHugh G, Steere AC. Source: The Journal of Infectious Diseases. 2003 April 15; 187(8): 1178-86. Epub 2003 Apr 02. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12695996&dopt=Abstract

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Posterior scleritis associated with Borrelia burgdorferi (Lyme disease) infection. Author(s): Krist D, Wenkel H. Source: Ophthalmology. 2002 January; 109(1): 143-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11772594&dopt=Abstract

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Predicting the risk of Lyme disease: habitat suitability for Ixodes scapularis in the north central United States. Author(s): Guerra M, Walker E, Jones C, Paskewitz S, Cortinas MR, Stancil A, Beck L, Bobo M, Kitron U. Source: Emerging Infectious Diseases. 2002 March; 8(3): 289-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11927027&dopt=Abstract

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Preventing Lyme disease. Author(s): Haufs MG. Source: The New England Journal of Medicine. 2003 September 18; 349(12): 1192; Author Reply 1192. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13679541&dopt=Abstract

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Prevention of Lyme disease in Dutch children: analysis of determinants of tick inspection by parents. Author(s): de Vries H, van Dillen S. Source: Preventive Medicine. 2002 August; 35(2): 160-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12200101&dopt=Abstract

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Psychiatric presentations of non-HIV infectious diseases. Neurocysticercosis, Lyme disease, and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection. Author(s): Schneider RK, Robinson MJ, Levenson JL. Source: The Psychiatric Clinics of North America. 2002 March; 25(1): 1-16. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11912935&dopt=Abstract

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Psychological states and neuropsychological performances in chronic Lyme disease. Author(s): Elkins LE, Pollina DA, Scheffer SR, Krupp LB. Source: Applied Neuropsychology. 1999; 6(1): 19-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10382567&dopt=Abstract

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QEEG and evoked potentials in central nervous system Lyme disease. Author(s): Chabot RJ, Sigal LH. Source: Clin Electroencephalogr. 1995 July; 26(3): 137-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7554300&dopt=Abstract

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Quality of Lyme disease serology. Lessons from the German Proficiency Testing Program 1999-2001. A preliminary report. Author(s): Hunfeld KP, Stanek G, Straube E, Hagedorn HJ, Schorner C, Muhlschlegel F, Brade V. Source: Wiener Klinische Wochenschrift. 2002 July 31; 114(13-14): 591-600. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12422607&dopt=Abstract

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Quality of Lyme disease tests. Author(s): Magnarelli LA. Source: Jama : the Journal of the American Medical Association. 1989 December 22-29; 262(24): 3464-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2685385&dopt=Abstract

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Quorum sensing by the Lyme disease spirochete. Author(s): Stevenson B, von Lackum K, Wattier RL, McAlister JD, Miller JC, Babb K. Source: Microbes and Infection / Institut Pasteur. 2003 September; 5(11): 991-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12941391&dopt=Abstract

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Racial differences in reported Lyme disease incidence. Author(s): Fix AD, Pena CA, Strickland GT. Source: American Journal of Epidemiology. 2000 October 15; 152(8): 756-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11052554&dopt=Abstract

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Re: “Racial differences in reported Lyme disease incidence”. Author(s): El-Shanawany I, Liebling R, Roue K, Jeffery P, Robbe I. Source: American Journal of Epidemiology. 2001 April 1; 153(7): 718. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11282801&dopt=Abstract

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Reactogenicity and immunogenicity of a Lyme disease vaccine in children 2-5 years old. Author(s): Beran J, De Clercq N, Dieussaert I, Van Hoecke C. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2000 December; 31(6): 1504-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11096024&dopt=Abstract

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Recent advances in the diagnosis of Lyme disease. Author(s): van Dam AP. Source: Expert Rev Mol Diagn. 2001 November; 1(4): 413-27. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11901856&dopt=Abstract

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Recognition of multiple antibody epitopes throughout Borrelia burgdorferi p66, a candidate adhesin, in patients with early or late manifestations of Lyme disease. Author(s): Ntchobo H, Rothermel H, Chege W, Steere AC, Coburn J. Source: Infection and Immunity. 2001 March; 69(3): 1953-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11179382&dopt=Abstract

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Recombinant assay for serodiagnosis of Lyme disease regardless of OspA vaccination status. Author(s): Gomes-Solecki MJ, Wormser GP, Schriefer M, Neuman G, Hannafey L, Glass JD, Dattwyler RJ. Source: Journal of Clinical Microbiology. 2002 January; 40(1): 193-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11773115&dopt=Abstract

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Regional cerebral blood flow and cognitive deficits in chronic lyme disease. Author(s): Fallon BA, Keilp J, Prohovnik I, Heertum RV, Mann JJ. Source: The Journal of Neuropsychiatry and Clinical Neurosciences. 2003 Summer; 15(3): 326-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12928508&dopt=Abstract

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Risk factors for lyme disease in Chester County, Pennsylvania. Author(s): Smith G, Wileyto EP, Hopkins RB, Cherry BR, Maher JP. Source: Public Health Reports (Washington, D.C. : 1974). 2001; 116 Suppl 1: 146-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11889282&dopt=Abstract

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Risk of Lyme disease: perceptions of residents of a Lone Star tick-infested community. Author(s): Armstrong PM, Brunet LR, Spielman A, Telford SR 3rd. Source: Bulletin of the World Health Organization. 2001; 79(10): 916-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11693973&dopt=Abstract

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Role of experience and context in learning to diagnose Lyme disease. Author(s): Clin Evid. 2002 Dec;(8):721-33 Source: The Journal of Continuing Education in the Health Professions. 2002 Summer; 22(3): 131-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12603910

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Selective up-regulation of matrix metalloproteinase-9 expression in human erythema migrans skin lesions of acute lyme disease. Author(s): Zhao Z, Chang H, Trevino RP, Whren K, Bhawan J, Klempner MS. Source: The Journal of Infectious Diseases. 2003 October 15; 188(8): 1098-104. Epub 2003 Oct 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14551878&dopt=Abstract

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Sensitive and specific serodiagnosis of Lyme disease by enzyme-linked immunosorbent assay with a peptide based on an immunodominant conserved region of Borrelia burgdorferi vlsE. Author(s): Liang FT, Steere AC, Marques AR, Johnson BJ, Miller JN, Philipp MT. Source: Journal of Clinical Microbiology. 1999 December; 37(12): 3990-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10565920&dopt=Abstract

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Serodiagnosis of Lyme disease by kinetic enzyme-linked immunosorbent assay using recombinant VlsE1 or peptide antigens of Borrelia burgdorferi compared with 2tiered testing using whole-cell lysates. Author(s): Bacon RM, Biggerstaff BJ, Schriefer ME, Gilmore RD Jr, Philipp MT, Steere AC, Wormser GP, Marques AR, Johnson BJ. Source: The Journal of Infectious Diseases. 2003 April 15; 187(8): 1187-99. Epub 2003 Apr 02. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12695997&dopt=Abstract

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Simultaneous involvement of third and sixth cranial nerve in a patient with Lyme disease. Author(s): Lell M, Schmid A, Stemper B, Maihofner C, Heckmann JG, Tomandl BF. Source: Neuroradiology. 2003 February; 45(2): 85-7. Epub 2002 December 18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12592489&dopt=Abstract

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Sorting out the manifestations of Lyme disease. Author(s): Sweeney SJ. Source: Jaapa. 2002 July; 15(7): 16-8, 21-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12192829&dopt=Abstract

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Spatiotemporal variation in a Lyme disease host and vector: black-legged ticks on white-footed mice. Author(s): Goodwin BJ, Ostfeld RS, Schauber EM. Source: Vector Borne and Zoonotic Diseases (Larchmont, N.Y.). 2001 Summer; 1(2): 12938. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12653143&dopt=Abstract

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Standardised in vitro susceptibility testing of Borrelia burgdorferi against wellknown and newly developed antimicrobial agents--possible implications for new therapeutic approaches to Lyme disease. Author(s): Hunfeld KP, Kraiczy P, Kekoukh E, Schafer V, Brade V. Source: International Journal of Medical Microbiology : Ijmm. 2002 June; 291 Suppl 33: 125-37. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12141737&dopt=Abstract

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Study highlights variation in Lyme disease presentation. Author(s): Quirk M. Source: The Lancet Infectious Diseases. 2002 May; 2(5): 266. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12062987&dopt=Abstract

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Sudden deafness and Lyme disease. Author(s): Lorenzi MC, Bittar RS, Pedalini ME, Zerati F, Yoshinari NH, Bento RF. Source: The Laryngoscope. 2003 February; 113(2): 312-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12567088&dopt=Abstract

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Systemic symptoms without erythema migrans as the presenting picture of early Lyme disease. Author(s): Steere AC, Dhar A, Hernandez J, Fischer PA, Sikand VK, Schoen RT, Nowakowski J, McHugh G, Persing DH. Source: The American Journal of Medicine. 2003 January; 114(1): 58-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12543291&dopt=Abstract

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Taking a bite out of Lyme disease. Author(s): Pauldine EF. Source: Nursing. 2003 April; 33(4): 49-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12690242&dopt=Abstract

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Targeted mutation of the outer membrane protein P66 disrupts attachment of the Lyme disease agent, Borrelia burgdorferi, to integrin alphavbeta3. Author(s): Coburn J, Cugini C. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 June 10; 100(12): 7301-6. Epub 2003 May 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12748384&dopt=Abstract

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The ecology of infectious disease: effects of host diversity and community composition on Lyme disease risk. Author(s): LoGiudice K, Ostfeld RS, Schmidt KA, Keesing F. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 January 21; 100(2): 567-71. Epub 2003 Jan 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12525705&dopt=Abstract

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The pathogenesis of Lyme disease. Author(s): Garcia-Monco JC, Benach JL. Source: Rheumatic Diseases Clinics of North America. 1989 November; 15(4): 711-26. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2555848&dopt=Abstract

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The presenting manifestations of Lyme disease and the outcomes of treatment. Author(s): Steere AC, Sikand VK. Source: The New England Journal of Medicine. 2003 June 12; 348(24): 2472-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12802042&dopt=Abstract

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The structure of a pyrophosphate-dependent phosphofructokinase from the Lyme disease spirochete Borrelia burgdorferi. Author(s): Moore SA, Ronimus RS, Roberson RS, Morgan HW. Source: Structure (Cambridge, Mass. : 2001). 2002 May; 10(5): 659-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12015149&dopt=Abstract

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Toward a more complete appreciation of the clinical spectrum of Borrelia burgdorferi infection: early Lyme disease without erythema migrans. Author(s): Sigal LH. Source: The American Journal of Medicine. 2003 January; 114(1): 74-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12543295&dopt=Abstract

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Transverse myelitis secondary to coexistent Lyme disease and babesiosis. Author(s): Oleson CV, Sivalingam JJ, O'Neill BJ, Staas WE Jr. Source: J Spinal Cord Med. 2003 Summer; 26(2): 168-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12828297&dopt=Abstract

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Treatment of patients with persistent symptoms and a history of Lyme disease. Author(s): Wyler DJ. Source: The New England Journal of Medicine. 2001 November 8; 345(19): 1425. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11794182&dopt=Abstract

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Treatment of patients with persistent symptoms and a history of Lyme disease. Author(s): McCaulley ME. Source: The New England Journal of Medicine. 2001 November 8; 345(19): 1424; Author Reply 1425. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11794181&dopt=Abstract

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Underreporting of Lyme disease by Connecticut physicians, 1992. Author(s): Meek JI, Roberts CL, Smith EV Jr, Cartter ML. Source: Journal of Public Health Management and Practice : Jphmp. 1996 Fall; 2(4): 61-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10186700&dopt=Abstract

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Underreporting of Lyme disease. Author(s): Young JD. Source: The New England Journal of Medicine. 1998 May 28; 338(22): 1629. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9606127&dopt=Abstract

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Unusual presentations of neuroborreliosis (Lyme disease) in childhood. Author(s): Huisman TA, Wohlrab G, Nadal D, Boltshauser E, Martin E. Source: Journal of Computer Assisted Tomography. 1999 January-February; 23(1): 39-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10050805&dopt=Abstract

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Update on the prevention, diagnosis, and treatment of Lyme disease. Author(s): Hu LT, Klempner MS. Source: Adv Intern Med. 2001; 46: 247-75. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11270961&dopt=Abstract

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Urticarial lesions and Lyme disease. Author(s): McFadden JP, Greaves MW. Source: Journal of the American Academy of Dermatology. 1991 July; 25(1 Pt 1): 131-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1880245&dopt=Abstract

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Use of electrocochleography for assessing endolymphatic hydrops in patients with Lyme disease and Meniere's disease. Author(s): Selmani Z, Pyykko I, Ishizaki H, Ashammakhi N. Source: Acta Oto-Laryngologica. 2002 March; 122(2): 173-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11936909&dopt=Abstract

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Use of serum immune complexes in a new test that accurately confirms early Lyme disease and active infection with Borrelia burgdorferi. Author(s): Brunner M, Sigal LH. Source: Journal of Clinical Microbiology. 2001 September; 39(9): 3213-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11526153&dopt=Abstract

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Use of the C3H/He Lyme disease mouse model for the recovery of a Spanish isolate of Borrelia garinii from erythema migrans lesions. Author(s): Oteo JA, Backenson PB, del Mar Vitutia M, Garcia Monco JC, Rodriguez I, Escudero R, Anda P. Source: Research in Microbiology. 1998 January; 149(1): 39-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9766208&dopt=Abstract

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Utility of a commercial immunoblot kit (BAG-Borrelia blot) in the diagnosis of the preliminary stages of Lyme disease. Author(s): Hernandez-Novoa B, Orduna A, Bratos MA, Eiros JM, Fernandez JM, Gutierrez MP, Alonso PA, Mantecon MA, Almaraz A, Oteo JA, Rodriguez-Torres A. Source: Diagnostic Microbiology and Infectious Disease. 2003 September; 47(1): 321-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12967745&dopt=Abstract

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Utilization and cost of serologic tests for Lyme disease in Maryland. Author(s): Strickland GT, Karp AC, Mathews A, Pena CA. Source: The Journal of Infectious Diseases. 1997 September; 176(3): 819-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9291343&dopt=Abstract

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Vaccination against Lyme disease with recombinant Borrelia burgdorferi outersurface lipoprotein A with adjuvant. Lyme Disease Vaccine Study Group. Author(s): Steere AC, Sikand VK, Meurice F, Parenti DL, Fikrig E, Schoen RT, Nowakowski J, Schmid CH, Laukamp S, Buscarino C, Krause DS. Source: The New England Journal of Medicine. 1998 July 23; 339(4): 209-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9673298&dopt=Abstract

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Vaccination as a modality to prevent Lyme disease. A status report. Author(s): Wormser GP. Source: Infectious Disease Clinics of North America. 1999 March; 13(1): 135-48, Vii. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10198796&dopt=Abstract

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Vaccination for Lyme disease: cost-effectiveness versus cost and value. Author(s): Sigal LH. Source: Arthritis and Rheumatism. 2002 June; 46(6): 1439-42. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12115172&dopt=Abstract

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Vaccines for Lyme disease. Author(s): Younus F, Luft BJ. Source: Curr Clin Top Infect Dis. 2001; 21: 349-65. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11572159&dopt=Abstract

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Variable cutaneous manifestations of Lyme disease. Author(s): Paparone PW, Paparone PA. Source: N J Med. 1993 March; 90(3): 200-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8446297&dopt=Abstract

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Variable serum immunoglobulin responses against different Borrelia burgdorferi sensu lato species in a population at risk for and patients with Lyme disease. Author(s): Bunikis J, Olsen B, Westman G, Bergstroom S. Source: Journal of Clinical Microbiology. 1995 June; 33(6): 1473-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7650170&dopt=Abstract

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Vasculitic mononeuritis multiplex in patient with Lyme disease. Author(s): Tezzon F, Corradini C, Huber R, Egarter Vigl E, Simeoni J, Stanek G, Ferrari G. Source: Italian Journal of Neurological Sciences. 1991 April; 12(2): 229-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1649149&dopt=Abstract

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Vector competence of Ixodes pacificus and Dermacentor occidentalis (Acari: Ixodidae) for various isolates of Lyme disease spirochetes. Author(s): Lane RS, Brown RN, Piesman J, Peavey CA. Source: Journal of Medical Entomology. 1994 May; 31(3): 417-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8057316&dopt=Abstract

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Vector interactions and molecular adaptations of lyme disease and relapsing fever spirochetes associated with transmission by ticks. Author(s): Ann Intern Med. 2002 Mar 19;136(6):I24 Source: Emerging Infectious Diseases. 2002 February; 8(2): 115-21. Review. /entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11900513

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Vector/host relationships of the Lyme disease spirochete, Borrelia burgdorferi. Author(s): Burgdorfer W. Source: Rheumatic Diseases Clinics of North America. 1989 November; 15(4): 775-87. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2685930&dopt=Abstract

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Western blot analysis for diagnosis of Lyme disease in acute facial palsy. Author(s): Furuta Y, Kawabata H, Ohtani F, Watanabe H. Source: The Laryngoscope. 2001 April; 111(4 Pt 1): 719-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11359146&dopt=Abstract

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Western blotting in the serodiagnosis of Lyme disease. Author(s): Dressler F, Whalen JA, Reinhardt BN, Steere AC. Source: The Journal of Infectious Diseases. 1993 February; 167(2): 392-400. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8380611&dopt=Abstract

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What about the rash that signals Lyme disease? Author(s): Leonard-Smith R. Source: Rn. 1993 August; 56(8): 9-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8362194&dopt=Abstract

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What is the long-term prognosis for patients with Lyme disease? Author(s): Greenawald MH, Vaughan S. Source: The Journal of Family Practice. 2000 May; 49(5): 397, 465. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10836768&dopt=Abstract

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Who should receive the Lyme disease vaccine? Author(s): Taege AJ. Source: Cleve Clin J Med. 2000 April; 67(4): 239-40. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10780094&dopt=Abstract

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Willy Burgdorfer: Lyme disease. Author(s): Sternbach G, Dibble CL. Source: The Journal of Emergency Medicine. 1996 September-October; 14(5): 631-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8933327&dopt=Abstract

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CHAPTER 2. NUTRITION AND LYME DISEASE Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and Lyme disease.

Finding Nutrition Studies on Lyme Disease 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 “Lyme disease” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

7

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 “Lyme disease” (or a synonym): •

Adsorption and biotin-streptavidin amplification in serologic tests for diagnosis of Lyme borreliosis. Author(s): Department of Entomology, Connecticut Agricultural Experiment Station, New Haven 06504. Source: Magnarelli, L A Anderson, J F J-Clin-Microbiol. 1991 September; 29(9): 1761-4 0095-1137

•

Characterization of outer membranes isolated from Borrelia burgdorferi, the Lyme disease spirochete. Source: Radolf, J.D. Goldberg, M.S. Bourell, K. Baker, S.I. Jones, J.D. Norgard, M.V. Infect-immun. Washington, D.C., American Society for Microbiology. June 1995. volume 63 (6) page 2154-2163. 0019-9567

•

Clinical manifestations, pathogenesis, and effect of antibiotic treatment on Lyme borreliosis in dogs. Author(s): James A. Baker Institute for Animal Health, Ithaca, New York, USA. [email protected] Source: Straubinger, R K Straubinger, A F Summers, B A Jacobson, R H Erb, H N WienKlin-Wochenschr. 1998 December 23; 110(24): 874-81 0043-5325

•

Episcleritis, conjunctivitis, and keratitis as ocular manifestations of Lyme disease. Author(s): Department of Ophthalmology, University of California School of Medicine, San Francisco. Source: Flach, A J Lavoie, P E Ophthalmology. 1990 August; 97(8): 973-5 0161-6420

•

Genetic transformation of the Lyme disease agent Borrelia burgdorferi with coumarin-resistant gyrB. Author(s): Laboratory of Vectors and Pathogens, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, Montana 59840. Source: Samuels, D S Mach, K E Garon, C F J-Bacteriol. 1994 October; 176(19): 6045-9 0021-9193

•

Gestational attenuation of Lyme arthritis is mediated by progesterone and IL-4. Author(s): Department of Immunology, Mayo Foundation, Rochester, MN 55905, USA. Source: Moro, M H Bjornsson, J Marietta, E V Hofmeister, E K Germer, J J Bruinsma, E David, C S Persing, D H J-Immunol. 2001 June 15; 166(12): 7404-9 0022-1767

•

Hemagglutination and proteoglycan binding by the Lyme disease spirochete, Borrelia burgdorferi. Source: Leong, J.M. Morrissey, P.E. Ortega Barria, E. Pereira, M.E.A. Coburn, J. Infectimmun. Washington, D.C., American Society for Microbiology. March 1995. volume 63 (3) page 874-883. 0019-9567

•

How can i avoid lyme disease? What to say to the patient who asks. Author(s): Laboratory Service, Alvin C. York Medical Center, Murfreesboro 37130. Source: Hamilton, D R Postgrad-Med. 1990 May 1; 87(6): 167-8, 173-6 0032-5481

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Identification of a candidate glycosaminoglycan-binding adhesin of the Lyme disease spirochete Borrelia burgdorferi. Source: Parveen, N. Leong, J.M. Mol-microbiol. Oxford : Blackwell Scientific Publications,. March 2000. volume 35 (5) page 1220-1234. 0950-382X

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Immunoglobulin M capture assay for serologic confirmation of early Lyme disease: analysis of immune complexes with biotinylated Borrelia burgdorferi sonicate enhanced with flagellin peptide epitope. Author(s): Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, USA. Source: Brunner, M Stein, S Mitchell, P D Sigal, L H J-Clin-Microbiol. 1998 April; 36(4): 1074-80 0095-1137

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Improved immunoglobulin M serodiagnosis in Lyme borreliosis by using a mucapture enzyme-linked immunosorbent assay with biotinylated Borrelia burgdorferi flagella. Author(s): Department of Infection Immunology, Statens Seruminstitut, Copenhagen, Denmark. Source: Hansen, K Pii, K Lebech, A M J-Clin-Microbiol. 1991 January; 29(1): 166-73 00951137

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LuxS-mediated quorum sensing in Borrelia burgdorferi, the lyme disease spirochete. Author(s): Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Medicine, Lexington 40536-0298, USA. [email protected] Source: Stevenson, Brian Babb, Kelly Infect-Immun. 2002 August; 70(8): 4099-105 00199567

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Lyme disease in California: interrelationship of ixodid ticks (Acari), rodents, and Borrelia burgdorferi. Source: Lane, R.S. Loye, J.E. J-Med-Entomol. Lanham, Md. : The Entomological Society of America. Sept 1991. volume 28 (5) page 719-725. 0022-2585

•

Multiple sclerosis vs Lyme disease: a case presentation to a discussant and a review of the literature. Author(s): Department of Neurology, Hadassah-Hebrew University Hospital, Medical Center, Ein-Karem, Jerusalem, Israel. Source: Karussis, D Weiner, H L Abramsky, O Mult-Scler. 1999 December; 5(6): 395-402 1352-4585

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Nitric oxide production during murine Lyme disease: lack of involvement in host resistance or pathology. Author(s): Department of Pathology, University of Utah School of Medicine, Salt Lake City 84132, USA. Source: Seiler, K P Vavrin, Z Eichwald, E Hibbs, J B Weis, J J Infect-Immun. 1995 October; 63(10): 3886-95 0019-9567

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Ocular Lyme borreliosis. Author(s): Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine, Florida 33101. Source: Winward, K E Smith, J L Culbertson, W W Paris Hamelin, A Am-J-Ophthalmol. 1989 December 15; 108(6): 651-7 0002-9394

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Protection of dogs from Lyme disease with a vaccine containing outer surface protein (Osp) A, OspB, and the saponin adjuvant QS21. Author(s): Cambridge Biotech Corp., Worcester, Massachusetts 01605. Source: Coughlin, R T Fish, D Mather, T N Ma, J Pavia, C Bulger, P J-Infect-Dis. 1995 April; 171(4): 1049-52 0022-1899

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Saliva of the Lyme disease vector, Ixodes dammini, blocks cell activation by a nonprostaglandin E2-dependent mechanism. Author(s): Department of Tropical Public Health, Harvard School of Public Health, Boston, Massachusetts 02115. Source: Urioste, S Hall, L R Telford, S R Titus, R G J-Exp-Med. 1994 September 1; 180(3): 1077-85 0022-1007

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Shedding light on lyme disease prevention. Source: Smith Fiola, D. Arbor-Age. Van Nuys, Calif. : Gold Trade Publications. May 1990. volume 10 (5) page 36-39, 41. 0279-0106

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Surface exposure and species specificity of an immunoreactive domain of a 66kilodalton outer membrane protein (P66) of the Borrelia spp. that cause Lyme disease. Source: Bunikis, J. Noppa, L. Ostberg, Y. Barbour, A.G. Bergstrom, S. Infect-immun. Washington, D.C., American Society for Microbiology. December 1996. volume 64 (12) page 5111-5116. 0019-9567

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

Nutrition

•

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

•

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

•

WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

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CHAPTER 3. ALTERNATIVE MEDICINE AND LYME DISEASE Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to Lyme disease. 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 Lyme disease 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 “Lyme disease” (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 Lyme disease: •

A comparative study of mammalian and reptilian alternative pathway of complement-mediated killing of the Lyme disease spirochete (Borrelia burgdorferi). Author(s): Kuo MM, Lane RS, Giclas PC. Source: J Parasitol. 2000 December; 86(6): 1223-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11191895&dopt=Abstract

•

Acute deterioration of Charcot-Marie-Tooth disease IA (CMT IA) following 2 mg of vincristine chemotherapy. Author(s): Hildebrandt G, Holler E, Woenkhaus M, Quarch G, Reichle A, Schalke B, Andreesen R. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2000 June; 11(6): 743-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10942065&dopt=Abstract

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Application of desiccant and insecticidal soap treatments to control Ixodes scapularis (Acari: Ixodidae) nymphs and adults in a hyperendemic woodland site. Author(s): Patrican LA, Allan SA. Source: Journal of Medical Entomology. 1995 November; 32(6): 859-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8551510&dopt=Abstract

•

Argyria in the ED. Author(s): Newman M, Kolecki P. Source: The American Journal of Emergency Medicine. 2001 October; 19(6): 525-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11593479&dopt=Abstract

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Canine surveillance system for Lyme borreliosis in Wisconsin and northern Illinois: geographic distribution and risk factor analysis. Author(s): Guerra MA, Walker ED, Kitron U. Source: The American Journal of Tropical Medicine and Hygiene. 2001 November; 65(5): 546-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11716112&dopt=Abstract

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Complement-mediated killing of Borrelia burgdorferi by nonimmune sera from sika deer. Author(s): Nelson DR, Rooney S, Miller NJ, Mather TN. Source: J Parasitol. 2000 December; 86(6): 1232-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11191897&dopt=Abstract

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Complement-mediated serum sensitivity among spirochetes that cause Lyme disease. Author(s): van Dam AP, Oei A, Jaspars R, Fijen C, Wilske B, Spanjaard L, Dankert J. Source: Infection and Immunity. 1997 April; 65(4): 1228-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9119456&dopt=Abstract

•

Control of Ixodes scapularis (Acari: Ixodidae) with topical self-application of permethrin by white-tailed deer inhabiting NASA, Beltsville, Maryland. Author(s): Solberg VB, Miller JA, Hadfield T, Burge R, Schech JM, Pound JM. Source: J Vector Ecol. 2003 June; 28(1): 117-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12831136&dopt=Abstract

•

Coordinate synthesis and turnover of heat shock proteins in Borrelia burgdorferi: degradation of DnaK during recovery from heat shock. Author(s): Cluss RG, Goel AS, Rehm HL, Schoenecker JG, Boothby JT. Source: Infection and Immunity. 1996 May; 64(5): 1736-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8613385&dopt=Abstract

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Current understanding of Borrelia burgdorferi infection, with emphasis on its prevention in dogs. Author(s): Kazmierczak JJ, Sorhage FE. Source: J Am Vet Med Assoc. 1993 December 1; 203(11): 1524-8. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8288471&dopt=Abstract

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Delineation of Borrelia burgdorferi p66 sequences required for integrin alpha(IIb)beta(3) recognition. Author(s): Defoe G, Coburn J. Source: Infection and Immunity. 2001 May; 69(5): 3455-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11292775&dopt=Abstract

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Diagnosing Lyme disease. Patients have to learn to help themselves. Author(s): Mervine P. Source: Bmj (Clinical Research Ed.). 2000 January 8; 320(7227): 121. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10671055&dopt=Abstract

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Diagnosing Lyme disease. Support group is needed in the United Kingdom. Author(s): Wright P. Source: Bmj (Clinical Research Ed.). 2000 January 8; 320(7227): 121. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10625277&dopt=Abstract

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Diagnostic value of PCR for detection of Borrelia burgdorferi in skin biopsy and urine samples from patients with skin borreliosis. Author(s): Brettschneider S, Bruckbauer H, Klugbauer N, Hofmann H. Source: Journal of Clinical Microbiology. 1998 September; 36(9): 2658-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9705410&dopt=Abstract

•

Effectiveness of host-targeted permethrin in the control of Ixodes dammini (Acari: Ixodidae) Author(s): Stafford KC 3rd. Source: Journal of Medical Entomology. 1991 September; 28(5): 611-7. Erratum In: J Med Entomol 1992 March; 29(2): 376. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1941927&dopt=Abstract

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Efficacy of a permethrin-based acaricide to reduce the abundance of Ixodes dammini (Acari: Ixodidae). Author(s): Deblinger RD, Rimmer DW. Source: Journal of Medical Entomology. 1991 September; 28(5): 708-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1941940&dopt=Abstract

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ELISA screening for Lyme disease in children with chronic arthritis. Author(s): Hammouda NA, Hegazy IH, el-Sawy EH. Source: J Egypt Soc Parasitol. 1995 August; 25(2): 525-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7665949&dopt=Abstract

•

Evaluation of host-targeted acaricide for reducing risk of Lyme disease in southern New York state. Author(s): Daniels TJ, Fish D, Falco RC. Source: Journal of Medical Entomology. 1991 July; 28(4): 537-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1941916&dopt=Abstract

•

Evaluation of host-targeted applications of permethrin for control of Borrelia-infected Ixodes ricinus (Acari: Ixodidae). Author(s): Mejlon HA, Jaenson TG, Mather TN. Source: Medical and Veterinary Entomology. 1995 April; 9(2): 207-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7787232&dopt=Abstract

•

Evaluation of permethrin and imidacloprid for prevention of Borrelia burgdorferi transmission from blacklegged ticks (Ixodes scapularis) to Borrelia burgdorferi-free dogs. Author(s): Spencer JA, Butler JM, Stafford KC, Pough MB, Levy SA, Bledsoe DL, Blagburn BL. Source: Parasitology Research. 2003 July; 90 Suppl 3: S106-7. Epub 2003 August 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12928869&dopt=Abstract

•

Forty years of canine vaccination. Author(s): Appel MJ. Source: Adv Vet Med. 1999; 41: 309-24. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9890024&dopt=Abstract

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Gonarthritis in the course of Lyme disease in a one-and-a-half-year-old child. Author(s): Zajadacz B, Juszkiewicz A. Source: Wiad Lek. 2002; 55(3-4): 243-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12182012&dopt=Abstract

•

How can i avoid lyme disease? What to say to the patient who asks. Author(s): Hamilton DR. Source: Postgraduate Medicine. 1990 May 1; 87(6): 167-8, 173-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2336417&dopt=Abstract

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Lyme disease and babesiosis: acaricide focused on potentially infected ticks. Author(s): Mather TN, Ribeiro JM, Spielman A.

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Source: The American Journal of Tropical Medicine and Hygiene. 1987 May; 36(3): 60914. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3555140&dopt=Abstract •

Lyme disease. Author(s): Brier SR. Source: Journal of Manipulative and Physiological Therapeutics. 1990 July-August; 13(6): 337-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2394950&dopt=Abstract

•

Neonatal jaundice, animal-induced injuries and disease, and immunizations. Author(s): Gerson WT. Source: Current Opinion in Pediatrics. 1997 August; 9(4): 447-55. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9300206&dopt=Abstract

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Optimization of polymerase chain reaction for the detection of Borrelia burgdorferi in biologic specimens. Author(s): Kaufman AC, Greene CE, McGraw RA. Source: J Vet Diagn Invest. 1993 October; 5(4): 548-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8286453&dopt=Abstract

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Pet-, animal-, and vector-borne infections. Author(s): Glaser C, Lewis P, Wong S. Source: Pediatrics in Review / American Academy of Pediatrics. 2000 July; 21(7): 219-32. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10878184&dopt=Abstract

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Prevention of Lyme disease. Author(s): Couch P, Johnson CE. Source: Am J Hosp Pharm. 1992 May; 49(5): 1164-73. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1595748&dopt=Abstract

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Reversible cerebral hypoperfusion in Lyme encephalopathy. Author(s): Logigian EL, Johnson KA, Kijewski MF, Kaplan RF, Becker JA, Jones KJ, Garada BM, Holman BL, Steere AC. Source: Neurology. 1997 December; 49(6): 1661-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9409364&dopt=Abstract

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The emergence of “emerging diseases”: a lesson in holistic epidemiology. Author(s): Kilbourne ED.

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Source: The Mount Sinai Journal of Medicine, New York. 1996 May-September; 63(3-4): 159-66. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8692162&dopt=Abstract •

Third-year evaluation of host-targeted permethrin for the control of Ixodes dammini (Acari: Ixodidae) in southeastern Connecticut. Author(s): Stafford KC 3rd. Source: Journal of Medical Entomology. 1992 July; 29(4): 717-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1495085&dopt=Abstract

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Tick toxicant. Author(s): Stanislow E. Source: Lancet. 1997 July 26; 350(9073): 294. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9242826&dopt=Abstract

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Treatment of clothing with a permethrin spray for personal protection against the western black-legged tick, Ixodes pacificus (Acari: Ixodidae). Author(s): Lane RS. Source: Experimental & Applied Acarology. 1989 May; 6(4): 343-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2743839&dopt=Abstract

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Underground medicine. A quest for state-of-the-art treatments is turning thousands of ordinary Americans into activists--and sometimes outlaws. Author(s): Lord M, Arrarte A, Dean J, Boram J. Source: U.S. News & World Report. 1992 May 11; 112(18): 62-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10170976&dopt=Abstract

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What's new in paediatric dermatology. Author(s): Rasmussen JE. Source: The Australasian Journal of Dermatology. 1984 August; 25(2): 45-53. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6397187&dopt=Abstract

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/

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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats

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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

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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/

The following is a specific Web list relating to Lyme disease; 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 Arthritis Source: Integrative Medicine Communications; www.drkoop.com Bell's Palsy Source: Integrative Medicine Communications; www.drkoop.com Breathing Difficulty Source: Integrative Medicine Communications; www.drkoop.com Carpal Tunnel Syndrome Source: Integrative Medicine Communications; www.drkoop.com Fatigue Source: Integrative Medicine Communications; www.drkoop.com Fever Source: Integrative Medicine Communications; www.drkoop.com Headache Source: Integrative Medicine Communications; www.drkoop.com Lightheadedness Source: Integrative Medicine Communications; www.drkoop.com Lyme Disease Source: Integrative Medicine Communications; www.drkoop.com Meningitis Source: Integrative Medicine Communications; www.drkoop.com

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Motor Disturbances Source: Integrative Medicine Communications; www.drkoop.com Numbness Source: Integrative Medicine Communications; www.drkoop.com Palpitations Source: Integrative Medicine Communications; www.drkoop.com Rash Source: Integrative Medicine Communications; www.drkoop.com Syncope Source: Integrative Medicine Communications; www.drkoop.com Uveitis Source: Integrative Medicine Communications; www.drkoop.com

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 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 LYME DISEASE Overview In this chapter, we will give you a bibliography on recent dissertations relating to Lyme disease. 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 “Lyme disease” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on Lyme disease, we have not necessarily excluded nonmedical dissertations in this bibliography.

Dissertations on Lyme Disease 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 Lyme disease. 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: •

A National Survey of Risk Perceptions and Practices to Prevent Tick-Borne Lyme Disease and Mosquito-Borne Viral Encephalitis by Herrington, James Edward, Jr.; PhD from Colorado State University, 2002, 256 pages http://wwwlib.umi.com/dissertations/fullcit/3063993

•

Attention in Children with Lyme Disease As Compared to Those with ADHD by Leonardi, Dana; PhD from Yeshiva University, 2001, 73 pages http://wwwlib.umi.com/dissertations/fullcit/3022685

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Implementation and Evaluation of a Longitudinal, Randomized Educational Intervention to Increase Use of Protective Behaviors against Tick Bites in an Area of Endemic Lyme Disease in Baltimore County, Maryland by Malouin, Rebecca Anne; PhD from The Johns Hopkins University, 2002, 225 pages http://wwwlib.umi.com/dissertations/fullcit/3046503

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The Interactions of Experience, Implicit Knowledge and Reflection in Learning to Diagnose Lyme Disease by Bakken, Lori Lynn Schiller, PhD from The University of Wisconsin - Madison, 1998, 228 pages http://wwwlib.umi.com/dissertations/fullcit/9839370

•

The Role of Matrix Metalloproteinases and the Toll Receptor in Lyme Disease Pathogenesis by Gebbia, Joseph A.; PhD from State University of New York at Stony Brook, 2002, 151 pages http://wwwlib.umi.com/dissertations/fullcit/3067608

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. CLINICAL TRIALS AND LYME DISEASE Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning Lyme disease.

Recent Trials on Lyme Disease The following is a list of recent trials dedicated to Lyme disease.8 Further information on a trial is available at the Web site indicated. •

Brain Imaging and Retreatment Study of Persistent Lyme Disease Condition(s): Lyme Disease; Lyme Neuroborreliosis Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS) Purpose - Excerpt: The purpose of this study is to determine whether patients with persistent memory problems after Lyme disease benefit from an additional longer course of IV antibiotic therapy; to use modern brain imaging technology to determine whether the problem in the central nervous system is primarily one of poor blood flow or one of impaired nerve cell functioning; and to try to identify biological markers prior to treatment that will identify patients who are more or less likely to respond to the study treatment. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00037479

8

These are listed at www.ClinicalTrials.gov.

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•

Evaluation of Characteristics

Lyme

Disease:

Clinical,

Microbiological

and

Immunological

Condition(s): Chronic Disease; Healthy; Lyme Arthritis; Lyme Disease; Multiple Sclerosis Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: This study will determine whether patients who have been infected with the Lyme bacteria, Borrelia burgdorferi, and treated with antibiotics still have the bacteria alive inside them and whether it is causing their symptoms. The information from this study may serve as a basis for developing stringent diagnostic criteria for Lyme disease and the establishment of future treatment trials. Individuals in the following categories may be eligible for this study: chronic Lyme disease; chronic Lyme arthritis; seropositive control (are infected with the bacteria that causes Lyme disease but do not have disease symptoms); recovered control (have been sick with Lyme disease but were treated successfully and are currently well); control with multiple sclerosis (patients with multiple sclerosis); and healthy volunteers. Patients in the chronic Lyme disease category must be between 13 and 65 years of age; all others must be between 18 and 65 years of age. Candidates will be screened with blood and urine tests. Participants will have a physical examination and the following tests: Blood tests Includes HLA-typing, a genetic test of immune system markers; Leukapheresis Collection of large numbers of white blood cells Whole blood is collected through a needle in an arm vein. The blood circulates through a machine that separates it into its components. The white cells are removed and the rest of the blood is returned to the body, either through the same needle used to draw the blood or through another needle in the other arm. (Alternatively, patients will 100 cc (about 7 tablespoons) of blood drawn.); Lumbar puncture (spinal tap) - Collection of cerebrospinal fluid (CSF, fluid that bathes the brain and spinal cord). A local anesthetic is administered and a needle is inserted in the space between the bones in the lower back where the cerebrospinal fluid circulates below the spinal cord. A small amount of fluid is collected through the needle; Magnetic resonance imaging (MRI) of the brain - Imaging of the brain using a strong magnetic field and radio waves instead of X-rays. During the scan, the patient lies on a table in a narrow cylinder containing a magnetic field. He or she can speak with a staff member via an intercom at all times during the procedure; Neuropsychologic testing; Some participants may also have a hearing test and urine collection. Participants whose test results are positive for Borrelia burgdorferi will be followed at NIH at intervals of 3 to 6 months until it is determined whether there is infection. Those who are infected will be offered treatment with the antibiotic ceftriaxone. Following treatment, patients will return to the NIH Clinical Center for follow-up visits 1 week after treatment and again at 3, 6 and 12 months. The lumbar puncture, hearing examination, blood and urine tests will be repeated at these visits to evaluate the response to treatment, and the leukapheresis will be repeated for research purposes. Patients whose MRI was abnormal during therapy will have a repeat MRI at the 3-month, 6-month and 1-year visits. All participants with chronic Lyme disease, chronic Lyme arthritis, seropositive controls and recovered controls may be reevaluated at intervals of 6 to 12 months. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001539

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Evaluation, Treatment, and Follow-up of Patients with Lyme Disease Condition(s): Lyme Disease Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: This study is designed to establish a population of patients with Lyme disease for evaluation, treatment and follow-up to learn more about the infection. Patients with active Lyme disease may be eligible for this study. Participants will have a medical history and physical examination and diagnostic evaluations as appropriate to their individual condition. Laboratory tests may include routing blood and urine tests, X-rays, or other imaging studies, body fluid or tissue cultures, skin biopsy and tests for allergic or immune responses. Treatment will include only medications approved by the Food and Drug Administration, given according to accepted dose schedules and ways of taking the medicines. All diagnostic tests and treatments will be according to standard medical practice for the disease. No experimental procedures will be offered under this protocol. Patients will be followed as needed for evaluation and treatment of their condition. In general, they will be asked to return at the end of therapy, then 3, 6 and 12 months later, and then every 6 to 12 months. More frequent visits may be required or less frequent visits may be allowed, depending on the individual's condition. Participants may be asked to undergo the following additional procedures for research purposes: - Extra blood draws to study Lyme disease and other inflammatory conditions. Blood will be drawn from arm veins. The total amount drawn during any 6week period will not exceed 450 cc (30 tablespoons) for adults and 7 cc (1/2 tablespoon) per kilogram (2.2 pounds) of body weight for children under 18 years of age. Leukapheresis to collect large numbers of white blood cells. Whole blood is collected through a needle in an arm vein, similar to donating blood. The blood circulates through a machine that separates it into its components, and the white cells are removed. The rest of the blood is returned to the body through the same needle. Only adults 18 years of age and older will be asked to undergo leukapheresis. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00028080

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Bacterial expression vectors containing DNA encoding secretion signals of lipoproteins Inventor(s): Stover; Charles K. (Silver Spring, MD) Assignee(s): MedImmune, Inc. (Gaithersburg, MD) Patent Number: 5,583,038 Date filed: November 17, 1992 Abstract: An expression vector for expressing a protein or polypeptide in a bacterium, which comprises a first DNA sequence encoding at least a secretion signal of a lipoprotein, and a second DNA sequence encoding a protein or fragment thereof, or polypeptide or peptide heterologous to the bacterium which expresses the protein or fragment thereof, or polypeptide or peptide. The bacterium expresses a fusion protein a lipoprotein or lipoprotein segment and the protein or fragment thereof, or polypeptide or peptide heterologous to the bacterium which expresses the protein or fragment thereof, or polypeptide or peptide. Such expression vectors increase the immunogenicity of the protein or fragment thereof, or polypeptide or peptide by enabling the protein or fragment thereof, or polypeptide or peptide to be expressed on the surface of the bacterium. Bacteria which may be transformed with the expression vector include mycobacteria such as BCG. The expression vectors of the present invention may be employed in the formation of live bacterial vaccines against Lyme disease wherein the bacteria express a surface protein of Borrelia burgdorferi, the causative agent of Lyme disease. Excerpt(s): This invention relates to expression vectors for expressing a protein in a bacterium, such as for example, a mycobacterium. More particularly, this invention relates to expression vectors for expressing and secreting proteins which are heterologous to the bacterium which expresses such proteins wherein such vectors further include DNA encoding at least the secretion signals of lipoproteins designed to achieve lipid acylation and surface expression of heterologous proteins. Certain mycobacteria represent major pathogens of man and animals. For example, tuberculosis is generally caused in humans by Mycobacterium tuberculosis, and in cattle by Mycrobacterium bovis, which may also be transmitted to humans and other animals. Mycobacteria leprae is the causative agent of leprosy. M. tuberculosis and mycobacteria of the avium-intracellulare-scrofulaceum group (MAIS group) represent major opportunistic pathogens of patients with acquired immune deficiency syndrome (AIDS). M. pseudotuberculosis is a major pathogen of cattle. On the other hand, Bacille Calmette-Guerin, or BCG, an avirulent strain of M. bovis, is widely used in human vaccines, and in particular is used as a live vaccine, which is protective against tuberculosis. BCG is the only childhood vaccine which is currently given at birth, has a very low incidence of adverse effects, and can be used repeatedly in an individual. (eg., in multiple forms). In addition, BCG and other mycobacteria (eg., M. smegmatis), employed in vaccines, have adjuvant properties among the best currently known and, therefore, stimulate a recipient's immune system to respond to antigens with great effectiveness. Web site: http://www.delphion.com/details?pn=US05583038__

Patents 143

•

Borrelia burgdorferi antigens and uses thereof Inventor(s): Hunt; Jeffrey C. (Lindenhurst, IL), Pilot-Matias; Tami J. (Libertyville, IL), Robinson; John M. (Gurnee, IL) Assignee(s): Abbott Laboratories (Abbott Park, IL) Patent Number: 5,643,733 Date filed: July 10, 1995 Abstract: This invention relates generally to an assay for Lyme disease which detects the antibody to Borrelia burgdorferi, the causative agent of Lyme disease. More specifically, the assay employs antigens derived from amino acid regions in the flagellum of Borrelia burgdorferi. These antigens are immunoreactive with antibodies to Borrelia burgdorferi but are not substantially immunoreactive with antibodies to Treponema pallidum, the syphilis causing agent. DNA sequences of the antigens, clones and vectors containing the DNA sequences are also disclosed. Polypeptides derived therefrom can be used as reagents for the detection of antibody to Borrelia burgdorferi in the body fluids from individuals with Lyme disease. Excerpt(s): Lyme disease is a multisystem illness caused by the tick-transmitted spirochete Borrelia burgdorferi (hereinafter referred to as "B. burgdorferi") (Burgdorfer, et al. 1982. Science 216:1317-1319; Steere, et al. 1983. N Engl J Med 308:733-740). Lyme borreliosis is the most common arthropod-borne infection in the United States and has been reported in many countries throughout Asia and Europe (Steere 1989. N Engl J Med 1:586-596). The early feature of the disease is a local infection of the skin, which may be followed by the development of systemic disease involving the nervous system, heart and joints (Steere 1989. N Engl J Med 1:586-596). Culture of the spirochete from human body fluids and antigen detection methods often are falsely negative in the diagnosis of Lyme disease (Steere, et al. 1983. N Engl J Med 308:733-740; Benach, et al. 1983 N Engl J Med 308:740-742), leaving serological methods for antibodies to B. burgdorferi as the most appropriate currently available means for diagnosis. Most current diagnostic assays for Lyme disease utilize whole or sonicated B. burgdorferi cells as the test antigen, although many investigators have demonstrated improved performance of these tests when subcellular fractions of the spirochete were used (Grodzicki, et al. 1988. J Infect Dis 157:790-797; Magnareli, et al. 1989. J Infect Dis 159:4349; Karlsson, et al. 1990. Eur J Clin Microbiol Infect Dis 9:169-177). The flagellar protein is an immunodominant protein that generally elicits the earliest immune response after infection (Craft, et al. 1986. Clin Invest 78:934-939; Dattwyler, et al. 1989. Rev Infect Dis 11:1494-1498). Flagellin-enriched fractions of B. burgdorferi have been shown to improve the performance of Lyme diagnostic assays (Hansen, et al. 1988. J Clin Microbiol 26:338-346). The specificity of these assays, however, may be reduced because of cross-reactivity of B. burgdorferi flagellum with the flagella of other spirochetes, most notably with Treponema pallidum (hereinafter referred to as "T. pallidum"), the causative agent of syphilis (Magnarelli, et al. 1987. J Infect Dis 156:183-188). Current Lyme disease immunoassays utilize solubilized B. burgdorferi as the source of antigen, leading to false positive reactions from individuals with certain conditions, including syphilis, leptospirosis and other spirochetal infections. The lack of specificity is due to the fact that these organisms express similar antigens, especially the highly conserved flagellin protein. Thus, most Lyme disease immunoassays suffer from false positive reactions when syphilis positive patients are analyzed. Many institutions determine syphilis serologic status on all Lyme positive patients; if they are positive for syphilis they are considered to be negative for Lyme disease. This cross-reactivity with syphilis patients can be reduced by adsorption of the patient sera with the Reiter strain of

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Treponema (Magnarelli, et al. 1990. J Clin Microbiol 28:1276-1279), but this decreases the sensitivity of Lyme-diagnostic assays. Web site: http://www.delphion.com/details?pn=US05643733__ •

Borrelia burgdorferi outer membrane proteins Inventor(s): Blanco; David R. (Calabassas, CA), Champion; Cheryl I. (Los Angeles, CA), Foley; Denise M. (Orange, CA), Kagan; Bruce L. (Pacific Palisades, CA), Lovett; Michael A. (Los Angeles, CA), Miller; James N. (Northridge, CA), Mirzabekov; Tajib A. (Newton, MA), Shang; Ellen S. (Calabasas, CA), Skare; Jonathan T. (College Station, TX), Tempst; Paul (New York, NY) Assignee(s): The Regents of the University of California (Oakland, CA) Patent Number: 6,153,194 Date filed: October 29, 1998 Abstract: The present invention presents three B. burgdorferi membrane proteins: Oms28, Oms45, and Oms66, each of about 28, 45, and 66 kDa respectively; and with average single channel conductances of about 0.6, 0.22, and 9.7 nS, respectively. Also disclosed are the methods for purifying these proteins from B. burgdorferi, methods for producing antibodies to these proteins, and the resulting antibodies. These proteins and their immunogenic fragments, and antibodies capable of binding to them are useful for inducing an immune response to pathogenic B. burgdorferi as well as providing a diagnostic target for Lyme disease. Further disclosed are the nucleotide and amino acid sequences, the cloning of the genes encoding the proteins and their recombinant proteins, and methods for obtaining the foregoing. Other B. burgdorferi outer membrane spanning proteins (Oms) obtainable by the isolation and purification methods of the present invention. Excerpt(s): This invention relates generally to membrane proteins and specifically to Borrelia burgdorferi membrane proteins, particularly outer membrane-spanning porin proteins, which are used to induce a protective immune response in animals. Such proteins can be used immunologically as vaccines for Lyme disease caused by this organism. Alternatively, diagnosis of Lyme disease can be performed by detecting the presence of the proteins, antibodies to the proteins, or polynucleotides which encode or can be translated into the proteins. Lyme disease is a tick-borne infection with worldwide distribution caused by Borrelia burgdorferi sensu lato. Borrelia burgdorferi sensu stricto (hereinafter referred to as "B. burgdorferi") initially causes a flu-like systemic illness that, if untreated, may develop into a disease characterized by arthritic, cardiac and neurological involvement {Steere, A. C., N. Eng. J. Med., 321:586-596 (1989)}. Although the clinical manifestations of Lyme disease have been well documented, basic knowledge relating the pathogenesis of Lyme borreliosis to specific molecular components, specifically outer membrane (OM) proteins, has been lacking due primarily to the lability of the OM of B. burgdorferi {Luft, B. J., Infect. & Immun., 57:3637-3645 (1989)}. Since OM proteins presumably mediate the host/pathogen interaction, identification and characterization of these molecules may provide important insights into the molecular pathogenesis of Lyme disease. There are two distinct features of the outer membrane of pathogenic spirochetes which have hindered the characterization of their constituent outer membrane proteins. The outer membrane of pathogenic spirochetes are extremely labile, resulting in the loss of a significant amount of the outer membrane, even under the mildest experimental conditions. In addition, this labile outer membrane of B. burgdorferi has been shown by freeze fracture

Patents 145

electron microscopy to contain at least 5-fold less transmembrane outer membrane proteins than that of typical enteric gram negative bacteria {Walker, E. M., et al., J. Bacteriol., 173:5585-5588 (1991)}. This fragility of the outer membrane and paucity of outer membrane proteins has made the application of standard outer membrane purification techniques to spirochetes unsuccessful. Web site: http://www.delphion.com/details?pn=US06153194__ •

Class I-type lysyl-TRNA synthetase Inventor(s): Ibba; Michael (Copenhagen, DK), Soll; Dieter (Hamden, CT) Assignee(s): Yale University (New Haven, CT) Patent Number: 6,492,131 Date filed: March 10, 2000 Abstract: A protein with canonical lysyl-tRNA synthetase activity was purified from Methanococcus maripaludis, cloned, and sequenced. The predicted amino acid sequence of the enzyme indicated a novel class I polypeptide structurally unrelated to class II lysyl-tRNA synthetase reported in eubacteria, eukaryotes, and the Crenarchaeote Sulfobus solfataricus. A similar class I polypeptide was isolated from Borrelia burgdorferi, the causative agent of Lyme disease, and an open reading frame encoding a class I-type lysyl-tRNA synthetase was identified in the genome of Treponema pallidum, the causative agent of syphilis. The B. burdorferi gene encoding tRNALysl was cloned and used to make tRNA in vitro. The fundamental difference between pathogen and host in an essential enzyme suggests that class I-type lysyl-tRNA synthetase provides a target for the development of medical and veterinary therapeutics and diagnostics for Borrelia and other microorganism infections. Excerpt(s): This invention relates to a new class I-type lysyl-tRNA synthetase isolated from archaebacteria and Borrelia. Lysyl-tRNA synthetase (LysRS) is essential for the translation of lysine codons during protein synthesis. In spite of the necessity for this enzyme in all organisms and the high degree of conservation among aminoacyl-tRNA synthetases (1), genes encoding a LysRS homologue have not been found by sequence similarity searches in the genomes of two Archaea, Methanococcus jannaschii (2) and Methanobacterium thermoautotrophicum (3). This raises the possibility that. LysRS, like the asparaginyl- and glutaminyl-tRNA synthetases (4), is not present, with lysyl-tRNA (Lys-tRNA) synthesized by tRNA-dependent transformation of a misacylated tRNA (5). Alternatively, these organisms may contain a LysRS activity encoded by a gene sufficiently different to those previously identified to prevent its detection by sequence similarity searches. This invention confirms the latter hypothesis and provides isolated and purified class I-type lysyl-tRNA synthetase (hereafter sometimes denoted herein as LysRSI) and active fragments and variants thereof, DNA and RNA sequences encoding class I-type lysyl-tRNA synthetase (and biological equivalents and fragments thereof), and methods for screening for class I-type lysyl-tRNA synthetase inhibitors for medical and veterinary use. It further provides methods for screening for infection of an organism by microorganisms expressing class I-type lysyl-tRNA synthetase. Web site: http://www.delphion.com/details?pn=US06492131__

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Compositions and methods for administering Borrelia DNA Inventor(s): Barbour; Alan G. (Irvine, CA), Carner; Kristin R. (San Diego, CA), Huebner; Robert C. (Stroudsburg, PA), Liang; Xiaowu (La Jolla, CA), Luke; Catherine J. (Irvine, CA), Norman; Jon A. (San Diego, CA) Assignee(s): Pasteur Merieux Serums et Vaccins (Lyons, FR), The University of Texas System (Austin, TX), Vical, Inc. (San Diego, CA) Patent Number: 6,451,769 Date filed: October 15, 1998 Abstract: Disclosed is a vaccine against Lyme Disease or its causative agent Borrelia burgdorferi (sensu stricto or sensu lato) containing a plasmid a DNA encoding a promoter for driving expression in a mammalian cell, DNA encoding a leader peptide for facilitating secretion/release of a prokaryotic protein sequence from a mammalian cell, a DNA encoding Borrelia OspA or OspB, and a DNA encoding a terminator. Disclosed too is an immunogenic composition against Lyme Disease or its causative agent Borrelia burgdorferi (sensu stricto or sensu lato) containing a plasmid comprising a DNA encoding a promoter for driving expression in a mammalian cell, DNA encoding a leader peptide for facilitating secretion/release of a prokaryotic protein sequence from a mammalian cell, a DNA encoding a Borrelia OspC, and a DNA encoding a terminator. And, methods for making and using such vaccines and the immunogenic composition are also disclosed. Excerpt(s): This invention relates to compositions and methods for administering Borrelia genospecies DNA encoding antigen(s) in vivo or in vitro. More particularly, this invention relates to compositions and methods for administering Borrelia genospecies DNA encoding an antigen or antigens, e.g., OspA (outer surface protein A) and/or OspB (outer surface protein B), and/or OspC (outer surface protein C), or fragments thereof such as fragments thereof containing at least one epitope of interest, for expression thereof, in vivo, ex vivo or in vitro. Lyme disease is a multisystem illness, transmitted by ticks of the Ixodes ricinus complex. The spirochaete Borrelia burgdorferi sensu lato is the etiologic agent of Lyme disease, which is now the most common arthropod borne disease in the United States, and is endemic in Central Europe (Barbour and Fish 1993). More particularly, there are three genospecies of Borrelia associated with Lyme disease: Borrelia burgdorferi, Borrelia afzelii and Borrelia garinii. Borrelia burgdorferi is the etiologic agent of Lyme disease in North America, and some European Lyme disease is considered to be Borrelia burgdorferi sensu stricto. Borrelia afzelii and Borrelia garinii are the major cause of European Lyme disease and are considered Borrelia burgdorferi sensu lato. Although Lyme disease is curable by antibiotic therapy in its early stages, if Lyme disease is allowed to progress, cardiac, neurological and joint abnormalities can arise. Investigations into the development of a human vaccine for Lyme disease are under way. The outer surface lipoprotein OspA of Borrelia burgdorferi is the current major candidate molecule for development of such a vaccine. Web site: http://www.delphion.com/details?pn=US06451769__

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Compositions and methods using the borreliacidal epitope(s) of borrelia burgdorferi outer surface protein C (OspC) for the diagnosis and prevention of lyme disease Inventor(s): Callister; Steven M. (La Crosse, WI), Jobe; Dean A. (La Crosse, WI), Lovrich; Steven D. (La Crosse, WI), Schell; Ronald F. (Dade, WI) Assignee(s): Gundersen Lutheran Medical Foundation (La Crosse, WI) Patent Number: 6,210,676 Date filed: July 30, 1999 Abstract: An OspC Dra fragment fusion peptide isolated from Borrelia burgdorferi is described herein for the prevention, treatment and early diagnosis of Lyme disease in humans and other animals. This invention also relates to a screening method detecting anti-Osp borreliacidal antibody activity, and antibodies reacting with a protein fragment encoded by a DraI-SmaI DNA fragment of OspC. Excerpt(s): Complete bibliographic citations of the references referred to herein by number in parentheses can be found in the Bibliography section, immediately preceding the claims. This invention relates to compositions and methods useful for the prevention, treatment and early diagnosis of Lyme disease in humans and other animals. More particularly, this invention relates to outer surface protein (Osp) polypeptides which are able to elicit in a patient the formation of a specific immune response which is effective to diagnose, predict successful eradication of infection or protect against Lyme disease in a mammalian host. This invention also relates to a screening method to detect anti-Osp borreliacidal antibody activity, and antibodies which react with a protein fragment encoded by a DraI-SmaI DNA fragment of OspC. Also within the scope of this invention are antibodies directed against Osp polypeptides, diagnostic kits comprising the antibodies or the polypeptides, and vaccines using borreliacidal epitopes of OspA, OspB or OspC or a conserved DNA sequence fragment together with or without a vaccine carrier. Lyme disease (Lyme borreliosis) is spread by a bite from an infected tick, and is the most commonly reported tick-borne infection in Europe and North America (1). This multi-system disorder has caused significant morbidity worldwide. Web site: http://www.delphion.com/details?pn=US06210676__

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Decorin binding protein compositions and methods of use Inventor(s): Guo; Betty (Houston, TX), Hook; Magnus (Houston, TX) Assignee(s): The Texas A & M University System (College Station, TX) Patent Number: 5,853,987 Date filed: January 22, 1996 Abstract: Disclosed are the dbp gene and dbp-derived nucleic acid segments from Borrelia burgdorferi, the etiological agent of Lyme disease, and DNA segments encoding dbp from related borrelias. Also disclosed are decorin binding protein compositions and methods of use. The DBP protein and antigenic epitopes derived therefrom are contemplated for use in the treatment of pathological Borrelia infections, and in particular, for use in the prevention of bacterial adhesion to decorin. DNA segments encoding these proteins and anti-(decorin binding protein) antibodies will also be of use in various screening, diagnostic and therapeutic applications including active and passive immunization and methods for the prevention of Borrelia colonization in an

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animal. These DNA segments and the peptides derived therefrom are contemplated for use in the preparation of vaccines and, also, for use as carrier proteins in vaccine formulations, and in the formulation of compositions for use in the prevention of Lyme disease. Excerpt(s): The present invention relates generally to the field of molecular biology. More particularly, certain embodiments concern methods and compositions comprising DNA segments, and proteins derived from bacterial species. More particularly, the invention provides gene compositions encoding a decorin (Dcn) binding protein (DBP) from Borrelia burgdorferi and the corresponding peptide epitopes and protein sequences comprising native and synthetically-modified Dcn binding site domains. Various methods for making and using these DNA segments, DNA segments encoding synthetically-modified ligand binding site domains, and native and synthetic proteins are disclosed, such as, for example, the use of DNA segments as diagnostic probes and templates for protein production, and the use of proteins, fusion protein carriers and peptides in various pharmacological and immunological applications. Lyme disease (Steere, 1989), or Lyme borreliosis, is transmitted by ticks, particularly of the genus 9Ixodes, and caused by spirochetes of the genus Borrelia. Lyme disease agents, that is borrelias isolated from humans or animals with clinical Lyme disease, are currently classified into at least three phylogenetic groups: B. burgdorferi sensu stricto, B. garinii, and B. afzelii. Strains potentially representing other phylogenetic groups of Lyme disease agents as well, such as group 25015, have been also isolated from ixodid ticks. Collectively these spirochetes are referred to as B. burgdorferi sensu lato, or simply B. burgdorferi. The genotypic and phenotypic variation among Lyme disease agents supporting the designation of these phylogenetic subgroupings is a major complicating factor for the design of effective vaccines or immunotherapeutic strategies for Lyme disease. Lyme disease is transmitted through the bite of a tick which attaches itself to the host and, upon feeding, deposits the spirochetes into the dermis of the skin. In the skin, B. burgdorferi replicates before endovascular dissemination to organs. Typically, an annular spreading skin lesion, erythema migrans, forms from the site of the tick bite. Early symptoms of Lyme disease are flu-like and may include fatigue and lethargy. Left untreated, Lyme disease can develop into a chronic, multisystemic disorder involving the skin, joints, heart, and central nervous system. Web site: http://www.delphion.com/details?pn=US05853987__ •

Decorin binding protein essential peptides and methods of use Inventor(s): Brown; Eric L. (Bellaire, TX), Hook; Magnus A. (Houston, TX) Assignee(s): The Texas A&M University System (College Station, TX) Patent Number: 6,517,838 Date filed: June 16, 2000 Abstract: Borrelia burgdorferi, the causative agent of Lyme disease, expresses on its surface a decorin binding protein, DbpA and DbpB. Lysine residues necessary for DbpA binding to decorin and DbpA peptides containing these critical residues essential for decorin binding are disclosed. It is further disclosed that vaccination using peptides incorporating these critical binding domains of DbpA can confer a delayed-type hypersensitivity response to DbpA and reduce the number of B. burgdorferi organisms present in infected animals.

Patents 149

Excerpt(s): The present invention relates generally to the fields of molecular biology and microbiology. More particularly, it concerns a method of use of residues necessary for ligand binding in a decorin binding protein, DbpA. More particularly, certain embodiments concern methods and compositions comprising DNA segments, and peptides derived from bacterial species. Lyme disease (LD) is a chronic, multisystemic disease caused by the spirochete Borrelia burgdorferi (1). It is transmitted to humans and other mammals during the blood meal of Ixodes ticks (2, 3) and it is the most common vector-borne disease in the United States (1). This initial skin infection is often accompanied by a local rash (erythema migrans) which can be followed by a general flulike illness. Untreated Lyme borreliosis can develop into a chronic, multisystemic disorder that may affect the joints (Lyme arthritis), skin, heart, and central nervous system (1). Microbial adhesion to and colonization of host tissue is an early, critical event in an infection process. In the case of LD, host tissue adherence appears to be of importance during different stages of the disease process. Initially, during an infected tick's blood meal, a small number of spirochetes are deposited in the dermis of the host where the bacteria appear to colonize collagen fibers (32,33). As the infection disseminates to other tissues, bacteria may colonize additional extracellular matrix (ECM) structures and host cells may be involved. Adherence of Borrelia burgdorferi to collagen fibers involves a specific binding of the spirochete to decorin, a dermatan sulfate proteoglycan which is associated with and "decorates" collagen fibers (17, 18). A dermal route of entry into the host appears to be important for the development of disease. Spirochetes administered intravenously are rapidly and effectively cleared by Kupffer cells in the liver (34), whereas those inoculated intradermaly consistently establish infection (35). Perhaps the initial dermal colonization allows the organism to adapt to in vivo conditions before blood stream dissemination. Web site: http://www.delphion.com/details?pn=US06517838__ •

Diagnostic tests for a new spirochete, Borrelia lonestari sp. nov. Inventor(s): Barbour; Alan G. (San Antonio, TX), Carter; Carol (Bulverde, TX) Assignee(s): Board of Regents University of Texas System (Austin, TX) Patent Number: 5,932,220 Date filed: May 8, 1995 Abstract: Bites from Amblyomma americanum, a hard tick, have been associated with a Lyme disease-like illness in the southeastern and south-central United States. Present in 2% of ticks collected in four states were uncultivable spirochetes. Through use of the polymerase chain reaction, partial sequences of the flagellin and 16s rRNA genes of microorganisms from Texas and New Jersey were obtained. The sequences showed that the spirochete was a Borrelia sp. but distinct from other known members of this genus, including B. burgdorferi, the agent of Lyme disease. Species-specific differences in the sequences of the flagellin protein, the flagellin gene and the 16s rRNA gene between the new Borrelia species and previously known species provide compositions and methods for assay for determining the presence of this new spirochete, or for providing evidence of past or present infection by this spirochete in animal reservoirs and humans. Excerpt(s): The present invention relates generally to the fields of infection and disease. More particularly, it concerns the identification of a new spirochete carried by the hard tick, Amblyomma americanum, found by the present inventor to be associated with a Lyme disease-like illness in the southeastern and south-central United States. Most particularly, the invention provides compositions, methods, and kits for the

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identification of the new spirochete for diagnostic purposes. A paradox about Lyme disease is the report of this tick-borne infection from areas in which transmission of the etiologic agent, B. burgdorferi, has not been documented (Sigal et al., 1991; Barbour et al., 1993). This phenomenon has been reported from Georgia and Missouri, but may be common in other parts of the southeastern and south-central United States (Centers for Disease Control and Prevention, 1989; 1991). The Lyme disease-like illness is a localized, expanding circular skin rash, sometimes succeeded by persistent, debilitating systemic symptoms (Masters, 1993; Donnell, 1992). Many of the patients with this illness have had negative serologic assays for antibodies to B. burgdorferi, a finding that has fueled a controversy about so-called "seronegative Lyme disease" (Sigal et al., 1991; Barbour et al., 1993). Although Ixodes scapularis ticks, the usual vector of the Lyme disease agent, has been identified in some of these geographic areas, the more commonly reported exposure for these patients has been to another hard tick, A. americanum, known as the "Lone Star tick" (Centers for Disease Control and Prevention 1989; 1991; Masters, 1993; Donnell, 1992). One conclusion from these observations is that the disease is caused by something other than B. burgdorferi and that the vector of the putative agent is A. americanum (Maupin et al., 1992). The incompetence of A. americanum as a vector of B. burgdorferi has been documented (Piesman et al., 1988; Mather et al., 1990; Mukolwe et al., 1992; Ryder et al., 1992). Nevertheless, there have been descriptions in these ticks of spirochetes that cross-react with antibodies to the Lyme disease agents (Maupin et al., 1992; Schulze et al., 1984). Until the discovery of B. burgdorferi and related Borrelia species in Ixodes spp. ticks a decade ago, Borrelia spp. had almost exclusively been found in soft or argasid ticks (Barbour et al., 1986). Web site: http://www.delphion.com/details?pn=US05932220__ •

Immunogenic formulation of OSPC antigen vaccines for the prevention and treatment of lyme disease and recombinant methods for the preparation of such antigens Inventor(s): Crowe; Brian (Vienna, AT), Dorner; Friedrich (Vienna, AT), Livey; Ian (Vienna, AT) Assignee(s): Baxter Vaccine AG (Vienna, AT) Patent Number: 6,486,130 Date filed: June 27, 1996 Abstract: A novel approach to Borrelia vaccine formulation taking into account serological, genotypic and epidemiological information by which OspC proteins from different strains of B burgdorferi are grouped together. OspC antigens are chosen in order to constitute a representative sample of such groupings, so that the resulting vaccine provides the greatest cross-protectivity with the fewest number of antigens. Excerpt(s): The present invention relates to the prevention and treatment of Lyme disease in mammals and in particular to immunogenic formulations comprising different serological forms of OspC to retard or prevent the development of Lyme disease. The invention also comprises recombinant methods for the preparation of novel antigens. Lyme disease or Lyme borreliosis are terms used to describe the diverse clinical symptoms associated with tick-borne spirochetal infections caused by Lyme Disease Borrelia. Common manifestations of Lyme disease include disorders affecting the skin [erythema migrans (EM) or acrodermatitis chronica atrophicans (ACA)], nervous system (neuro-borreliosis), and joints (arthritis) but other organs and tissues may become infected and diseased. Lyme disease has a world-wide distribution and is

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the most prevalent tick-borne disease in both the United States and Europe. The range of clinical symptoms commonly associated with Lyme disease in Europe is broader than that in the United States, with skin and nervous system disorders being common in Europe but rare in the United States, whereas arthritis is more common in the United States than in Europe. The clinical symptoms in North America appear to be a subset of those observed in Europe. Lyme disease is typically treated with antibiotics. Treatment may be delayed, however, due to the often complex clinical picture and the lack of widely available, reliable diagnostic tests. If the disease is allowed to proceed to a chronic condition, treatment with antibiotics is more difficult and is not always successful. Furthermore the prospect that permanent damage is induced is likely to be increased during the course of a prolonged infection. Accordingly, a vaccine to prevent Lyme disease is desirable. Web site: http://www.delphion.com/details?pn=US06486130__ •

Insect repellent lotions and sprays Inventor(s): Beldock; Donald T. (New York, NY), Beldock; John A. (Washington, DC) Assignee(s): Primavera Laboratories, Inc. (Rye, NY) Patent Number: 5,648,398 Date filed: August 31, 1994 Abstract: An insect repellent is provided and includes terpineol, citronella, and one or both of rhodinol extra and geraniol as actives provided in a conveying medium. The actives are used in small percentages, e.g. as little as 0.01%, preferably at between 0.05% and 0.08%, and preferably less than 1%, yet are synergistically efficacious, particularly against ticks carrying Lyme disease. The conveying medium can be a cosmetic moisturizer lotion, with or without a sun screen. For a spray, the conveying medium can be water or alcohol based. An attractive fragrance is preferably provided as approximately 0.4% of the insect repellent The lotion or spray is safely applied in liberal quantities to humans and animals without unpleasant side effects such as stinging. Excerpt(s): The present invention relates generally to insect repellents in lotion and spray form. More particularly, the present invention relates to insect repellents for humans and animals which are particularly efficacious in repelling ticks carrying Lyme disease, as well as biting flies and triatomes (Chagas bugs). For purposes herein, the term "insect" is to be understood in its broadest sense to include ticks, Chages bugs, biting flies, etc. Insects have long been carriers and spreaders of diseases as they not only feed on animals, but on humans as well. In North America, mosquitoes, ticks, and black flies are the three major groups of arthropods pestiforous to humans. While black flies and mosquitoes in North America are primarily a nuisance, a tick bite can be more serious. In particular, significant attention in the northeast United States recently has been focused upon the Lyme disease ticks (ixodes damini) which have spread in geographical area as well as in number, and which carry the potentially debilitating Lyme disease. Similarly, in warmer climates such as Latin America, a serious and potentially fatal malady known as Chagas' disease are carried by triatomes (Chagas bugs) which are active at night and feed on people as they sleep. In Africa, mosquitoes carry malaria. In an attempt to repel insects, people have turned to widely marketed lotions and sprays (e.g. Cutters, DeepWoods Off, and Tick Garde) which contain N,Ndiethyl-m-toluamide (DEET) as their active ingredient. While DEET is an effective repellent, it is not particularly pleasing in smell, it stings when applied, and its use has a number of harmful side-effects to humans. DEET is injurious to eyes, mucous

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membranes, and sensitive skin. In addition, because DEET is absorbed through the skin, toxic systemic reactions may result as well. For example, in August 1989, the New York State Department of Health investigated five reports of generalized seizures which were believed to be associated with the topical application of DEET. Other symptoms and maladies associated with repeated exposure to DEET have included irritability, confusion, insomnia, encephalopathy, and coma. As a result, cautionary statements regarding use of DEET have been issued by the Centers for Disease Control and the states of New York, Connecticut, New Jersey, and Utah. Web site: http://www.delphion.com/details?pn=US05648398__ •

Method for diagnosis of lyme disease Inventor(s): Dodge; Deborah E. (Albany, CA), White; Thomas J. (Oakland, CA) Assignee(s): Roche Molecular Systems, Inc. (Branchburg, NJ) Patent Number: 5,912,117 Date filed: October 9, 1992 Abstract: Methods and reagents are provided for amplifying and detecting target nucleic acid sequences in a sample suspected of containing Borrelia spirochetes using the polymerase chain reaction (PCR) process. The PCR process employs primers and probes which are derived from the 16S ribosomal RNA gene of Borrelia burgdorferi and Borrelia hermsii. Excerpt(s): The invention relates generally to methods and reagents for the detection of Lyme disease, a multisystem bacterial infection transmitted by Ixodid ticks. More particularly, the methods employ polymerase chain reaction to amplify genomic nucleic acid sequences specific to the etiologic agent of Lyme disease, Borrelia burgdorferi. Lyme disease is a complex multisystem disorder caused by the tick-borne spirochete Borrelia buradorferi. This disease has three clinical stages that can overlap or occur alone: stage one--early disease, including a characteristic expanding skin lesion (erythema chronicum migrans) and constitutional flu-like symptoms; stage two--cardiac and neurological disease; and stage three--arthritis and chronic neurological syndromes. Presently, the incidence of reported Lyme disease is increasing, which is probably due to improved awareness and recognition of the disease, as well as to an actual increase in incidence and geographic spread. B. burgdorferi can be isolated from blood or skin biopsies taken from acutely ill patients, but the yield is low and the procedures are difficult. Serologic testing for antibodies using an enzyme-linked immunosorbent assay (ELISA) or indirect immunofluorescence assay (IFA) is the standard method used to confirm a clinical diagnosis, but current tests are poorly standardized, and falsenegative or false-positive results can occur (Barbour, (1989) Ann Intern Med 110:501). In addition to misdiagnosis caused by lack of standardization of serologic testing, crossreactivity with Treponema and with other Borrelia may occur. Patients with stage one or two disease may be seronegative because it may take as long as three to six months after exposure for antibodies to become detectable with currently available tests. Patients who develop later stages of the illness may occasionally be seronegative if they were treated acutely with antibiotics (Dattwyler et al., (1988) N Engl J Med 319:1441). Previously untreated patients with a late stage of the disease are, apparently, almost always seropositive. Web site: http://www.delphion.com/details?pn=US05912117__

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Method for treating garments with insect repellent Inventor(s): Collins; Daniel R. (P.O. Box 344, Sagamore, MA 02561) Assignee(s): none reported Patent Number: 6,054,182 Date filed: April 8, 1998 Abstract: A method of delivery of insect repellent which incorporates a delivery device which provides for release of insect repellent to fabrics within an automatic laundry dryer at dryer operating temperatures for treating garments for the purpose of repelling insects and which controls the amount and toxicity of a repellent applied directly to garments, particularly children's garments, and which eliminates the direct application of toxic repellent to the skin of a user for use in controlling the spread of Lyme Disease. Excerpt(s): The present invention relates to an active agent delivery device for use in applying insect repellent to clothes as part of the drying cycle of a clothes dryer. In particular the invention is directed to a delivery device which provides for release of insect repellent to fabrics within an automatic laundry dryer at dryer operating temperatures for treating children's garments for the purpose of repelling deer ticks to prevent Lyme Disease. Many types of insects are classified as pests, and many efforts have been made to eradicate or, at the very least, control them. An early application was the product FLIT, developed for the purpose of ridding an area of pests, the trademark advertising slogan showing that once an offensive insect was encountered, "Quick Henry The Flit" was applied by means of a pump gun with spray device (see FIGS. 1-3). Notwithstanding the development of effective poisons, which have been substantially effective in controlling insects such as mosquitoes, it has been found that many poisons, a case in point being the chemical commonly known as DDT, have undesirable effects on human and other animal life and therefore uses of many are now regulated or forbidden. See Rachel Carson, Silent Spring. More recently efforts have been directed to controlling offensive insects, rather than to eradicating them. Products such as 6-12 have been marketed as an aerosol, replacing the pump gun. This delivery was very popular, so much so that we are now faced with the threat of global warming. For environmental and health reasons the aerosol spray has proved more of a threat than a solution. Web site: http://www.delphion.com/details?pn=US06054182__

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Method for treatment of lyme disease Inventor(s): McMichael; John (Delanson, NY) Assignee(s): Milkhaus Laboratory, Inc. (Delanson, NY) Patent Number: 6,592,875 Date filed: April 21, 2000 Abstract: The present invention relates to a treatment for patients having Lyme disease by administering a composition comprising an Borrelia burgdorferi antigen at a subvaccine level effective to alleviate symptoms of Lyme disease. Excerpt(s): This invention relates generally to the treatment of Lyme Disease and compositions for use therein. Lyme Disease is a tick-bourne multisystem inflammatory disorder caused by the spirochete Borrelia burgdorferi. The disorder was first recognized in 1975 because of a clustering of cases in Lyme Connecticut. In the United States, the white-footed mouse and deer are the preferred hosts for the immature and

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adult ticks (I. dammini), respectively. The disease is divided into early disease (stages 1 and 2) and late disease (stage 3). Stage 1 is characterized by the presence of a distinctive skin lesion, erythema migrans. Stage 2 is a disseminated phase of the infection, with manifestations in the skin, CNS, musculoskeletal system and heart. Late disease, or stage 3 reflects persistent infection that is clinically manifest for more that one year after onset. Common clinical features include carditis, neurologic abnormalities and arthritis. Web site: http://www.delphion.com/details?pn=US06592875__ •

Methods and compositions for diagnosing lyme disease Inventor(s): LeFebvre; Rance B. (Davis, CA), Perng; Guey-Chen (San Gabriel, CA) Assignee(s): The Regents of the University of California (Oakland, CA) Patent Number: 5,977,339 Date filed: January 17, 1997 Abstract: A chromosomal gene of Borrelia burgdorferi which encodes a conserved antigen of approximately 79 kD has been isolated and sequenced. The chromosomal gene, the gene product, and antibodies to the gene product may be used in diagnostic methods for the detection of Borrelia burgdorferi infection. The antigen and fragments thereof are suitable for use in vaccine compositions and methods. Excerpt(s): Lyme disease was first described in the late 1970's as a unique grouping of arthritic symptoms in patients from Lyme, Conn. Subsequent investigation demonstrated that the disease is caused by infection with Borrelia burgdorferi, a spirochete, following exposure to deer (ixodid) ticks. It is now known that lyme disease in humans is a multi-systemic disorder characterized by dematologic, rheumatologic, cardiac, and neurologic manifestations. While several isolates of Borrelia burgdorferi from North America and Europe have been characterized at both the genetic and antigenic level, the unequivocal diagnosis of lyme disease remains problematic. Isolation and cultivation of borrelia from infected patients is difficult and not practical for routine diagnosis. Immunological and genetic detection methods have not become generally available, at least in part because the known major antigens of Borrelia burgdorferi have previously been thought to be coded on linear plasmid and have demonstrated significant antigenic variation with regard to the level of expression and molecular weight. There have also been reports of serological cross-reactivity with related human pathogens, such as B. hermsii (the causative agent of tick-born relapsing fever) and Treponema palladium (the causative agent of syphilis). It would therefore be desirable to provide improved methods for diagnosing lyme disease and in particular for unequivocally determining the presence of Borrelia burgdorferi in patient samples. To provide such methods, it would be desirable to identify genetic and antigenic information which is widely conserved among Borrelia burgdorferi strains and which can be used in a variety of detection protocols. More specifically, it would be desirable to identify a conserved chromosomal gene which encodes a major antigenic protein, where the gene can serve as the basis for genetic screening assays and the antigen can serve as the basis for immunologic screening assays. Web site: http://www.delphion.com/details?pn=US05977339__

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Methods for diagnosing early Lyme disease Inventor(s): Padula; Steven J. (Simsbury, CT) Assignee(s): University of Connecticut (Storrs, CT) Patent Number: 5,620,862 Date filed: November 24, 1993 Abstract: The invention relates to DNA encoding Borrelia burgdorferi sensu stricto outer surface protein C. Purified and recombinant forms of a 23 kDa protein from a Connecticut isolate of B. burgdorferi are described. The 23 kDa protein, referred to as p23 or OspC, can be used for immunodiagnostic assays for detection of early Lyme disease. The protein, amino acid coding for the protein and DNA sequences can be used to prevent Lyme disease, to diagnose/detect B. burgdorferi in human or animal tissues or body fluids. Antibodies specific for the protein can also be generated. Excerpt(s): Lyme disease is a multisystem infection caused by the tick-borne spirochete, B. burgdorferi (Steere, 1989). Because of the low yield of both culture and direct visualization techniques for identification of this organism, the diagnosis of Lyme disease has relied on serologic confirmation in patients with characteristic clinical findings. Recognizing Lyme disease in the early stages can be difficult, however, because patients may not manifest the characteristic rash or may have only non-specific flu-like symptoms. This difficulty of diagnosis is compounded by the delayed emergence of a humoral response to the spirochete as detected by available serologic tests (Steere, 1989). These tests, which currently lack standardization, also do not readily distinguish between reactivity to B. burgdorferi proteins and cross-reactive proteins from commensual or other pathogenic organisms (Hansen et al., 1988; Magnarelli et al., 1987). Delay in establishing the diagnosis of Lyme disease in its early stages is clinically important because timely institution of appropriate antibiotic treatment can prevent the serious sequelae from this potentially chronic infection (Dattwyler et al., 1990; Steere et al., 1983). Initial studies with immunoblot analysis of patients from North America with the early manifestations of Lyme disease found IgM reactivity predominantly against the 41 kDa flagellar protein of B. burgdorferi (Barbour et al., 1986; Craft et al., 1986). In hope of improving the level of detection of the antibody response in early Lyme disease, studies have utilized enriched preparations and recombinant forms of the 41 kDa flagellar protein as target antigen for serologic testing (Magnarelli et al., 1992; Coleman et al., 1987). This approach was prompted by the initial immunoblot studies with B. burgdorferi lysates in which an early and predominant IgM antibody response to the flagellar protein was demonstrated by Craft et al., 1986. Use of the flagellar proteinbased serologic tests may be problematic because of the relatively frequent finding of cross-reactive antibodies to conserved flagellar epitopes from commonly occurring commensual and pathogenic spirochetes, such as those found in the mouth (Magnarelli et al., 1990; Russell et al., 1984). Web site: http://www.delphion.com/details?pn=US05620862__

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Methods of inhibiting an autoimmune response in a human suffering from an autoimmune disease by administering an antibody that binds to a protein to which monoclonal antibody 5C8 binds Inventor(s): Chess; Leonard (Scarsdale, NY), Lederman; Seth (New York, NY), Yellin; Michael J. (Riverdale, NY) Assignee(s): The Trustees of Columbia University in the City of New York (New York, NY) Patent Number: 6,610,294 Date filed: October 20, 1994 Abstract: This invention provides a method of inhibiting an autoimmune response in an animal suffering from an autoimmune disease selected from the group consisting of psoriasis, Lyme disease and hyper IgE syndrome which comprises administering to the animal, in an amount effective to treat the autoimmune disease, an antibody that binds specifically to a protein specifically recognized by monoclonal antibody 5c8 produced by the hybridoma having ATCC Accession No. HB 10916. Excerpt(s): Throughout this application, various publications are referenced by the last name of the authors, followed by the year of publication within parenthesis. Full citations for these publications may be found at the end of the specification, immediately preceding the claims. The disclosures of these publications are hereby incorporated by reference into this application in order to more full describe the state of the art as known skilled therein as of the date of the invention described and claimed herein. In a contactdependent process termed "T cell helper function," CD4.sup.30 T lymphocytes direct the activation and differentiation of B lymphocytes and thereby regulate the humoral immune response by modulating the specificity, secretion and isotype-encoded functions of antibody molecules (Mitchell, et al., 1968; Michison, 1971; White, et al., 1978; Reinherz, et al. 1979; Janeway, et al. 1988; O'Brien, et al., 1988; Rahemtulla, et al., 1991; and Grusby, et al., 1991). The T cell surface molecules that mediate the contactdependent elements of T cell helper function are not yet fully known to one (Noelle, et al., 1991). The process by which T cells help B cells to differentiate has been divided into two distinct phases: the inductive and effector phases (Vitetta, et al., 1989; Noelle, et al., 1990). In the inductive phase, resting T cells contact antigen-primed B cells and this association allows clonotypic T cell receptor (TCR)-CD4 complexes to interact with Ia/Ag complexes on B cells (Janeway, et al., 1988; Katz, et al., 1973; Zinkernagel, 1976; Sprent, 1978a; Sprent, 1978b; Jones, et al., 1981; Julius, et al., 1982; Chestnut, et al., 1981; Rogozinski, et al., 1984). TCR/CD4 recognition of Ia/Ag results in the formation of stable T-B cognate pairs and bidirectional T and B cell activation (Sanders, et al., 1986; Snow, et al., 1983; Krusemeier, et al., 1988; Noelle, et al., 1989; Bartlett, et al., 1989; Kupfer, et al., 1987). In the effector phase, activated T cells drive B cell differentiation by secreting lymphokines (Noelle, et al., 1983; Thompson, et al., 1985) and by contactdependent stimuli (Noelle, et al., 1989; Clement, et al., 1984; Crow, et al., 1986; Brian, 1988; Hirohata, et al., 1988; Jover, et al., 1989; Whalen, et al., 1988; Pollok, et al., 1991; Bartlett, et al., 1990), both of which are required for T cells to drive small, resting B cells go terminally differentiate into Ig secreting cells (Clement, et al., 1984; Martinez, et al., 1981; Andersson, et al., 1980). Web site: http://www.delphion.com/details?pn=US06610294__

Patents 157

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Modified western blot membrane and method for detecting lyme disease and other tick-borne diseases Inventor(s): Levin; Andrew E. (Wellesley, MA) Assignee(s): Immunetics, Incorporated (Cambridge, MA) Patent Number: 6,013,460 Date filed: September 12, 1997 Abstract: Modified Western blot membranes and methods of using same are provided which allow confirmation of Lyme disease and screening for at least one additional tickborne disease. The membranes and methods of the present invention may thus be used to screen for the presence of tick-borne diseases which may be transferred along with Lyme disease. A Western blot assay may also be employed to confirm the presence of such additional tick-borne disease. Excerpt(s): The present invention relates generally to a diagnostic method for detecting tick-borne disease and more specifically, a modified Western blot membrane and method of using same for detecting Lyme disease as well as other tick-borne diseases which may accompany Lyme disease during its transmission. In particular, the modified Western blot membrane and method of the present invention may be used to simultaneously confirm Lyme disease and screen for at least one additional tick-borne disease. Lyme disease is a progressive, systemic infection caused by the spirochete Borrelia burgdorferi. The disease is transmitted to man by the bite of the deer tick (Ixodes scapularis and other species). Diagnostic tests for Lyme disease rely mainly on the detection of human antibodies to spirochetal antigens. The principal test used for screening human sera for antibodies to the Lyme spirochete is enzyme-linked immunosorbent assay (ELISA). Due to the significant inaccuracies inherent in ELISA, sera which are ELISA-positive or indeterminate are often subjected to a confirmatory test. The confirmatory test now in most common use and officially recommended by the U.S. Centers for Disease Control (CDC) is the Western blot. In a conventional Western blot assay, antigens of a given pathogen are resolved into discrete bands on the surface of a paper-like nitrocellulose membrane. The serum to be tested is allowed to react with the antigen bands, and serum antibodies which bind specific bands are detected with a labeled anti-human antibody reagent. Typically, results of the Western blot test appear as a series of bands on a membrane strip. The pattern of bands is compared with the band pattern of known positive sera to produce a diagnostic result. The exact position of bands, and the number of bands which correlate with positivity, differ depending on the pathogen. Considerable effort has been expended to develop new and improved diagnostic tests for Lyme disease. For example, U.S. Pat. No. 5,187,065 discloses methods of detecting Lyme disease in mammals that otherwise show seronegativity due to the generation of immune complexes which "hide" the antibodies raised to the spirochete; disassociation of such complexes followed by immunological assay procedures such as ELISA are described. U.S. Pat. No. 5,470,712 provides bioassays which incorporate non-flaggellar B. burgdorferi proteins, or antibodies raised to such proteins, to create an assay where such proteins or antibodies are bound to a surface and form complexes with certain components of the serum. Similarly, U.S. Pat. No. 5,308,753 teaches the formation of assays which may be used to diagnose Lyme and other diseases which induce primary or secondary IgM antibody-mediated immunity. U.S. Pat. No. 5,217,872 teaches a method of detecting B. burgdorferi antigens through an assay which utilizes vesicle proteins released from the spirochete, while U.S. Pat. Nos. 5,494,797 and 5,324,630 teach the detection of the Lyme spirochete via oligonucleotide probes. U.S. Pat. No. 4,888,276 describes a reliable, noninvasive method for detecting antigens of B.

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burgdorferi from the urine of affected individuals and U.S. Pat. No. 5,155,022 teaches an improved method of assaying for Lyme disease by eliminating crossreacting antibodies. Both U.S. Pat. Nos. 4,859,419 and 5,100,626 provide apparati that are able to assay multiple samples for a specific disease such as Lyme. However, none of these patents teach a method of simultaneously assaying for Lyme disease and other diseases. Web site: http://www.delphion.com/details?pn=US06013460__ •

Nucleic acid amplification oligonucleotides and probes to Lyme disease associated Borrelia Inventor(s): Carter; Nick (San Diego, CA), Hogan; James J. (Coronado, CA), Yang; Yeasing (San Diego, CA) Assignee(s): Gen-Probe Incorporated (San Diego, CA) Patent Number: 6,074,826 Date filed: October 17, 1997 Abstract: The present invention discloses hybridization assay probes, amplification primers, nucleic acid compositions and methods useful for detecting Borrelia nucleic acids. Hybridization assay probes and amplification primers that selectively detect Lyme disease-associated Borrelia and distinguish those Borrelia from Borrelia hermsii are disclosed. Other hybridization probes selectively detect Borrelia hermsii and not Lyme disease-associated Borrelia are also described. Excerpt(s): The inventions described and claimed herein relate to the design and use of amplification oligonucleotides and nucleic acid probes to Borrelia organisms associated with Lyme disease, which allow detection of the organism in test samples, e.g., from tissue samples and body fluids, and from cultures. Lyme disease is a frequently diagnosed human disease and is the most prevalent tick-borne disease in North America, Europe and other parts of the world with a moderate climate. See, A. G. Barbour & D. Fish, Science 260:1610-16 (1993); J. F. Anderson, Rev. Insect Dis. 11:5145159 (1989); A. C. Steere, N. Engl. J. Med., 331:586-96 (1989). Lyme disease or Lyme borreliosis is a multistage infection caused by Borrelia spirochetes. The Borrelia organism is transmitted to humans and animals by infected Ixodes ticks. White-tailed deer and the white-footed mouse, Peromyscus leucopus, serve as primary reservoirs in nature for the adult tick and larval forms, respectively. Lyme borreliosis infection in humans and animals causes a number of different clinical manifestations depending upon the stage of the infection. Early infection of humans is usually a flu-like illness with a characteristic skin rash called erythema migrans. The erythema migrans spreads centrifugally and is usually ring-shaped. The erythema migrans usually develops within 1-5 weeks after a tick bite and spontaneously resolves in several weeks or months. See, H. W. Pfister et al., Lancet 343:1013 (1994). Web site: http://www.delphion.com/details?pn=US06074826__

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OspA DNA and lyme disease vaccine Inventor(s): Barbour; Alan G. (San Antonio, TX), Bergstrom; Sven (Umea, SE), Magnarelli; Louis A. (Durham, CT) Assignee(s): Symbicom Aktiebolag (Umea, SE) Patent Number: 6,183,986 Date filed: June 6, 1995 Abstract: Disclosed and claimed is an isolated DNA molecule having a nucleotide sequence encoding substantially pure OspA, as well as vectors containing such DNA, uses of such DNA, and compositions containing such vectors. Excerpt(s): The present invention relates to immunogenically active fractions of Borrelia burgdorferi spirochaetes comprising antigenic polypeptides, proteins, glycolipids and carbohydrates useful for immunization against and diagnosis of Lyme disease, a method of preparing the immunogenically active fractions, a vaccine comprising an immunogenically effective amount of one or several of the immunologically active fractions or a part thereof, a diagnostic agent comprising one or several of the immunogenically active fractions or a part thereof, a DNA fragment encoding an antigenic polypeptide related to the outer membrane protein OspA present in the immunogenically active fractions, a monoclonal or polyclonal antibody directed against one or several of the immunogenically active fractions or antigenic polypeptide, and the use of the fractions, polypeptide or antibody for diagnostic and therapeutic purposes. Lyme disease is a zoonosis caused by the tick-borne spirochaete B. burgdorferi (1). When a susceptible host is bitten by an ixodid tick, B. burgdorferi organisms enter the skin. In humans the initial skin manifestation is termed erythema chronicum migrans (ECM) whereas a long-standing infection of the skin produces acrodermatitis chronica atrophicans (2). The Borrelia organisms also enter the circulatory system of the host and are distributed to various organs, including the brain and joints (3). A secondary spread of the pathogens produces a variety of clinical syndromes, including lymphocytic meningoradiculitis (4), myocarditis (5) and chronic arthritis (6). In many patients the infection of some tissues, particularly the brain and joints, persists for years and can be severely disabling. These forms of chronic Lyme disease are a consequence of the host's inability to rid itself of the infectious agent and perhaps the development of an autoimmune reaction (7). Diagnosis of Lyme disease has chiefly been based on clinical evidence. The best marker during the primary stage of infection has been the presence of erythema chronicum migrans (ECM) but these skin lesions may not always develop or they may manifest atypically (7). Moreover, Lyme disease can be confused with other illnesses characterized by neurologic or arthritic manifestations. When clinical histories are incomplete, serologic testing with determination of antibody titers is the best laboratory method of diagnosis. Indirect fluorescent antibody (IFC) staining tests and enzyme-linked immunosorbent assays (ELISA) are used to detect total immunoglobulins (8) or class-specific IgM and IgG antibodies to B. burgdorferi (9). ELISA is usually preferred because the procedures are more easily standardized and automated and because absorbance values can be statistically analyzed to give more objective results (8). Web site: http://www.delphion.com/details?pn=US06183986__

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OspE, OspF, and S1 polypeptides in borrelia burgdorferi Inventor(s): Barthold; Stephen W. (Madison, CT), Fikrig; Erol (Guilford, CT), Flavell; Richard A. (Killingworth, CT), Kantor; Fred S. (Orange, CT), Lam; Tuan T. (San Jose, CA) Assignee(s): Yale University (New Haven, CT) Patent Number: 5,656,451 Date filed: September 8, 1993 Abstract: Methods and compositions for the prevention, treatment and diagnosis of Lyme disease. Novel B. burgdorferi polypeptides, serotypic variants thereof, fragments thereof and derivatives thereof. Fusion proteins and multimeric proteins comprising same. Multicomponent vaccines comprising novel B. burgdorferi polypeptides in addition to other immunogenic B. burgdorferi polypeptides. DNA sequences, recombinant DNA molecules and transformed host cells useful in the compositions and methods. Antibodies directed against the novel B. burgdorferi polypeptides, and diagnostic kits comprising the polypeptides or antibodies. Excerpt(s): This invention relates to compositions and methods useful for the prevention, diagnosis and treatment of Lyme disease. More particularly, this invention relates to novel B. burgdorferi polypeptides which are able to elicit in a treated animal, the formation of an immune response which is effective to prevent or lessen the severity, for some period of time, of B. burgdorferi infection. This invention also relates to multicomponent vaccines comprising one or more of the novel B. burgdorferi polypeptides. Also within the scope of this invention are antibodies directed against the novel B. burgdorferi polypeptides and diagnostic kits comprising the antibodies or the polypeptides. Lyme borreliosis is the most common vector-borne infection in the United States [S. W. Barthold, et al., "An Animal Model For Lyme Arthritis", Ann. N.Y. Acad. Sci., 539, pp. 264-73 (1988)]. It has been reported in every continent except Antarctica. The clinical hallmark of Lyme Disease is an early expanding skin lesion known as erythema migrans, which may be followed weeks to months later by neurologic, cardiac, and joint abnormalities. The causative agent of Lyme disease is a spirochete known as Borrelia burgdorferi, transmitted primarily by Ixodes ticks of the Ixodes ricinus complex. B. burgdorferi has also been shown to be carried in other species of ticks and in mosquitoes and deer flies, but it appears that only ticks of the I. ricinus complex are able to transmit the disease to humans. Web site: http://www.delphion.com/details?pn=US05656451__

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Passive vaccine against Lyme disease Inventor(s): Eichmann; Klaus (Freiburg, DE), Kramer; Michael (Heidelberg, DE), Reinhard; Wallich (Heidelberg, DE), Schaible; Ulrich E. (Freiburg, DE), Simon; Markus M. (Freiburg, DE) Assignee(s): Deutsches Krebsforschun Zentrum Stiftung des Offentlichen Rechts (Heidelberg, DE), Max-Planck-Gesellschaft zur Forderung der Wissenschaften e.V. (Gottingen, DE) Patent Number: 5,780,030 Date filed: March 20, 1995

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Abstract: The present invention provides a vaccine against Lyme disease, wherein it contains one or more monoclonal antibodies which are specific for the 31 kD antigen (OspA) or the 34 kD antigen (OspB) of Borrelia burgdorferi. The present invention also provides a process for obtaining this vaccine, as well as new monoclonal anti-bodies and antigens. Excerpt(s): The present invention is concerned with a vaccine against Lyme disease, with a process for obtaining said vaccine, with new monoclonal antibodies, with new antigens and with new recombinant DNA's and vectors. Lyme borreliosis is the most common infectious disease transmitted by ticks in the temperate regions. It is caused by the spirochete Borrelis burgdorferi which is transmitted to humans in particular by ticks of the genus Ixodes. The disease is a chronic, progressive infection which attacks many organs, such as the skin, the central and peripheral nervous system, the heart, the liver, the kidneys and musculoskeletal system. Since a reliable treatment of this disease by therapy with antibiotics is difficult, at the moment great efforts are being made to investigate the pathogen itself and the immune response of the host to infection with Borrelia burgdorferi. In the case of persons afflicted by lyme disease, there is admittedly ascertained a high titre of antibodies against Borrelia burgdorferi which, however, do not provide any protection against the infection. It is assumed that the pathogen passes over very quickly from the blood circulation into the tissues and can there no longer be directly reached by the immune system. This would mean that a protection by antibodies is only possible immediately after commencement of the infection, i.e. as long as the pathogen is still present in the blood circulation. The fact that a natural infection with Borrelia burgdorferi has been found in various kinds of animals has led to attempts to establish laboratory models for Lyme disease. This also took place with limited success. Thus, in the case of experiments which had the object of inducing in mice a specific immune response for Borrelia burgdorferi, it was found that the infection of inbred mouse strains with a prolonged cultured isolate of Borrelia burgdorferi led to moderate but significant pathomorphological changes in various organs, such as the brain, the heart, the lungs and the kidneys, which were comparable to those which are to be observed in patients with Lyme disease (see Schaible et al., Infect. Immun., 1, 41/1988). The development of a serious aspect of the disease in animals was presumably prevented either by the immune defense of the host and/or by the reduced virulence of spirochetes cultured in vitro for a comparatively long period of time (see Johnson et al., J. clin licrobiol.20, 747/1984; Schwan et al., Infect. and Immun., 56, 1837/1988). Web site: http://www.delphion.com/details?pn=US05780030__ •

PCR detection of Borrelia burgdorferi Inventor(s): Persing; David H. (Rochester, MN) Assignee(s): Mayo Foundation for Medical Education and Research (Rochester, MN) Patent Number: 6,087,097 Date filed: May 3, 1996 Abstract: A method for detecting in a biological sample the presence of Lyme-disease causing spirochetes using the polymerase chain reaction (PCR). This method includes the steps of: isolating DNA from the biological sample; amplifying the isolated DNA under hybridizing conditions with a primer pair that targets portions of extrachromosomal linear plasmid gene encoding outer surface protein A (OspA) or outer surface protein B (OspB) of the Lyme-disease causing spirochetes, probing the amplified DNA under hybridizing conditions with a labeled gene probe; and detecting

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the labeled gene probe that hybridized to the amplified DNA of the Lyme-disease causing spirochetes. Excerpt(s): Lyme borreliosis (Lyme disease), a systemic illness with a wide spectrum of clinical symptoms, was named for Lyme, Conn., where the disease was identified. Although subsets of the diverse clinical manifestations of Lyme disease were recorded in Europe early in this century, recognition of the disease as a distinct clinical entity did not occur until the mid-1970s. Today, Lyme disease is the most common tickborne zoonosis in the United States, with more than 6000 human infections reported each year. Lyme disease is a multisystem disorder with dermatologic, neurologic and musculoskeletal components that is caused by the spirochete Borrelia burgdorferi. The risk of a human acquiring Lyme disease is dependent on an interplay of microbial, environmental, and demographic factors. Ultimately, transmission is effected by nymphal ticks of the Ixodes ricinus complex. Illness usually develops three to thirty days following the tick bite, and often begins with a primary skin lesion called erythema migrans, followed by cardiac, neurologic, or arthritic symptoms. These resulting symptoms vary in severity, are disease stage dependent, and often mimic other conditions. This multifaceted presentation often delays and confuses clinical diagnosis. Currently bacterial culture and serologic methods are used in diagnosis. See, A. C. Steere, N. Engl. J. Med., 321, 568-596 (1989). In the early stages of Lyme disease, B. burgdorferi can be readily recovered by culture from biopsy specimens of the erythema migrans skin lesions. P. D. Mitchell et al., Am. J. Clin. Pathol., 99, 104 (1993). However, as the disease progresses, the organism becomes increasingly difficult to detect by culture. In addition, limited sensitivity and specificity and lack of test standardization between laboratories have hindered the interpretation of results. Web site: http://www.delphion.com/details?pn=US06087097__ •

Peptides and assays for the diagnosis of lyme disease Inventor(s): Liang; Fang Ting (Covington, LA), Philipp; Mario T. (Mandeville, LA) Assignee(s): The Administrators of the Tulane Educational Fund (New Orleans, LA) Patent Number: 6,475,492 Date filed: April 28, 1999 Abstract: A peptide consisting of an invariable 26-amino-acid-long region, named IR.sub.6, which is antigenically conversed among strains and species of the B. burgdorferi sensu lato complex, and immunodominant in both human and nonhuman primate hosts is described. This peptide is characterized by the sequence MKKDDQIAAAMVLRGMAKDGQFALKD (SEQ ID NO:1). This peptide is useful for rapid and specific diagnosis of Lyme disease, as are proteins containing this peptide and nucleic acid sequences encoding this peptide and these proteins. Excerpt(s): The present invention relates generally to the field of diagnostic compositions and methods useful in the diagnosis of Lyme borreliosis. The bacterium Borrelia burgdorferi (sensu lato) is the causative agent of Lyme borreliosis, i.e., Lyme disease. This disease is transmitted by the bite of various species of Ixodes ticks carrying the spirochete. The main reservoir of the infection in the United States is the white footed mouse, Peromyscus leucopus, and the infection can be transmitted to many mammalian species including dogs, cats, and man [J. G. Donahue, et al., Am. J. Trop. Med. Hyg., 36:92-96 (1987); R. T. Green, et al, J. Clin. Micro., 26:648-653 (1988)]. Despite the presence of an active immune response, the disease persists for years in patients.

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Such persistence is postulated to be the result, at least in part, of antigenic variation in the bacterial proteins [J. R. Zhang et al, Cell, 89:275-285 (1997)]. However, the diagnosis of Lyme disease in humans and animals has been compromised by the lack of definitive serology leading to rapid and accurate testing. Current diagnostic tests suffer from low sensitivity and specificity, as illustrated by a recent survey of diagnostic laboratories' performance issued by the Wisconsin State Laboratory of Hygiene [L. Bakken et al., J. Clin. Microbiol., 35:537 (1997)]. Web site: http://www.delphion.com/details?pn=US06475492__ •

Recombinant vaccine against Lyme disease Inventor(s): Bey; Russell F. (Arden Hills, MN), Caputa; Anthony C. (Nanuet, NY), Murtaugh; Michael P. (Roseville, MN) Assignee(s): Regents of the University of Minnesota (Minneapolis, MN) Patent Number: 5,554,371 Date filed: April 14, 1994 Abstract: A highly-antigenic, recombinant polypeptide of a molecular weight of about 110-kD by SDS-PAGE is disclosed, which is derived by transforming E. coli with a 7.1 kB DNA fragment from EcoR1-digested B. burgdorferi DNA, followed by identification of cloned transformants expressing polypeptides which bind to anti-B. burgdorferi antibodies. Excerpt(s): The genus Borrelia is included in the order Spirochaetales ("spirochetes") and family Spirochaetaceae. Borrelia species are associated with arthropod hosts and often have limited geographical ranges. Lyme borreliosis, a systemic illness with a wide spectrum of clinical symptoms, was named for Lyme, Conn., where the disease was recognized and studied in 1975. The illness usually develops 3 to 30 days following the bite of an ixodid tick which transmits Borrelia burgdorferi to humans and animals. The disease in humans often begins with a primary skin lesion called erythema migrans (EM) which may be followed by cardiac, neurologic, or arthritic symptoms. The primary clinical sign in dogs and horses is lameness. Antigenic proteins can be isolated from B. burgdorferi by immunoprecipitation, extraction from SDS polyacrylamide gels, or by molecular cloning and expression. The first two methods require large numbers of organisms, creating a logistical problem with B. burgdorferi, which has a generation time of 8 to 24 hours at 32.degree. C. and reaches a maximum cell density of 10.sup.7 to 10.sup.8 cells/ml. Web site: http://www.delphion.com/details?pn=US05554371__

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Sonicated borrelia burgdorferi vaccine Inventor(s): Alliger; Howard M. (Melville, NY), Frey; Alan (Highland Park, NJ) Assignee(s): Rx Technologies, Inc. (Garden City, NY) Patent Number: 5,582,829 Date filed: July 28, 1992 Abstract: A process for the preparation of a vaccine from substantially viable spirochetal bacteria of Borrelia, preferably Borrelia burgdorferi having immunogenic or therapeutic properties and capable of inducing an immune or therapeutic response against Lyme

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Disease when administered to a patient is described. The product for use against Lyme Disease is produced by ultrasound treatment of substantially viable spirochetal bacteria of Borrelia burgdorferi. The invention produces a product and a method of treatment that can be used for the immunization and/or therapy of a patient against Lyme Disease to minimize or prevent the contraction of the disease or to treat the disease. Excerpt(s): This invention relates to a process for producing a vaccine from viruses or cells, the vaccine so produced, and the method of use of the vaccine. More particularly, this invention relates to a vaccine against Borrelia burgdorferi, the causative agent of Lyme disease in humans. More particularly, this invention relates to a method wherein viruses or cells, and in particular, the spirochete Borrelia burgdorferi in substantially viable form, are disrupted using ultrasound. The resulting preparation can be used as a vaccine (for prevention and/or therapy) for the disease caused by the specific microorganism. Research has been focused for many years on the use of immunotherapy to prevent disease. Web site: http://www.delphion.com/details?pn=US05582829__ •

TH2-specific gene Inventor(s): Gu; Wei (Brookline, MA), Lehar; Sophie (Boston, MA), Levinson; Doug (Sherborn, MA) Assignee(s): Millennium Pharmaceuticals, Inc. (Cambridge, MA) Patent Number: 6,190,909 Date filed: June 25, 1997 Excerpt(s): The present invention relates to the discovery, identification and characterization of nucleic acids that encode a novel protein differentially expressed within the TH2 cell subpopulation (hereinafter referred to as STIF). The invention encompasses STIF nucleotides, host cell expression systems, STIF proteins, fusion proteins, polypeptides and peptides, antibodies to the STIF protein, transgenic animals that express a STIF transgene, or recombinant knock-out animals that do not express the STIF protein, and compounds that modulate STIF gene expression or STIF activity that can be used for diagnosis, drug screening, clinical trial monitoring, and/or used to treat STIF based disorders, such as proliferative disorders and T-lymphocyte-related disorders including, but not limited to, chronic inflammatory diseases and disorders, such as Crohn's disease, reactive arthritis, including Lyme disease, insulin-dependent diabetes, organ-specific autoimmunity, including multiple sclerosis, Hashimoto's thyroiditis and Grave's disease, contact dermatitis, psoriasis, graft rejection, graft versus host disease, sarcoidosis, atopic conditions, such as asthma and allergy, including allergic rhinitis, gastrointestinal allergies, including food allergies, eosinophilia, conjunctivitis, glomerular nephritis, certain pathogen susceptibilities such as helminthic (e.g., leishmaniasis) and certain viral infections, including HIV, and bacterial infections, including tuberculosis and lepromatous leprosy. Two distinct types of T lymphocytes are recognized: CD8.sup.+ cytotoxic T lymphocytes (CTLs) and CD4.sup.+ helper T lymphocytes (TH cells). CTLs recognize and kill cells which display foreign antigens on their surfaces. CTL precursors display T cell receptors that recognize processed peptides derived from foreign proteins, in conjunction with class I MHC molecules, on other cell surfaces. This recognition process triggers the activation, maturation and proliferation of the precursor CTLS, resulting in CTL clones capable of destroying the cells exhibiting the antigens recognized as foreign. The cell-mediated, or cellular, immune response, functions to neutralize microbes which inhabit intracellular locations. Foreign antigens,

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such as, for example, viral antigens, are synthesized within infected cells and presented on the surfaces of such cells in association with class I MHC molecules. This, then, leads to the stimulation of the CD8.sup.+ class I MHC-restricted CTLs. Web site: http://www.delphion.com/details?pn=US06190909__ •

Tick (Ixodes scapularis) vector saliva-induced Lyme disease spirochete (Borrelia burgdorferi) antigens as vaccine candidates Inventor(s): Mather; Thomas N. (Wakefield, RI), Nelson; David R. (Wakefield, RI), Scorpio; Angelo (Columbia, MD) Assignee(s): Providence Plantations (Providence, RI), The Board of Governors for Higher Education, State of Rhode Island (Providence, RI) Patent Number: 6,312,915 Date filed: January 29, 1997 Abstract: The invention relates to a method by which new antigens from vector-borne pathogens may be discovered and analyzed by incubating the viable pathogens in the saliva of their vector host. Three such antigens, proteins with the approximate molecular weights of 19, 22 and 24 kDa, have been discovered and analyzed from a strain of B. burgdorferi T-15. The proteins provide a route for the development of immunodiagnostics for Lyme disease and related disorders. The proteins and related amino acids and DNA sequences may also be used for the immunization, for the detection of B. burgdorfei in human or body fluids, and also for the generation of specific antibodies for use in diagnosis, epidemiology, prevention of and treatment of Lyme disease. Excerpt(s): The present invention relates to the use of the saliva of a member of the family Ixodidae to induce the expression of proteins by Borrelia burgdorferi. Novel tick saliva-induced B. burgdorferi proteins can be used for the potential development of a vaccine against Lyme disease and for improved diagnostic kits for the detection of Lyme disease. Borrelia burgdorferi, a spirochete, is the causative agent of Lyme disease. It is a vector borne pathogen, transmitted by ticks of the Ixodes scapularis and Ixodes pacificus complexes in the United States. Burgdorfer W., B. burgdorferi: Its Relationships to Tick Vectors, In Staken (ed): Lyme Borreliosis, II, Zbl Bakt Supplement 18, Stuttgart-New York, Gustav Fischer, 8-13, 1989. Infection with B. burgdorferi is the most common tick-borne infectious disease in the United States. In endemic areas, between 30 and 90% of Ixodes ticks are infected with this organism. The illness caused by B. burgdorferi is a multisystem infection that affects the skin, central nervous system, peripheral nerves, the heart and the joints, with nerve and joint involvement being the most common. Steere, A. C., S. E. Malawista, J. A. Hardin, S. Ruddy, W. Askenase, and W. A. Andiman, Erythema Chronicum Migrans and Lyme Arthritis: the Enlarging Spectrum, Ann Intern Med. 86:685-698, 1977a. The dissemination of spirochetes over time from the site of infection has been documented in a mouse model. Barthold, S. W., D. H. Persing, A. L. Armstrong, and R. A. Peeples, Kinetics of B. burgdorferi Dissemination and Evolution of Disease after Intradermal Inoculation of Mice, AM J. Pathol, 139:263-273, 1991. In these experiments it was shown that the spirochetes were multifocal in distribution with a predilection for collagenous connective tissue of joints, heart, arteries, nerves, muscles, skin and other tissues. In humans, nerve, joint and heart involvement is usually manifested when the disease reaches a chronic state. The pathogensis to a chronic state of nerve involvement, termed neuroborreliosis, is unclear, but may be due to a direct effect of the spirochetes at the site of infection, the host

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response to B. burgdorferi, or the host response to tissue antigens that may mimic those of Borrelia burgdorferi. Fikrig, E., R. Berland, M. Chen, S. Williams, L. H. Signal, and R. A. Flavell, Serological Response to B. burgdorferi Flagellin Demonstrates an Epitope Common to a Neuroblastoma Cell Line, Proc. Natl. Acad. Sci. 90:183-187, 1993. For example, spirochetes can be detected in the cerebrospinal fluid of patients with neuroborreliosis with a corresponding high level of antigen specific T-cells which suggests that a local immune response may be involved in the disease. However, the presence of spirochetes has yet to be demonstrated in biopsy specimens of affected nerve tissue suggesting that clinical manifestations may be due to some type of molecular mimicry. Indeed, it has been shown that antibodies reactive to a certain epitope of the B. burgdorferi flagellin molecule cross react with a neuroblastoma cell line. Fikrig, E., R. Berland, M. Chen, S. Williams, L. H. Sigal , and R. A. Flavell, Serological Response to B. burgdorferi Flagellin Demonstrates an Epitope Common to a Neuroblastoma Cell Line, Proc. Natl. Acad. Sci. 90:183-187, 1993. Development of arthritic symptoms is similarly complex. Patients who develop arthritis usually show involvement of the knee joint with an increase of polymorphonuclear granulocytes in the synovial fluid. Steere, A. C., S. E. Malawista, and D. R. Snydman, Lyme Arthritis: An Epidemic of oligoarticular Arthritis in Children and Adults in Three Connecticut Communities, Arthritis Rheum. 20:7-17, 1977. It has been hypothesized that spirochetes trigger a local immune response with autoreactive features in the joint, symptoms which may continue after the organisms no larger are viable. Girouard, L., D. C. Laux, S. Jindal, and D. R. Nelson, Immune Recognition of Human Hsp60 by Lyme Disease Patient Sra, Microb. Pathog. 14:287-297, 1993; and Steere, A. C., J. Feld, and R. Winchester, Association of Chronic Lyme Arthritis with Increased Frequencies of DR4 and 3, Arthritis Rheum. 31:98 (Abstract), 1988. As with nerve biopsies, culturing of spirochetes from synovial fluid of the joints is exceedingly difficult, being reported only twice, and direct observation is also rare. These phenomena are especially true as the disease progresses. Recent advances in the ability to detect small amounts of DNA using polymerase chain reaction (PCR) has led to conflicting results regarding the presence of spirochetes in the joint. Nocton, J. J., F. Dressler, B. J. Rutledge, P. N. Rys, D. H. Persing, and A. C. Steere, Detection of B. burgdorferi DNA by Polymerase Chain Reaction in Synovial Fluid in Lyme Arthritis, N. Engl. J. Med. (In press); and Malawista, S. E., T. L. Moore, D. E. Dodge, T. J. White, R. T. Schoen, and D. H. Persing, Failure of Multitarget Detection of Borrelia burgdorferi-Associated DNA Sequences in Synovial Fluids of Patients with Juvenile Rheumatoid Arthritis: A Cautionary Note, Arthritis Rheum. 35:246-247, 1992. Thus, as with neuroborreliosis, there appear to be two possibilities: septic arthritis with live organisms in the joint, and reactive arthritis where a microbial antigen at a remote site stimulates an immune response involving either antibodies or cytotoxic mononuclear cells that cross-react with a compartment of host tissue. Web site: http://www.delphion.com/details?pn=US06312915__ •

Vaccine for the prevention of lyme disease Inventor(s): Dorner; Friedrich (Vienna, AT), Livey; Ian (Vienna, AT) Assignee(s): Baxter Aktiengesellschaft (Vienna, AT) Patent Number: 6,221,363 Date filed: June 25, 1992 Abstract: An effective immunogen against Lyme borreliosis in mammals comprises homogenous B. burgdorferi pC protein and a physiologically-acceptable excipient.

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Excerpt(s): The present invention relates to the prevention of Lyme disease in mammals. More specifically, the invention relates to immunogenic formulations and to methods for using them to retard or prevent the development of Lyme disease. The phrases "Lyme disease" and "Lyme borreliosis" generically denote tick-borne infections caused by the spirochaete Borrelia burgdorferi, representing the most common tick-transmitted disease in both the United States and Europe. Lyme disease is similar to syphilis because it affects many organs, most commonly the skin, nervous system, heart and joints, and because it develops in stages and may become chronic. Since Lyme disease may mimic other diseases, a need exists for accurate diagnostic tools, especially in difficult cases where the clinical picture is inconclusive. There is also a need for methods to treat or prevent the disease. Antibiotic therapy may be effective if initiated soon after infection, but prolonged, high dosage treatment is necessary once the disease has progressed. Moreover, antibiotic therapy is not always successful. See Preac Mursic et al., Infection 18: 332-341 (1990). Accordingly, a vaccine to prevent Lyme disease is desirable. Web site: http://www.delphion.com/details?pn=US06221363__

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

Agents and method for diagnosing lyme disease and borreliosis vaccine Inventor(s): DIlgimen, Aydan; (Berlin, DE), Jungblut, Peter; (Berlin, DE), Thies, Sascha; (Berlin, DE), Wittmann, Brigitte; (Berlin, DE) Correspondence: Bruce Londa; Norris, Mclaughlin & Marcus, P.A.; 220 East 42nd Street, 30th Floor; New York; NY; 10017; US Patent Application Number: 20030138868 Date filed: September 30, 2002 Abstract: The invention relates to agents for diagnosing and/or treating Lyme disease which contain the antigens of glyceraldehyde-3-phosphate-dehydrog- enase (GAPDH), oligopeptide permease, oligopeptide ABC transporter periplasmic BP(oppA-2)(Bb), glycosyl transferase IgtD homologue, heat shock protein 90, VLSE fragment, (U76406) putative v1s rec. casette V1s6 Borrelia burgdorferi, flagellin protein Borrelia garinii, (AE001578) conserved hypothetical protein cp32-6 Borrelia burgdorferi, membrane assoc. protein p66 percursor Borrelia burgdoferii, oligopeptide ABC transporter periplasmic BP (oppA-4)(Bc), fructose-biphosphate aldose (fba) Borrelia burgdorferi, DNAK protein Heat Shock Protein 70 Borrelia burgdorferi, orfE Borrelia burgdorferi, outer surface protein B precursor Borrelia burgdorferi, L-lactate dehydrogenase (ldh), P83/100 gene Borrelia burgdorferi, enolase 2-phosphoglycerate Borrelia burgdorferi, flagellin Protein Borrelia garinii, hypothetical protein BBE28 Borrelia burgdorferi, DNA direct. RNA polymerase (rpoA) homolog, P66 protein (fragment), flagellin (fragment), DNA direct. RNA polymerase, integral outer membran protein p66, pyruvate kinase (pyk) homolog, phosphoglycerate kinase (pgk) and/or BBU28760 NID, and/or

10

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

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fragments thereof and/or the nucleic acid sequences encoding said antigens and/or said fragments. Excerpt(s): The invention relates to agents and a method for the diagnosis of Lyme Disease and a Borreliosis-vaccine. The following antigens of Borreliosis were identified, which are characterized by high specifity and sensitivity: Glyceraldehyde-3-phosphatedehydrogenase GAPDH, oligopeptide permease, oligopeptide ABC transporter periplasmic BP (oppA-2)(Bb), glycosyl transferase IgtD homolog, heat shock protein 90, VLSE fragment, (U76406) putative v1s rec. casette V1s6 Borrelia burgdorferi, flagellin protein Borrelia garinii, (AE001578) conserved hypothetical protein cp32-6 Borrelia burgdorferi, membrane assoc. protein p66 percursor Borrelia burgdoferii, oligopeptide ABC transporter periplasmic BP (oppA-4)(Bc), fructose-biphosphate aldose (fba) Borrelia burgdorferi, DNAK protein heat shock protein 70 Borrelia burgdorferi, orfE Borrelia burgdorferi, outer surface protein B precursor Borrelia burgdorferi, L-lactate dehydrogenase (ldh), P83/100 gene Borrelia burgdorferi, enolase 2-phosphoglycerat Borrelia burgdorferi, flagellin protein Borrelia garinii, hypothetical protein BBE28 Borrelia burgdorferi, DNA direct. RNA polymerase (rpoA) homolog, P66 protein (fragment), flagellin (fragment), DNA direct. RNA polymerase, integral outer membran protein p66, pyruvate kinase (pyk) homolog, phosphoglycerat kinase (pgk) and/or BBU28760 NID. One of the most common human infectious diseases transferred by tickborne bacteria is Lyme Borreliosis (LM). The illness is caused by Spirochetes of Borrelia burgdorferi complexes. The illness is manifested in different variations: e.g., as Erythema migrans (EM), Neuroborreliosis, Akrodermatitis chronica athrophicans (ACA), Lymphadenosis cutis benigna (LCB), Lymphozytic Meningoradiculitis (Bannwarth-Syndrome). The species of Borrelia burgdorferi complexes (also named Borrelia burgdorferi sensu lato) are divided in three main genospecies, B. burgdorferi sensu stricto, B. garinii und B. afzelii. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Control of lyme disease spirochete Inventor(s): Borchert, Jeff N.; (Ft. Collins, CO), Poche, Richard M.; (Wellington, CO) Correspondence: Dean P. Edmundson; P.O. Box 179; Burton; TX; 77835; US Patent Application Number: 20030036564 Date filed: August 8, 2002 Abstract: A method is described for controlling the spread of Lyme disease spirochete from rodents which have been infected. The method involves orally administering to the rodents a composition which includes an antibiotic, e.g. chloramphenicol, thiamphenicol, florfenicol, or a salt or derivative thereof, or mixtures of antibiotics, capable of killing the spirochete. Bait compositions are described which include an antibiotic. The bait compositions may be solid or liquid. Excerpt(s): This application is based upon, and claims the benefit of, our U.S. Provisional Application No. 60/310,884, filed Aug. 8, 2001. This invention relates to methods and techniques for controlling Lyme disease spirochete in rodents. Lyme disease has increased about 25-fold since national surveillance began in 1982. The average number of human cases reported from 1993-1997 was 12,500, according to CDC (Center for Disease Control, 1999). The CDC reports that Lyme disease accounts for more than 95% of all reported vector-borne illnesses in the US and more than 128,000 human cases have been reported to health authorities. The disease is reportedly primarily localized to

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states in the northeastern, mid-Atlantic, and upper north-central regions and to several areas in northwestern California. In the United States, two ticks of the Ixodes genus, Ixodes scapularis in the East and Ixodes pacificus in the West commonly carry the spirochete that causes the disease and are in a two-year enzootic cycle with rodents (primarily Peromyscus leucopus) and deer (primarily Odocoileus virginianus). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Culture media for growing spirochetes Inventor(s): Mattman, Lida; (Grosse Pointe, MI), Moayad, Hamid; (Bedford, TX), Phillips, Steven E.; (Ridgefield, CT) Correspondence: Toby H. Kusmer; Mcdermott, Will & Emery; 28 State Street; Boston; MA; 02109; US Patent Application Number: 20010036658 Date filed: December 1, 2000 Abstract: Culture media for use in the growth of mutant bacteria, particularly for the growth of sub-types of bacteria, generally known as cell wall deficient organisms, especially spirochetes. A method for reliably and reproducibly culturing various forms of cell wall deficient organisms from the blood of ill patients, and particularly for reliably and reproducibly culturing spirochetes from the blood and other body fluids of patients with chronic Lyme Disease or with multiple sclerosis. Excerpt(s): This application is a continuation-in-part of U.S. patent application Ser. No. 08/994,295, filed Dec. 19, 1997. This application also claims priority to U.S. provisional patent applications No. 60/168,544, filed Dec. 2, 1999, and 60/239,960, filed Oct. 13, 2000. The invention relates to culture media for use in the growth of bacteria having a particular form. More particularly, the invention relates to culture media which are suitable for the growth of subtypes of bacteria, generally known as cell wall deficient organisms, and has been found to be particularly useful for the growth of spirochetal organisms. The invention also relates to a method for reliably and reproducibly culturing various forms of cell wall deficient organisms from the blood of ill patients, and particularly for reliably and reproducibly culturing spirochetes from the blood of patients with chronic Lyme Disease and from the blood of patients with multiple sclerosis (MS). Cell wall deficient organisms are mutant forms, which have been demonstrated as deriving from virtually every class of bacteria and fungus. Historically, the culture media which are available in the art to grow various non-cell wall deficient organisms have not been found to be suitable for the sustained growth of cell wall deficient organisms. Therefore, there exists a need for suitable culture media that are capable of sustaining the growth of a large variety of cell wall deficient organisms. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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•

Deer tick protection device Inventor(s): Cosenza, Paul M.; (Auburn, MA) Correspondence: Timothy A. French; Fish & Richardson P.C.; 225 Franklin Street; Boston; MA; 02110-2804; US Patent Application Number: 20020124457 Date filed: February 26, 2002 Abstract: A device for use during outdoor activities for protection against crawling insects such as deer ticks carrying Lyme Disease includes a set of protection elements. The elements consist of a substrate with an adhesive layer at each surface. A first (inner) adhesive layer is provided for removable attachment of the protection element upon clothing surfaces in regions adjacent to clothing openings where a second (outer) adhesive layer is exposed to impede advancement of crawling insects toward clothing openings, and preferably to securely trap deer ticks that contact the surface. One or both adhesive surfaces may be covered with release sheets removed prior to use. A shield may extend outwardly from the plane of the substrate, generally above the outer adhesive layer, to shield the adhesive surface from the elements, e.g., rain, dew, dust, leaves, grasses, etc., for extending the effective life of the protection element. A method for use of a protection device of the invention during outdoor activities for protection against crawling insects such as deer ticks carrying Lyme Disease is also described. Excerpt(s): This application claims benefit of U.S. Provisional Patent Application No. 60/274,325, filed Mar. 8, 2001, the complete disclosure of which is incorporated herein by reference. This invention relates to devices for bodily protection against crawling insects in the outdoors, and, more particularly, against deer ticks carrying Lyme Disease. In the northeast region of the United States, and in many other regions of the world, the threat of deer ticks carrying Lyme Disease has become an increasing concern for those participating in outdoors activities. Those with particular concerns include walkers and hikers, birdwatchers, hunters, and parents with children. Recommendations by public health officials for precautions against contracting Lyme Disease from deer ticks include, e.g., wearing long pants and shirts with long sleeves, tucking long hair into a cap or hat, tucking shirt tails into pants, placing pant cuffs inside socks or boots, and careful inspection of the body after each exposure. However, deer ticks are extremely small, and the presence of a deer tick may be overlooked even with the most careful inspection. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Methods for treating or inhibiting neurotoxin-mediated syndromes Inventor(s): Hudnell, H. Kenneth; (Pocomoke, MD), Shoemaker, Ritchie; (Pocomoke, MD) Correspondence: Mcdonnell Boehnen Hulbert & Berghoff; 300 South Wacker Drive; Suite 3200; Chicago; IL; 60606; US Patent Application Number: 20030219400 Date filed: February 10, 2003 Abstract: The present invention discloses methods of treating or inhibiting one or more of sick building syndrome (SBS), post-Lyme Disease Syndrome (PLDS), and chronic fatigue syndrome (CFS) by administering to a patient in need thereof an amount

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effective of cholestyramine and/or.alpha.-melanocyte stimulating hormone to treat or inhibit one or more of these syndromes. Excerpt(s): This application claims priority to U.S. provisional application serial No. 60/356,443, filed Feb. 13, 2002, and U.S. provisional application serial No. 60/356,539, filed Feb. 13, 2002. The present invention relates to the field of medicine, chronic illnesses, and pharmaceuticals. Human illness associated with neurotoxin-forming environmental microbial organisms has been reported. For instance, the human illness designated as possible estuarine-associated syndrome (PEAS) has been linked to exposure to estuaries inhabited by toxin-forming dinoflagellate. Humans may be exposed through direct contact with estuarine water or by inhalation of aerosolized or volatilized toxin(s) (Shoemaker, R C, (1997) Md Med J. 46:521; Shoemaker, R C et al. Environ Health Perspect (2001) 109:539) The acute and chronic symptoms associated with the disease include cough, secretory diarrhea, headache, fatigue, memory impairment, rash, difficulty in concentrating, light sensitivity, burning skin upon water contact, muscle ache, upper airway obstruction, shortness of breath, confusion, red or tearing eyes, weakness and vertigo. In the absence of a serological test, and the identification of a specific dinoflagellate neurotoxin, the diagnosis of PEAS and the link to neurotoxin relies on a neurotoxicological test, visual contrast sensitivity (VCS). A toxin-trapping agent, cholestyramine (CSM), has been used in patients diagnosed with PEAS that have a deficit in VCS (Shoemaker, R C et al. Environ Health Perspect (2001) 109:539). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods of treating cytokine mediated diseases Inventor(s): Moss, Neil; (Ridgefield, CT), Regan, John Robinson; (Larchmont, NY) Correspondence: Boehringer Ingelheim Corporation; 900 Ridgebury Road; P O Box 368; Ridgefield; CT; 06877; US Patent Application Number: 20030060455 Date filed: September 9, 2002 Abstract: Disclosed are methods of treating acute and chronic inflammation in the lung caused by inhalation of smoke, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, sepsis, chronic obstructive pulmonary disease, traumatic arthritis, congestive heart failure and restenosis following percutaneous transluminal coronary angioplasty, known to be cytokine mediated, using aromatic heterocyclic compounds described in WO 00/55139. Excerpt(s): This application claims benefit to U.S. provisional application serial No. 60/318,958 filed Sep. 13, 2001. This invention relates to methods of treating acute and chronic inflammation in the lung caused by inhalation of smoke, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease and congestive heart failure indicated to be cytokine mediated diseases using aromatic heterocyclic compounds disclosed in PCT publication WO 00/55139. In WO 00/55139 there are described aromatic heterocyclic compounds useful in treating certain cytokine mediated diseases. Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are important biological entities collectively referred to as proinflammatory cytokines. These, along with several other related molecules, mediate the inflammatory response associated with the

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immunological recognition of infectious agents. The inflammatory response plays an important role in limiting and controlling pathogenic infections. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Novel borrelia burgdorferi polypeptides and uses thereof Inventor(s): Gross, Dawn; (Brighton, MA), Huber, Brigitte T.; (Cambridge, MA), Meyer, Abbie; (Roslindale, MA), Willett, Theresa; (Watertown, MA) Correspondence: David S. Resnick; Nixon Peabody Llp; 101 Federal Street; Boston; MA; 02110; US Patent Application Number: 20020039586 Date filed: March 20, 2001 Abstract: The present invention provides novel polypeptides which are substantially free of a B. burgdorferi spirochete or fragments thereof and which are thus useful in compositions and methods for the treatment and prevention of B. burgdorferi infection and Lyme disease. In one preferred embodiment, this invention provides modified OspA polypeptides and pharmaceutically effective compositions and methods comprising those polypeptides. A preferred modified OspA polypeptide is set forth in FIG. 1, below. Preferred modified OspA polypeptides are characterized by modifications which diminish and/or ablate their ability to bind the human MHC allele DRB*0401. Excerpt(s): The present invention is directed to novel Borrelia Burgdorferi polypeptides and uses thereof. Lyme borreliosis (Lyme disease) is the most common vector-borne infection in the United States [S. W. Barthold, et al., "An Animal Model For Lyme Arthritis", Ann. N.Y. Acad. Sci., 539, pp. 264-73 (1988)]. It has been reported in every continent except Antarctica. The clinical hallmark of Lyme Disease is an early expanding skin lesion known as erythema migrans, which may be followed weeks to months later by neurologic, cardiac, and joint abnormalities. The causative agent of Lyme disease is a spirochete known as Borrelia burgdorferi, transmitted primarily by Ixodes ticks of the Ixodes ricinus complex. B. burgdorferi has also been shown to be carried in other species of ticks and in mosquitoes and deer flies, but it appears that only ticks of the I. ricinus complex are able to transmit the disease to humans. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Oligonucleotides and methods for detecting borrelia burgdorferi Inventor(s): Exner, Maurice; (Mission Viejo, CA), Hamdan, Hasnah; (Riverside, CA), Lewinski, Michael; (San Clemente, CA) Correspondence: Foley & Lardner; P.O. Box 80278; San Diego; CA; 92138-0278; US Patent Application Number: 20030108875 Date filed: December 4, 2001 Abstract: The present invention provides methods and compositions for determining the presence and/or amount of Borrelia burgdorferi nucleic acids in a test sample related to Lyme disease. In particular, substantially purified oligonucleotide primers and probes are described that can be used for qualitatively and quantitatively detecting Borrelia burgdorferi nucleic acid in a test sample by amplification methods. The present

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invention also provides primers and probes for generating and detecting control nucleic acid sequences that provide a convenient method for assessing internal quality control of the Borrelia burgdorferi assay. Excerpt(s): The present invention relates generally to compositions and methods for detecting nucleic acids for the organism Borrelia burgdorferi in a test sample. The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention. Lyme disease, also known as Lyme borreliosis, is a ticktransmitted, spirochetal, inflammatory disorder causing a rash (erythema [chronicum] migrans) that may be followed weeks to months later by neurologic, cardiac, or joint abnormalities. Lyme disease was recognized in 1975 because of close clustering of cases in Lyme, Conn. It has since been reported in many states in USA and numerous foreign countries. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

SURFACE ANTIGENS AND PROTEINS USEFUL IN COMPOSITIONS FOR THE DIAGNOSIS AND PREVENTION OF LYME DISEASE Inventor(s): PHILIPP, MARIO T.; (MANDEVILLE, LA) Correspondence: Howson And Howson; Spring House Corporate Center; PO Box 457; Spring House; PA; 19477; US Patent Application Number: 20030059894 Date filed: December 13, 1999 Abstract: A novel isolated Borrielia burgdorferi sensu lato surface antigen is characterized by a relative molecular mass of 39.5 kDa. This antigen is expressed in vitro by spirochetes of a B. burgdorferi sensu lato strain. This antigen induces antibodies which kill spirochetes of a B. burgdorferi sensu lato strain by ADCK in vitro. Novel Borrelia cassette string protein or fragments thereof are also useful, as is the P39.5 protein in diagnosing Lyme disease and in compositions for treatment or prophylaxis thereof. Excerpt(s): The present invention relates generally to the field of pharmaceutical and diagnostic compositions useful in the diagnosis, treatment and prophylaxis of Lyme borreliosis. More specifically, the invention provides an isolated natural surface antigen of Borellia and antibodies thereto for use in the diagnosis, treatment or prevention of Lyme disease. Borrelia burgdorferi (sensu lato) is a generic term which encompasses several Borrelia species associated with, and believed to be, the causative agent of Lyme borreliosis (Lyme disease): B. burgdorferi sensu stricto, B. garinii, and B. afzelii. This disease is transmitted by the bite of various species of Ixodes ticks carrying the spirochete. The main reservoir of the infection in the United States is the white footed mouse, Peromyscus leucopus, and the infection can be transmitted to many mammalian species including dogs, cats, and man [J. G. Donahue, et al, Am. J. Trop. Med. Hyg., 36:92-96 (1987); R. T. Green, et al, J. Clin. Micro., 26:648-653 (1988)]. Despite the presence of an active immune response, the disease persists for years in patients. Such persistence is postulated to be the result, at least in part, of antigenic variation in the bacterial proteins [J. R. Zhang et al, Cell, 89:275-285 (1997)]. The diagnosis of Lyme disease in humans and animals has been compromised by the lack of definitive serology leading to rapid and accurate testing. Current diagnostic tests suffer from low sensitivity and specificity, as illustrated by a recent survey of diagnostic laboratories' performance

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issued by the Wisconsin State Laboratory of Hygiene [L. Bakken et al, J. Clin. Microbiol., 35:537 (1997)]. A simple, sensitive and specific diagnostic composition and method for early detection of Lyme disease is needed in the art. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

VMP-like sequences of pathogenic Borrelia Inventor(s): Barbour, Alan G.; (Newport Beach, CA), Hardham, John M.; (Gales Ferry, CT), Howell, Jerrilyn K.; (Houston, TX), Norris, Steven J.; (Houston, TX), Weinstock, George M.; (Houston, TX), Zhang, Jing-Ren; (Delmar, NY) Correspondence: Thomas M. Boyce, ESQ.; Fulbright & Jaworski L.L.P.; 600 Congress Avenue, Suite 2400; Austin; TX; 78701; US Patent Application Number: 20030060618 Date filed: August 16, 2002 Abstract: The present invention relates to DNA sequences encoding Vmp-like polypeptides of pathogenic Borrelia, the use of the DNA sequences in recombinant vectors to express polypeptides, the encoded amino acid sequences, application of the DNA and amino acid sequences to the production of polypeptides as antigens for immunoprophylaxis, immunotherapy, and immunodiagnosis. Also disclosed are the use of the nucleic acid sequences as probes or primers for the detection of organisms causing Lyme disease, relapsing fever, or related disorders, and kits designed to facilitate methods of using the described polypeptides, DNA segments and antibodies. Excerpt(s): The invention relates to the field of molecular biology; in particular, to immunogenic compositions and recombinant VMP-like genes useful for treatment and diagnosis of Lyme disease. Also included are methods for the determination of virulence factors in Lyme disease. Lyme disease is a bacterial infection caused by pathogenic spirochetes of the genus Borrelia. The infection can occur in humans, dogs, deer, mice and other animals, and is transmitted by arthropod vectors, most notably ticks of the genus Ixodes. Borrelia burgdorferi, the most common cause of Lyme disease in North America, was first cultured in 1982. B. garinii and B. afzelii are the most common infectious agents of Lyme disease in Europe, and another species, B. japonicum, has been described in Japan. These organisms are closely related and cause similar manifestations with multiple stages: an expanding rash at the site of the tick bite (erythema migrans); fever, lymphadenopathy, fatigue, and malaise; effects of disseminated infection, including carditis, meningoradiculitis, and polyarthritis; and chronic manifestations including arthritis and neurologic disorders. Lyme disease is often difficult to diagnose because of shared manifestations with other disorders, and it can also be refractory to treatment during late stages of the disease. It is most common in areas such as suburban regions of upstate New York and Connecticut, where large populations of deer and white-footed mice serve as the principal mammalian hosts and reservoirs of infection. Approximately 10,000 cases of Lyme disease in humans are reported per year in the United States, and it is also a significant veterinary problem due to a high infection rate of dogs and other domestic animals in endemic regions. B. burgdorferi, the etiologic agent of Lyme disease, is able to persist for years in patients or animals despite the presence of an active immune response (Steer, 1989; Schutzer, 1992). Antigenic variation has been postulated previously as a mechanism whereby B. burgdorferi evades the immune response in the mammalian host (Schwan et al., 1991; Wilske et al., 1992). Antigenic variation has been defined as changes in the structure or expression of antigenic proteins that occurs during infection at a frequency greater than

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the usual mutation rate (Borst and Geaves, 1987; Robertson and Meyer, 1992; Seifert and So, 1988). 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 Lyme disease, 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 “Lyme disease” (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 Lyme disease. You can also use this procedure to view pending patent applications concerning Lyme disease. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

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CHAPTER 7. BOOKS ON LYME DISEASE Overview This chapter provides bibliographic book references relating to Lyme disease. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on Lyme disease 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 “Lyme disease” (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 Lyme disease: •

Lyme Disease: The Cause, the Cure, the Controversy Source: Baltimore, MD: Johns Hopkins University Press. 1996. 274 p. Contact: Johns Hopkins University Press, 2715 North Charles Street, Baltimore, MD 21218-4319. Summary: This book for the general public or individuals with Lyme disease presents a comprehensive discussion of what is known about Lyme disease. Chapters explain what Lyme disease is and how it is spread; describe the symptoms and consequences of Lyme disease; identify all of the diagnostic tests for Lyme disease and discuss the meaning of test results; examine proven and unproven treatments for Lyme disease, focusing on antibiotic therapy and alternative medicines; compare Lyme disease with other conditions, such as fibromyalgia and chronic fatigue syndrome; discuss depression; and offer guidelines for preventing Lyme disease. Case reports of four individuals are used throughout the book to illustrate the varying course of Lyme disease in different

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individuals. A report demonstrates the problems confronting individuals who test negative for Lyme disease but are convinced that Lyme disease explains their symptoms. A list of resources is included. 7 figures and 3 photographs. •

Everything You Need To Know About Lyme Disease and Other Tick-Borne Disorders Source: Somerset, NJ: John Wiley and Sons, Inc. 1997. 256 p. Contact: Available from John Wiley and Sons, Inc. Distribution Center, 1 Wiley Drive, Somerset, NJ 08875-1272. (800) 225-5945 or (732) 469-4400. Fax (732) 302-2300. E-mail: [email protected]. Website: catalog.wiley.com. PRICE: $14.95 plus shipping and handling. Also available from Lyme Disease Foundation. 1 Financial Plaza, 18th Floor, Hartford, CT 06103. (800)886-LYME or (860) 525-2000. Fax (860) 525-TICK. E-mail: [email protected]. Website: www.lyme.org. PRICE: $18.00; bulk orders available at cost. Summary: This book provides the general public and people who have Lyme disease with comprehensive information about this tick-borne illness. The book begins with a chapter on the public health threat posed by Lyme disease. This chapter provides an overview of progression, diagnosis, and treatment; an explanation of the science of Lyme disease; and a description of other tick-borne disorders. Chapter two discusses ticks' life cycle and method of feeding. Other topics include the forces that have converged to increase the threat of ticks, factors influencing the likelihood of becoming ill from a tick bite, and types of ticks. The next chapter presents significant events in the history of Lyme disease. Chapter four presents the signs and symptoms of localized and disseminated Lyme disease. The fifth chapter discusses the diagnosis of Lyme disease in terms of getting a diagnosis and undergoing antibody tests to detect Borrelia burgdorferi, as well as types of antibody and direct detection tests. Chapter six addresses treatment, focusing on choosing health professionals, taking antibiotics, persuading an insurer to pay for treatment, and obtaining emotional support. This is followed by a chapter that describes other tick-borne disorders, including babesiosis, ehrlichiosis, Rocky Mountain spotted fever, Colorado tick fever, tularemia, relapsing fever, Powassan encephalitis, and tick paralysis. Subsequent chapters provide guidelines on using proper equipment to remove a tick, protecting oneself and family members from ticks, and modifying property to create tick-free zones. Final chapters report on the promise of a vaccine for Lyme disease and discuss the risks of tick bites to animals. 6 appendixes, 28 figures, 1 table, and numerous references.

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 “Lyme disease” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “Lyme disease” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “Lyme disease” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

21st Century Collection Centers for Disease Control (CDC) Emerging Infectious Diseases (EID) - Comprehensive Collection from 1995 to 2002 with Accurate and

Books

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Detailed Information on Dozens of Serious Virus and Bacteria Illnesses - Hantavirus, Influenza, AIDS, Malaria, TB, Pox, Bioterrorism, Smallpox, Anthrax, Vaccines, Lyme Disease, Rabies, West Nile Virus, Hemorrhagic Fevers, Ebola, Encephalitis (Core Federal Information Series) by U.S. Government; ISBN: 1592480675; http://www.amazon.com/exec/obidos/ASIN/1592480675/icongroupinterna •

Applied Neuropsychology: Special Issue: Neuropsychological Aspects of Lyme Disease: 1999 by Richard F. Kaplan (Editor) (1999); ISBN: 0805898174; http://www.amazon.com/exec/obidos/ASIN/0805898174/icongroupinterna

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Aspects of Lyme Borreliosis by K. Weber, W. Borgdorfer (Editor) (1992); ISBN: 0387556281; http://www.amazon.com/exec/obidos/ASIN/0387556281/icongroupinterna

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Aspects of Lyme Borreliosis by K. Weber (Editor), W. Burgdorfer (Editor); ISBN: 3540556281; http://www.amazon.com/exec/obidos/ASIN/3540556281/icongroupinterna

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Bull's-Eye: Unraveling the Mystery of Lyme Disease by Jonathan A. Edlow (2003); ISBN: 0300098677; http://www.amazon.com/exec/obidos/ASIN/0300098677/icongroupinterna

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Chronic Fatigue, Fibromyalgia, and Lyme Disease by Burton Goldberg, Larry, Jr. Trivieri (2003); ISBN: 1587611910; http://www.amazon.com/exec/obidos/ASIN/1587611910/icongroupinterna

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Cicm 1: 4 Lyme Disease by Fessia; ISBN: 0812113381; http://www.amazon.com/exec/obidos/ASIN/0812113381/icongroupinterna

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Coping With Lyme Disease (Coping) by Karen Donnelly; ISBN: 0823931994; http://www.amazon.com/exec/obidos/ASIN/0823931994/icongroupinterna

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Coping with Lyme Disease, 3rd Edition by Denise Lang, Kenneth Leigner (2004); ISBN: 0805075631; http://www.amazon.com/exec/obidos/ASIN/0805075631/icongroupinterna

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Coping With Lyme Disease: A Practical Guide to Dealing With Diagnosis and Treatment by Denise V. Lang, Joseph Territo (1997); ISBN: 0805047751; http://www.amazon.com/exec/obidos/ASIN/0805047751/icongroupinterna

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Disarming Lyme Disease : A Scientific American article [DOWNLOAD: PDF] by Fred S. Kantor (Author); ISBN: B00006BNNE; http://www.amazon.com/exec/obidos/ASIN/B00006BNNE/icongroupinterna

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Ecology and Environmental Management of Lyme Disease by Howard S. Ginsberg (Editor) (1993); ISBN: 0813519284; http://www.amazon.com/exec/obidos/ASIN/0813519284/icongroupinterna

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Ecology and Management of Tick and Lyme Disease at Fire Island National Seashore and Selected Eastern National Parks (Scientific Monograph, 92/20) by Howard S. Ginsberg; ISBN: 9992743204; http://www.amazon.com/exec/obidos/ASIN/9992743204/icongroupinterna

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Everything You Need to Know About Lyme Disease by Karen Donnelly; ISBN: 0823932168; http://www.amazon.com/exec/obidos/ASIN/0823932168/icongroupinterna

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Everything You Need to Know About Lyme Disease and Other Tick-Borne Disorders, 2nd Edition by Karen Vanderhoof-Forschner (Author); ISBN: 0471407933; http://www.amazon.com/exec/obidos/ASIN/0471407933/icongroupinterna

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Know about lyme disease, a serious tick-carried disease (SuDoc A 13.104:L 98/2) by U.S. Dept of Agriculture; ISBN: B000106N6Y; http://www.amazon.com/exec/obidos/ASIN/B000106N6Y/icongroupinterna

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Learning About Lyme Disease by Jo Ann Heltzel (1992); ISBN: 0963304100; http://www.amazon.com/exec/obidos/ASIN/0963304100/icongroupinterna

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Let's Talk About Having Lyme Disease (The Let's Talk Library) by Elizabeth Weitzman (2003); ISBN: 0823950298; http://www.amazon.com/exec/obidos/ASIN/0823950298/icongroupinterna

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Lyme Borreliosis (NATO Asi Series A: Life Sciences, Vol 260) by John S. Axford, David H.E. Rees (Editor) (1994); ISBN: 0306446642; http://www.amazon.com/exec/obidos/ASIN/0306446642/icongroupinterna

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Lyme borreliosis : proceedings of the Second International Symposium on Lyme Disease and Related Disorders, Vienna, 1985; ISBN: 0895742292; http://www.amazon.com/exec/obidos/ASIN/0895742292/icongroupinterna

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Lyme Borreliosis II (Zentralblatt Fur Bakteriologie Supplement 18) by Gerold Stanek (Editor) (1989); ISBN: 089574306X; http://www.amazon.com/exec/obidos/ASIN/089574306X/icongroupinterna

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Lyme Borreliosis: Biology, Epidemiology and Control by J. Gray (Editor), et al (2003); ISBN: 0851996329; http://www.amazon.com/exec/obidos/ASIN/0851996329/icongroupinterna

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Lyme Borreliosis: Proceedings of the Second International Symposium on Lyme Disease and Related Disorders, Vienna 1985 by Gerold Stanek, et al; ISBN: 0895742306; http://www.amazon.com/exec/obidos/ASIN/0895742306/icongroupinterna

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Lyme Disease by Gail B. Stewart, Elizabeth J. Scholl (2003); ISBN: 1560069074; http://www.amazon.com/exec/obidos/ASIN/1560069074/icongroupinterna

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Lyme Disease by Alvin Silverstein, et al (2000); ISBN: 0531117510; http://www.amazon.com/exec/obidos/ASIN/0531117510/icongroupinterna

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Lyme Disease by Anderson (1995); ISBN: 0787215082; http://www.amazon.com/exec/obidos/ASIN/0787215082/icongroupinterna

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Lyme Disease (1993); ISBN: 9992643552; http://www.amazon.com/exec/obidos/ASIN/9992643552/icongroupinterna

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Lyme Disease by Russell C. Johnson (Designer), et al (1991); ISBN: 0962266906; http://www.amazon.com/exec/obidos/ASIN/0962266906/icongroupinterna

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Lyme Disease by Patricia K., MD Coyle; ISBN: 1556643659; http://www.amazon.com/exec/obidos/ASIN/1556643659/icongroupinterna

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Lyme Disease by Ronald L. Hoffman; ISBN: 0879836172; http://www.amazon.com/exec/obidos/ASIN/0879836172/icongroupinterna

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Lyme Disease by Judy Monroe; ISBN: 0736807519; http://www.amazon.com/exec/obidos/ASIN/0736807519/icongroupinterna

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Lyme Disease by Daniel Rahn (Editor), Janine Evans (Editor); ISBN: 0943126584; http://www.amazon.com/exec/obidos/ASIN/0943126584/icongroupinterna

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Lyme Disease by Byrnes; ISBN: 0070095469; http://www.amazon.com/exec/obidos/ASIN/0070095469/icongroupinterna

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Lyme Disease (A First Books) by Elaine Landau; ISBN: 0531109313; http://www.amazon.com/exec/obidos/ASIN/0531109313/icongroupinterna

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Lyme Disease (Deadly Diseases and Epidemics) by I. Edward, Ph.d Alcamo (Editor), Len Yannielli; ISBN: 0791074633; http://www.amazon.com/exec/obidos/ASIN/0791074633/icongroupinterna

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Lyme Disease (Diseases and People) by Scott Veggeberg (1998); ISBN: 076601052X; http://www.amazon.com/exec/obidos/ASIN/076601052X/icongroupinterna

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Lyme disease : a public information guide (SuDoc HE 20.7808:L 98) by U.S. Dept of Health and Human Services; ISBN: B00010BRC4; http://www.amazon.com/exec/obidos/ASIN/B00010BRC4/icongroupinterna

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Lyme Disease 1991; ISBN: 0963234803; http://www.amazon.com/exec/obidos/ASIN/0963234803/icongroupinterna

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Lyme Disease 1991: Patient Physician Perspectives from the U S and Canada by Lora Mermin (Editor), Kathy Cavert; ISBN: 096323482X; http://www.amazon.com/exec/obidos/ASIN/096323482X/icongroupinterna

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Lyme disease a tick-borne illness that can affect the whole family (SuDoc D 105.32:L 98) by U.S. Dept of Defense; ISBN: B00010DMW2; http://www.amazon.com/exec/obidos/ASIN/B00010DMW2/icongroupinterna

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Lyme Disease and Other Pest-Borne Illnesses (Venture Books) by Sean P. MacTire; ISBN: 0531125238; http://www.amazon.com/exec/obidos/ASIN/0531125238/icongroupinterna

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Lyme disease and related disorders; ISBN: 0897664752; http://www.amazon.com/exec/obidos/ASIN/0897664752/icongroupinterna

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Lyme Disease and Related Disorders (Annals of the New York Academy of Sciences, Vol 539) by Edward M. Bosler (Editor), Jorge Luis Benach; ISBN: 0897664744; http://www.amazon.com/exec/obidos/ASIN/0897664744/icongroupinterna

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Lyme Disease and the Nervous System by Louis Reik (1991); ISBN: 0865773947; http://www.amazon.com/exec/obidos/ASIN/0865773947/icongroupinterna

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Lyme Disease and the Ss Elbrus by Rachel Verdon (2002); ISBN: 1930859384; http://www.amazon.com/exec/obidos/ASIN/1930859384/icongroupinterna

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Lyme Disease the Great Imitator: How to Prevent and Cure It by Alvin Silverstein, et al; ISBN: 0962365394; http://www.amazon.com/exec/obidos/ASIN/0962365394/icongroupinterna

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Lyme Disease: A Mother's Perspective by Karen Angotti; ISBN: 0963390236; http://www.amazon.com/exec/obidos/ASIN/0963390236/icongroupinterna

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Lyme Disease: An Annotated Bibliography; ISBN: 9992998512; http://www.amazon.com/exec/obidos/ASIN/9992998512/icongroupinterna

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Lyme Disease: Molecular and Immunologic Approaches (Current Communications in Cell & Molecular Biology, Vol. 6) by Steven E. Schutzer (Editor) (1992); ISBN: 0879693770; http://www.amazon.com/exec/obidos/ASIN/0879693770/icongroupinterna

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Lyme Disease: My Search for a Diagnosis by Linda Hanner (1991); ISBN: 0962266914; http://www.amazon.com/exec/obidos/ASIN/0962266914/icongroupinterna

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Lyme Disease: Selected Articles from New England Journal of Medicine, Mmwr, and Massachusetts Medicine. (1987); ISBN: 0910133220; http://www.amazon.com/exec/obidos/ASIN/0910133220/icongroupinterna

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Lyme Disease: The Cause, the Cure, the Controversy by Alan G. Barbour (1996); ISBN: 0801852455; http://www.amazon.com/exec/obidos/ASIN/0801852455/icongroupinterna

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Lyme Disease: The Untold Story by Dennis Lakin (1998); ISBN: 189062215X; http://www.amazon.com/exec/obidos/ASIN/189062215X/icongroupinterna

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Microorganisms: From Smallpox to Lyme Disease by Thomas D. Brock (Editor); ISBN: 0716720841; http://www.amazon.com/exec/obidos/ASIN/0716720841/icongroupinterna

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Outwitting Ticks: The prevention and Treatment of Lyme Disease and Other Ailments Caused by Ticks, Scorpions, Spiders, and Mites by Susan Carol Hauser (Author); ISBN: 1585740217; http://www.amazon.com/exec/obidos/ASIN/1585740217/icongroupinterna

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Proceedings of the 2nd Workshop on Lyme Disease in the Southeast Brownestone Hotel, Raleigh, North Carolina, September 7-9, 1993 (SuDoc Y 3.T 25:2 W 89/3); ISBN: B00010SMDQ; http://www.amazon.com/exec/obidos/ASIN/B00010SMDQ/icongroupinterna

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Protect Yourself from Lyme Disease (1989); ISBN: 9993652539; http://www.amazon.com/exec/obidos/ASIN/9993652539/icongroupinterna

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Protect yourself from lyme disease (SuDoc A 13.104:L 98/3) by U.S. Dept of Agriculture; ISBN: B000106N78; http://www.amazon.com/exec/obidos/ASIN/B000106N78/icongroupinterna

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Protect Yourself from Lyme Disease: The New York Medical College Guide to Prevention, Detection, and Treatment by Diana Benzaia, Diana Benzala; ISBN: 0440204372; http://www.amazon.com/exec/obidos/ASIN/0440204372/icongroupinterna

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Rabies, Lyme Disease, Hanta Virus: And Other Animal-Borne Human Diseases in the United States and Canada by E. Lendell Cockrum (1997); ISBN: 1555611389; http://www.amazon.com/exec/obidos/ASIN/1555611389/icongroupinterna

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Save removed ticks and label with date you removed them, if you develop symptoms take the tick with you to the doctor, lyme disease ain't no fun (SuDoc A 13.104:L 98/4) by U.S. Dept of Agriculture; ISBN: B000106N5K; http://www.amazon.com/exec/obidos/ASIN/B000106N5K/icongroupinterna

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Surviving Lyme Disease Using Alternative Medicine by David A. Jernigan (1999); ISBN: 0967462304; http://www.amazon.com/exec/obidos/ASIN/0967462304/icongroupinterna

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The 2002 Official Patient's Sourcebook on Lyme Disease by James N., Md. Parker (Editor), Philip M., Ph.D. Parker (Editor) (2002); ISBN: 0597831696; http://www.amazon.com/exec/obidos/ASIN/0597831696/icongroupinterna

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The Widening Circle : A Lyme Disease Pioneer Tells Her Story by Polly Murray (Author) (1996); ISBN: 0312140681; http://www.amazon.com/exec/obidos/ASIN/0312140681/icongroupinterna

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

Handbook of Lyme borreliosis Author: Feaga, Wendy P.; Year: 1986; Madison, Wis.:

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Lyme borreliosis and tick-borne encephalitis Author: Oschmann, Patrick.; Year: 1992; Bremen, Germany: UNI-MED Verlag, c1999; ISBN: 3895994499

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Lyme disease: a pediatric perspective Author: Zemel, Lawrence S.; Year: 1993; Toronto, Ont.: Journal of Rheumatology Pub. Co., c1992

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Lyme disease: a summary of the occupational health concern Author: Baxter, James A.; Year: 1989; Hamilton, Ont.: Canadian Centre for Occupational Health and Safety, [1989]; ISBN: 066013246X

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Lyme disease: an annotated bibliography 1989. Author: National Arthritis and Musculoskeletal and Skin Diseases Information Clearinghouse (U.S.); Year: 1991; Bethesda, MD (Box AMS, Bethesda 20892): National Arthritis and Musculoskeletal and Skin Diseases Information Clearinghouse, 1989

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Lyme disease: HHS programs and resources: report to congressional requesters Author: United States. General Accounting Office.; Year: 1996; Washington, D.C.: The Office, [2001]

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Lyme disease: January 1985 through December 1988: 850 citations Author: Scannell, Kristine.; Year: 1989; Bethesda, Md.: U.S. Dept. of Health and Human Services, Public Health Service, National Institutes of Health, National Library of Medicine, Reference Section; Washington, D.C.: Sold by the Supt. of Docs., U.S. G.P.O., [1989]

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Lyme disease: the cause, the cure, the controversy Author: Barbour, Alan G.,; Year: 1993; Baltimore: Johns Hopkins University Press, 1996; ISBN: 0801852242 http://www.amazon.com/exec/obidos/ASIN/0801852242/icongroupinterna

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Lyme disease. Author: American Council on Science and Health.; Year: 1992; New York, N.Y.: American Council on Science and Health, 1990

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Proceedings of the Second National Conference on Serologic Diagnosis of Lyme Disease: October 27-29, 1994, Dearborn, Michigan; sponsors, Association of State and Territorial Public Health Laboratory Directors, U.S. Centers for Disease Control and Prevention, Michigan Department of Health. Author: Association of State and Territorial Public Health Laboratory Directors (U.S.); Year: 1994; Washington, D.C.: The Association, [1994?]

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Report of a WHO Workshop on Lyme Borreliosis: Piestany, Slovakia, 6 October 1993.; Year: 1993; Geneva: World Health Organization, [1993]

11

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

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Report of WHO Workshop on Lyme Borreliosis Diagnosis and Surveillance: Warsaw, Poland, 20-22 June 1995; Year: 1994; [Geneva]: World Health Organization, [1995]

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WHO Workshop on Lyme Borreliosis Diagnosis and Surveillance: Warsaw, Poland, 20-22 June 1995.; Year: 1990; [Geneva]: World Health Organization, Veterinary Public Health Unit, c1995

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

Chapter 12-C: Infectious Disorders: Lyme Disease Source: in Klippel, J.H., et al., eds. Primer on the Rheumatic Diseases. 12th ed. Atlanta, GA: Arthritis Foundation. 2001. p. 269-274. Contact: Available from Arthritis Foundation. P.O. Box 1616, Alpharetta, GA 300091616. (800) 207-8633. Fax (credit card orders only) (770) 442-9742. Website: www.arthritis.org. PRICE: $69.95 plus shipping and handling. ISBN: 0912423293. Summary: This section of a chapter on infectious disorders provides health professionals with information on the epidemiology, pathogenesis, clinical features, laboratory findings, treatment, and prevention of Lyme disease. This multisystem inflammatory disease is caused by the tick borne spirochete Borrelia burgdorferi. Although the way in which this spirochete causes Lyme disease is unclear, it may bind to and activate host proteolytic enzymes, allowing it to escape the inoculation site and disseminate. The symptoms of Lyme disease can be categorized as early localized, early disseminated, and late disease. Early localized disease includes erythema migrans (EM) and nonspecific complaints resembling viral syndrome. Early disseminated disease occurs days to months following a tick bite, and it may occur without preceding EM. Cardiac and neurologic involvement are the two most common manifestations. Late disease occurs months to years after infection. The chronic arthritis of Lyme disease usually affects the knee. Late neurologic features of infection include encephalopathy, neurocognitive dysfunction, and peripheral neuropathy. Pregnancy complicated by Lyme disease is a major concern because maternal-fetal transmission might cause congenital abnormalities or fetal death. Diagnosis is based on the history and objective physical findings. Serologic, neuropsychologic, and electrophysiologic testing, as well as brain magnetic imaging, may be helpful. Testing of inflammatory fluids for the presence of specific antibodies is the only way to be certain that inflammation is caused by B. burgdorferi. Antibiotic treatment in early disease usually prevents progression and is curative. The best way to prevent Lyme disease is to perform careful and frequent tick checks when in an endemic area, remove ticks before they can bite, shower using a washcloth at the end of the day to dislodge ticks, wear long pants and long sleeved, light colored shirts, and tuck pant legs into socks so that ticks cannot gain access to the skin. A vaccine for Lyme disease has been developed and tested. 2 tables and 23 references.

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

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

AIDS and Other Epidemics Contact: Films for the Humanities and Sciences, PO Box 2053, Princeton, NJ, 08543, (800) 257-5126. Summary: This videorecording discusses AIDS and other epidemics including bubonic plague, black death, influenza, polio, small pox, malaria, and yellow fever. Recent epidemics include AIDS, lyme disease and the rising spread of tuberculosis (TB). The videorecording states that prevention needs to be emphasized and implemented when addressing these diseases.

Bibliography: Multimedia on Lyme Disease The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the

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multimedia database, go to the following Web site: http://locatorplus.gov/. Select “Search LOCATORplus.” Once in the search area, simply type in Lyme disease (or synonyms). Then, in the option box provided below the search box, select “Audiovisuals and Computer Files.” From there, you can choose to sort results by publication date, author, or relevance. The following multimedia has been indexed on Lyme disease: •

Clinical spectrum & immunodiagnostic testing for lyme disease [videorecording] Source: [presented by] Marshfield Video Network, in cooperation with Marshfield Clinic, St. Joseph's Hospital and Marshfield Medical Research Foundation; Year: 1988; Format: Videorecording; Marshfield, WI: The Clinic, c1988

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Cutaneous manifestations of Lyme disease [videorecording] Source: Donald C. Abele; Year: 1996; Format: Videorecording; Secaucus, N.J.: Network for Continuing Medical Education, c1996

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Early signs of lyme disease [videorecording] Source: [presented by] Marshfield Video Network, in cooperation with Marshfield Clinic, St. Joseph's Hospital [and] Marshfield Medical Research Foundation; Year: 1988; Format: Videorecording; Marshfield, WI: Marshfield Clinic, c1988

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Late manifestations of lyme disease [videorecording] Source: [presented by] Marshfield Video Network, in cooperation with Marshfield Clinic, St. Joseph's Hospital, and Marshfield Medical Research Foundation; Year: 1988; Format: Videorecording; Marshfield, WI: The Clinic, c1988

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Lyme disease [videorecording] Source: a presentation of the Office of Clinical Center Communications; produced by Medical Arts and Photography Branch; Year: 1990; Format: Videorecording; [Bethesda, Md.]: National Institutes of Health, 1990

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Lyme disease [videorecording] Source: [presented by] Marshfield Video Network, in cooperation with Marshfield Medical Research Foundation, Marshfield Clinic, St. Joseph's Hospital; Year: 1987; Format: Videorecording; Marshfield, WI: The Network, [1987]

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Lyme disease [videorecording] Source: Allen C. Steere, Jr; Year: 1994; Format: Videorecording; [Bethesda, MD: National Institutes of Health, 1994]

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Lyme disease [videorecording]: 1989 update Source: [presented by] Marshfield Clinic, Saint Joseph's Hospital [and] Marshfield Medical Research Foundation; Year: 1989; Format: Videorecording; Marshfield, WI: Marshfield Regional Video Network, [1989]

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Lyme disease [videorecording]: danger in the grass Source: [presented by] ABC News; Year: 1989; Format: Videorecording; [New York, N.Y.: ABC, 1989]

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Lyme disease [videorecording]: detection and treatment Source: with Raymond J. Dattwyler and Benjamin Luft; Year: 1988; Format: Videorecording; Secaucus, N.J.: Network for Continuing Medical Education, c1988

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Lyme disease [videorecording]: the great imitator Source: produced by Agromedicine Program, Clemson University/Medical University of South Carolina and the Health Communications Network, Medical University of South Carolina; Year: 1990; Format: Videorecording; Charleston, S.C.: MUSC-HCN, c1990

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Lyme disease [videorecording]: the hidden vector Source: Anne Nicholson-Weller; Year: 1984; Format: Videorecording; New York: Network for Continuing Medical Education, 1984

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Lyme disease [videorecording]: what you need to know Source: Centers for Disease Control (CDC) [and] Photo Researchers, Inc; Year: 1990; Format: Videorecording; [United States?]: Midnight of Prods., c1990

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Lyme disease [videorecording]: who let the ticks out? Source: NYN, New York Network, SUNYSAT; sponsored by School of Public Health, University at Albany. [et al.]; Year: 2002; Format: Videorecording; Waldorf, MD: Public Health Foundation, c2002

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Lyme disease and concomitant tick-borne infections [videorecording] Source: Benjamin J. Luft; Year: 1997; Format: Videorecording; Secaucus, N.J.: Network for Continuing Medical Education, c1997

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Lyme disease in rural America [videorecording] Source: a presentation of Marshfield Clinic, Cooperative Extension, University of Wisconsin--Extension, and Office of Outreach Development, University of Wisconsin--Madison; Year: 1991; Format: Videorecording; Marshfield, WI: The Clinic and Board of Regents, University of Wisconsin System, c1991

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Molecular genetics of the lyme disease spirochete [videorecording]: teaching a new bug old tricks Source: Office of Research Services, Medical Arts and Photography Branch; Year: 2002; Format: Videorecording; [Bethesda, Md.: National Institutes of Health, 2002]

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Special considerations in lyme disease [videorecording] Source: [presented by] Marshfield Video Network, in cooperation with Marshfield Clinic, St. Joseph's Hospital, and Marshfield Medical Research Foundation; Year: 1988; Format: Videorecording; Marshfield, WI: The Clinic, c1988

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The elucidation of Lyme arthritis [videorecording] Source: Medical Arts and Photography Branch; Year: 1999; Format: Videorecording; [Bethesda, Md.: National Institutes of Health, 1999]

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

News Services and Press Releases One of the simplest ways of tracking press releases on Lyme disease 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 “Lyme disease” (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 Lyme disease. 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 “Lyme disease” (or synonyms). The following was recently listed in this archive for Lyme disease: •

Anti-IL-17 therapy halts arthritis in mice with Lyme disease Source: Reuters Industry Breifing Date: July 10, 2003

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Results mixed for post-Lyme disease antibiotics Source: Reuters Health eLine Date: June 23, 2003

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Lyme disease treatable with fewer antibiotics Source: Reuters Health eLine Date: May 05, 2003

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Antibiotic therapy for early Lyme disease need not exceed 10 days Source: Reuters Industry Breifing Date: May 05, 2003

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Lyme disease incidence increasing in Holland Source: Reuters Industry Breifing Date: March 14, 2003

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Lyme disease cases increasing in Holland Source: Reuters Health eLine Date: March 14, 2003

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Lyme disease risk rises as species disappear: study Source: Reuters Health eLine Date: January 06, 2003

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Lyme disease vaccine not cost effective for most individuals Source: Reuters Industry Breifing Date: July 16, 2002

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'Bull's eye' rash not always found in Lyme disease Source: Reuters Health eLine Date: March 19, 2002

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Lyme disease vaccine pulled off US market Source: Reuters Health eLine Date: February 26, 2002

•

US Lyme disease cases doubled since 1991 Source: Reuters Health eLine Date: January 17, 2002

•

Lyme disease moves south along rivers Source: Reuters Health eLine Date: November 15, 2001

•

New rapid test streamlines diagnosis of Lyme disease Source: Reuters Industry Breifing Date: September 19, 2001

•

Instant results from new test for Lyme disease Source: Reuters Health eLine Date: September 10, 2001

•

Researchers optimistic about new Lyme disease vaccines Source: Reuters Industry Breifing Date: July 27, 2001

•

Single dose of drug prevents Lyme disease: study Source: Reuters Health eLine Date: June 12, 2001

•

Single dose of doxycycline may prevent development of Lyme disease Source: Reuters Industry Breifing Date: June 12, 2001

Periodicals and News

•

Golfers at risk for Lyme disease near the green Source: Reuters Health eLine Date: May 18, 2001

•

Scientists fight Lyme disease with corn bins Source: Reuters Health eLine Date: May 10, 2001

•

Decorin-binding proteins important in Lyme disease pathogenesis Source: Reuters Medical News Date: March 28, 2001

•

Lyme disease incidence in US has doubled since 1990 Source: Reuters Medical News Date: March 16, 2001

•

Number of reported Lyme disease cases on the rise Source: Reuters Health eLine Date: March 15, 2001

•

Lyme disease vaccine deemed cost effective in endemic areas Source: Reuters Industry Breifing Date: March 02, 2001

•

New test for Lyme disease described Source: Reuters Industry Breifing Date: March 01, 2001

•

IGeneX urine antigen test called unreliable for diagnosis of Lyme disease Source: Reuters Medical News Date: February 26, 2001

•

SmithKline, FDA downplay concerns about Lyme disease vaccine Source: Reuters Industry Breifing Date: November 21, 2000

•

African Americans lack Lyme disease information Source: Reuters Health eLine Date: October 23, 2000

•

No evidence chronic Lyme disease exists, scientists say Source: Reuters Health eLine Date: September 08, 2000

•

Antibodies against Lyme disease antigen resolve arthritis in infected mice Source: Reuters Industry Breifing Date: August 07, 2000

•

Imugen gets patent on test to distinguish Lyme disease from vaccine response Source: Reuters Industry Breifing Date: July 10, 2000

•

Lyme disease confusion could lead to mistreatment Source: Reuters Health eLine Date: June 27, 2000

•

Lyme disease cases up 70% in the 1990s Source: Reuters Health eLine Date: April 28, 2000

191

192 Lyme Disease

•

OSHA guides outdoor workers on avoiding Lyme disease Source: Reuters Health eLine Date: April 25, 2000

•

Migrating birds can act as hosts of Lyme disease spirochete Source: Reuters Medical News Date: February 17, 2000

•

Migrating birds can carry Lyme disease Source: Reuters Health eLine Date: February 16, 2000

•

Most Lyme disease patients treated with antibiotics have favorable long-term outcome Source: Reuters Medical News Date: February 02, 2000

•

Good news for Lyme disease patients Source: Reuters Health eLine Date: February 01, 2000

•

AAP issues guidelines on prevention of Lyme disease in children Source: Reuters Medical News Date: January 14, 2000

•

Guidelines aim to prevent Lyme disease in children Source: Reuters Health eLine Date: January 13, 2000

•

Musculoskeletal, neurologic status in Lyme disease patients normal at 6 years Source: Reuters Medical News Date: December 21, 1999

•

Lyme disease not associated with long-term health risks Source: Reuters Health eLine Date: December 20, 1999

•

Candidate microbial and autoantigens detected in CNS Lyme disease Source: Reuters Medical News Date: December 14, 1999

•

New test may detect early Lyme disease Source: Reuters Medical News Date: November 30, 1999

•

New type of Lyme disease found in southeastern US Source: Reuters Health eLine Date: November 19, 1999

•

New test may help diagnose Lyme disease Source: Reuters Health eLine Date: September 24, 1999

•

Improved blood test may facilitate diagnosis of Lyme borreliosis Source: Reuters Medical News Date: September 24, 1999

•

Serology useful to support a clinical diagnosis of Lyme disease Source: Reuters Medical News Date: July 08, 1999

Periodicals and News

•

Lyme disease shots work given in less than 1 year Source: Reuters Health eLine Date: June 10, 1999

•

Control of nymphal ticks important for Lyme disease prevention Source: Reuters Medical News Date: April 19, 1999

•

Maternal Lyme disease unrelated to congenital cardiac anomalies Source: Reuters Medical News Date: April 02, 1999

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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 “Lyme disease” (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 “Lyme disease” (or synonyms). If you know the name of a company that is relevant to Lyme disease, 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/.

194 Lyme Disease

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 “Lyme disease” (or synonyms).

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

Bell's Palsy: Unmasking Facial Paralysis Source: Mayo Clinic Women's Healthsource. 2(12): 6. December 1998. Contact: Available from Mayo Clinic Women's Healthsource. P.O. Box 56931, Boulder, CO 80322-6931. (800) 876-8633 or (303) 604-1465. Summary: This brief newsletter article describes Bell's palsy, a temporary paralysis of the major facial nerve. Bell's palsy comes on suddenly and its cause is unknown. However, 75 percent of those who get it have an upper respiratory infection first. It may also be associated with diabetes, high blood pressure, trauma, toxins, or Lyme disease. The article lists the symptoms, which usually hit their peak within 48 hours of onset, including sudden paralysis or weakness on one side of the face, facial droop and difficulty with facial expressions, facial stiffness, possible pain behind or in front of the ear on the affected side, sensitivity to sound on the affected side, headache, and loss of taste on the front portion of the tongue. The author notes that treatment for Bell's isn't usually necessary, except to protect the eye from corneal damage (a risk if the eye cannot blink). The author reminds readers that these symptoms mandate a visit to a health care provider, to rule out conditions such as a tumor or stroke (which can cause similar symptoms).

Academic Periodicals covering Lyme Disease Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to Lyme disease. In addition to these sources, you can search for articles covering Lyme disease 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.

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195

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.”

197

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

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

198 Lyme Disease

following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to Lyme disease: Azithromycin •

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

Corticosteroids •

Dental - U.S. Brands: Kenalog in Orabase; Orabase-HCA; Oracort; Oralone http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202010.html

•

Inhalation - U.S. Brands: AeroBid; AeroBid-M; Azmacort; Beclovent; Decadron Respihaler; Pulmicort Respules; Pulmicort Turbuhaler; Vanceril; Vanceril 84 mcg Double Strength http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202011.html

•

Nasal - U.S. Brands: Beconase; Beconase AQ; Dexacort Turbinaire; Flonase; Nasacort; Nasacort AQ; Nasalide; Nasarel; Nasonex; Rhinocort; Vancenase; Vancenase AQ 84 mcg; Vancenase pockethaler http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202012.html

•

Ophthalmic - U.S. Brands: AK-Dex; AK-Pred; AK-Tate; Baldex; Decadron; Dexair; Dexotic; Econopred; Econopred Plus; Eflone; Flarex; Fluor-Op; FML Forte; FML Liquifilm; FML S.O.P.; HMS Liquifilm; Inflamase Forte; Inflamase Mild; I-Pred; Lite Pred; Maxidex; Ocu-Dex; Ocu-Pred; Ocu-Pr http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202013.html

•

Otic - U.S. Brands: Decadron http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202014.html

•

Rectal - U.S. Brands: Anucort-HC; Anu-Med HC; Anuprep HC; Anusol-HC; Anutone-HC; Anuzone-HC; Cort-Dome; Cortenema; Cortifoam; Hemorrhoidal HC; Hemril-HC Uniserts; Proctocort; Proctosol-HC; Rectosol-HC http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203366.html

Doxycycline •

Dental - U.S. Brands: Atridox http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203716.html

Erythromycins •

Systemic - U.S. Brands: E.E.S.; E-Base; E-Mycin; ERYC; EryPed; Ery-Tab; Erythro; Erythrocin; Erythrocot; Ilosone; Ilotycin; My-E; PCE; Wintrocin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202223.html

Headache Medicines, Ergot Derivative-Containing •

Systemic - U.S. Brands: Cafergot; Cafertine; Cafetrate; D.H.E. 45; Ercaf; ErgoCaff; Ergomar; Ergostat; Gotamine; Migergot; Wigraine http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202216.html

Lyme Disease Vaccine •

Systemic - U.S. Brands: LYMErix http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203759.html

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199

Penicillins •

Systemic - U.S. Brands: Amoxil; Bactocill; Beepen-VK; Betapen-VK; Bicillin L-A; Cloxapen; Crysticillin 300 A.S.; Dycill; Dynapen; Geocillin; Geopen; Ledercillin VK; Mezlin; Nafcil; Nallpen; Omnipen; Omnipen-N; Pathocil; Pen Vee K; Pentids; Permapen; Pfizerpen; Pfizerpen-AS; Pi http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202446.html

Permethrin •

Systemic - U.S. Brands: http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203759.html

Probenecid •

Systemic - U.S. Brands: Benemid; Probalan http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202480.html

Tetracyclines •

Systemic - U.S. Brands: http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202480.html

•

Systemic - U.S. Brands: Achromycin V; Declomycin; Doryx; Dynacin; Minocin; Monodox; Terramycin; Vibramycin; Vibra-Tabs http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202552.html

•

Topical - U.S. Brands: Achromycin; Aureomycin; Meclan; Topicycline http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202553.html

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

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

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

200 Lyme Disease

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. 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.

201

APPENDICES

203

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

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

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

12

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

204 Lyme Disease

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

Physician Resources

205

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

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

13

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

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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 Gateway15 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.16 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “Lyme disease” (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 6498 109 717 18 2 7344

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

15

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

16

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

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

Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community 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 Biologists20 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.21 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.22 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

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

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

•

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

20 Adapted 21

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. 22 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.

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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 Lyme disease 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 Lyme disease. 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 Lyme disease. 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 “Lyme disease”:

210 Lyme Disease

•

Guides on Lyme disease Arthritis http://www.nlm.nih.gov/medlineplus/arthritis.html

•

Other guides Heart Diseases http://www.nlm.nih.gov/medlineplus/heartdiseases.html Laboratory Tests http://www.nlm.nih.gov/medlineplus/laboratorytests.html Lyme Disease http://www.nlm.nih.gov/medlineplus/lymedisease.html Pets and Pet Health http://www.nlm.nih.gov/medlineplus/petsandpethealth.html Rheumatoid Arthritis http://www.nlm.nih.gov/medlineplus/rheumatoidarthritis.html Tick Bites http://www.nlm.nih.gov/medlineplus/tickbites.html

Within the health topic page dedicated to Lyme disease, the following was listed: •

General/Overviews Lyme Disease http://www.nlm.nih.gov/medlineplus/tutorials/lymediseaseloader.html Lyme Disease Source: Arthritis Foundation http://www.arthritis.org/resources/arthritistoday/2000_archives/2000_03_04_101 _lyme.asp Lyme Disease Source: National Center for Infectious Diseases http://www.cdc.gov/ncidod/dvbid/lyme/index.htm

•

Diagnosis/Symptoms Lyme Disease Test Source: American Association for Clinical Chemistry http://www.labtestsonline.org/understanding/analytes/lyme/test.html Lyme Disease: A Patient's Guide, Diagnosis Source: American College of Physicians http://www.acponline.org/lyme/patient/diagnosis.htm We Want You to Know About Lyme Disease: It's Difficult to Diagnose Source: Food and Drug Administration http://www.fda.gov/cdrh/consumer/lymedisease.html

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Treatment Chronic Lyme Disease Symptoms Not Helped By Intensive Antibiotic Treatment Source: National Institute of Allergy and Infectious Diseases http://www.nih.gov/news/pr/jun2001/niaid-12.htm Tick Removal: A Step-by-Step Guide Source: Nemours Foundation http://kidshealth.org/parent/general/body/tick_removal.html

•

Specific Conditions/Aspects Frequently Asked Questions: Lyme Disease Source: American Lyme Disease Foundation http://www.aldf.com/FAQ.asp Lyme Disease and Animals Source: National Center for Infectious Diseases http://www.cdc.gov/healthypets/diseases/lyme.htm Neurological Sequelae of Lyme Disease Source: National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/health_and_medical/disorders/lyme_doc.htm Travelers' Health: Lyme Disease Source: National Center for Infectious Diseases http://www.cdc.gov/travel/diseases/lyme.htm

•

Children Lyme Disease Source: Nemours Foundation http://kidshealth.org/parent/infections/bacterial_viral/lyme.html Recipe for Tick Soup Source: Agricultural Research Service http://www.ars.usda.gov/is/kids/insects/story3/insectstory.htm

•

From the National Institutes of Health Lyme Disease - The Facts, The Challenge Source: National Institute of Allergy and Infectious Diseases http://www.niaid.nih.gov/publications/lyme/niaid%2520lymedisbookf2.pdf

•

Organizations American Lyme Disease Foundation http://www.aldf.com/ Arthritis Foundation http://www.arthritis.org/ Lyme Disease Foundation http://www.lyme.org/ National Center for Infectious Diseases http://www.cdc.gov/ncidod/index.htm

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National Institute of Allergy and Infectious Diseases http://www.niaid.nih.gov/ •

Pictures/Diagrams Picture Gallery: Rashes Source: Lyme Disease Foundation http://www.lyme.org/gallery/rashes.html Picture Gallery: Ticks Source: Lyme Disease Foundation http://www.lyme.org/gallery/ticks.html

•

Prevention/Screening Lyme Disease Vaccine: What You Need to Know http://www.cdc.gov/nip/publications/vis/vis-lyme.pdf Lyme Disease: A Patient's Guide, Prevention Source: American College of Physicians http://www.acponline.org/lyme/patient/prevention.htm Spotlight On: Protecting Yourself and Your Family from Lyme Disease Source: National Center for Infectious Diseases http://www.cdc.gov/ncidod/dvbid/lyme/lymespot2002.htm

•

Research Duration of Antibiotic Treatment for Early Lyme Disease Source: American College of Physicians http://www.annals.org/cgi/content/full/138/9/I-27 Lyme Disease Research Efforts of the National Institute of Allergy and Infectious Diseases Source: National Institute of Allergy and Infectious Diseases http://www.niaid.nih.gov/research/lyme.htm Lyme Disease Vaccine: Preventing an Emerging Disease Source: National Institute of Allergy and Infectious Diseases http://www.niaid.nih.gov/publications/discovery/lyme.htm Secrets of the Woods: Acorns, Biodiversity and Lyme Disease Source: National Institute of Allergy and Infectious Diseases http://www.niaid.nih.gov/newsroom/focuson/bugborne01/ostfeld.htm

•

Statistics Lyme Disease: Epidemiology Source: National Center for Infectious Diseases http://www.cdc.gov/ncidod/dvbid/lyme/epi.htm

•

Teenagers Lyme Disease Source: Nemours Foundation http://kidshealth.org/teen/infections/skin_rashes/lyme_disease.html

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What's My Lyme Disease Risk? Source: Nemours Foundation http://kidshealth.org/teen/diseases_conditions/brain_nervous/lyme_risk_teen.ht ml 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 Lyme disease. 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: •

Lyme Disease Source: Atlanta, GA: Arthritis Foundation. 1997. 10 p. Contact: Available from Arthritis Foundation. P.O. Box 1616, Alpharetta, GA 300091616. (800) 207-8633. Fax (credit card orders only) (770) 442-9742. http://www.arthritis.org. PRICE: Single copy free from local Arthritis Foundation chapter (call 800-283-7800 for closest local chapter); bulk orders may be purchased from address above. Summary: This brochure for people with Lyme disease provides information on this bacterial infection that is transmitted by the bite of an infected tick. In the early stage, the disease may cause only mild flulike symptoms, but then a large, expanding red skin rash may develop around the bite. Joint or muscle pain can also follow. In later stages, Lyme disease can cause nervous system problems as well as arthritis, and immune system difficulties. It explains how early treatment with antibiotics can prevent more serious problems from developing. People can minimize exposure by wearing protective clothing, checking for ticks after being outdoors, keeping pets from roaming outside when ticks are active, and clearing brush and cutting long grass near the house. In addition, the brochure identifies sources of additional information. 3 figures.

•

We Want You to Know About Lyme Disease: It's Difficult to Diagnose Source: Centers for Devices and Radiological Health, 1999. 4 p. Contact: Available from Centers for Devices and Radiological Health. Website: www.fda.gov/cdrh/consumer/lymedisease.html. Summary: This fact sheet provides the health consumer with information on the etiology, symptoms, prevention, diagnosis, and treatment of Lyme disease. Lyme disease is an infection caused by Borrelia burgdorferi, a bacterium that is transmitted by

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the bite of an Ixodes tick. This tick is usually smaller than dog or cattle ticks and attaches itself to hairy or moist areas of the body such as the groin, armpits, or scalp. A large red rash at the site of the bite is usually the first symptom. This is followed by flu-like symptoms (muscle and joint aches, chills, fever, headache, and swollen lymph nodes) and fatigue. Blood tests are used to check for antibodies to the bacterium. Because it takes two to five weeks for these antibodies to appear in the blood, the blood test cannot be done immediately after the bite occurs. To make the diagnosis of Lyme disease, history of possible tick bite, symptoms, and positive results of the blood test need to be present. Oral antibiotics are prescribed if there are definite symptoms of Lyme disease. Precautions include avoiding woody and grassy areas in summer months, wearing light colored, long-sleeved clothing, spraying insect repellant with DEET onto clothes and exposed skin, and doing a careful body check for ticks. A new vaccine (trade-name Lymerix) has been approved by the FDA for preventing Lyme disease and is 78 precent effective. •

Understanding Lyme Disease: Prevention and Treatment Source: San Bruno, CA: StayWell Company. 1997. 6 p. Contact: Available from StayWell Company. 1100 Grundy Lane, San Bruno, CA 940663030. (800) 333-3032. Website: www.staywell.com. PRICE: Call or write for current pricing on single and bulk orders. Summary: This illustrated pamphlet provides the general public with information on the prevention and treatment of Lyme disease and the proper removal of a tick. Lyme disease is caused by bacteria that can be passed into the bloodstream through the bite of certain ticks. Common symptoms include a red, round rash; tiredness; sore or painful joints; headaches; and stiffness. Ways to prevent Lyme disease include avoiding areas infected with ticks, dressing with care, using insect repellent, staying on paved or cleared paths and trails, checking pets for ticks, and inspecting the body for ticks before going indoors. Diagnosis is based on a medical history, a physical examination, and, sometimes, a blood test. Antibiotics are used to treat the disease.

•

Poster Guide to Lyme Disease Source: Hartford, CT: Lyme Disease Foundation. 1998. 8 p. Contact: Available from Lyme Disease Foundation. 1 Financial Plaza, 18th Floor, Hartford, CT 06103. (800)886-LYME or (860) 525-2000. Fax (860) 525-TICK. E-mail: [email protected]. Website: www.lyme.org. PRICE: $1.00; bulk orders available at cost. Summary: This pamphlet provides people who have Lyme disease (LD) with information on this bacterial infection caused by a spirochete named Borrelia burgdorferi. The pamphlet presents the general signs and symptoms of LD, as well as those specific to the skin, brain, heart and blood vessels, lungs, eyes, joints and muscles, liver, gastrointestinal system, and spleen. Other topics include the antibody and direct detection tests used to help diagnose LD, treatment, examples of LD rashes, and guidelines on reducing the risk of tick bites and removing a tick properly. The pamphlet concludes with information about the Lyme Disease Foundation. 10 figures.

•

Guide to Lyme Disease Source: Hartford, CT: Lyme Disease Foundation. 1997. 8 p.

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Contact: Available from Lyme Disease Foundation. 1 Financial Plaza, 18th Floor, Hartford, CT 06103. (800)886-LYME or (860) 525-2000. Fax (860) 525-TICK. E-mail: [email protected]. Website: www.lyme.org. PRICE: $1.00; bulk orders available at cost. Summary: This pamphlet provides the general public with information about Lyme disease (LD), a bacterial infection caused by a spirochete called Borrelia burgdorferi. The spirochetes live in animals in nature. When certain ticks bite infected animals, they ingest the bacteria, then transmit the infection through subsequent feedings to other hosts, including humans and pets. The pamphlet explains how LD affects the brain, eyes, skin, heart and blood vessels, joints, liver, lungs, muscles, gastrointestinal system, spleen, and fetus. It identifies antibody and direct detection tests that may be used to help diagnose LD and explains how it is treated. The pamphlet offers tips on removing a tick and reducing the chances of getting a tick bite. In addition, the pamphlet provides information on the Lyme Disease Foundation and lists many of the free services it offers. 6 figures. •

Frequently Asked Questions About Lyme Disease Source: Hartford, CT: Lyme Disease Foundation. 1997. 6 p. Contact: Available from Lyme Disease Foundation. 1 Financial Plaza, 18th Floor, Hartford, CT 06103. (800)886-LYME or (860) 525-2000. Fax (860) 525-TICK. E-mail: [email protected]. Website: www.lyme.org. PRICE: $1.00; bulk orders available at cost. Summary: This pamphlet uses a question and answer format to provide the general public with information about Lyme disease (LD). The pamphlet describes the features of the LD rash and discusses the possible transmission of LD to an unborn child during pregnancy. Various tests may be used to help diagnose LD, such as immune systembased tests (the lymphocyte stimulation assay, antibody tests, and the Western blot test) and direct detection-based tests (the antigen capture assay and the polymerase chain reaction test). The pamphlet provides reasons for false-negative and false-positive antibody test results. Other topics include relapse, sexual transmission of LD, treatment methods, and reasons for early treatment.

•

Questions and Answers About the Lyme Disease Vaccine Source: Patient Care. 33(11): 209. June 15, 1999. Summary: This patient information sheet uses a question and answer format to provide the public with information about the Lyme disease vaccine, which has been approved only for people over 15 years old. The vaccine is suggested for those who are at high or moderate risk of getting Lyme disease. Factors placing people at high risk include living in a county where Lyme disease is common, having deer on residential property, and working or spending leisure time outdoors on a frequent or prolonged basis where Lyme disease is common. The vaccine should be given in three doses. The first dose should be followed by a second one a month later. The third dose should be administered 12 months after the second one. The vaccine is very effective, but it may not protect everyone. Therefore, people who receive the vaccine should still take precautions to protect themselves against tick bites. 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 “Lyme disease” (or synonyms). The following was recently posted: •

Practice guidelines for the treatment of Lyme disease Source: Infectious Diseases Society of America - Medical Specialty Society; 2000 July; 14 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2672&nbr=1898&a mp;string=Lyme+AND+disease

•

Prevention of Lyme disease Source: American Academy of Pediatrics - Medical Specialty Society; 2000 January; 6 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2767&nbr=1993&a mp;string=Lyme+AND+disease

•

Recommendations for the use of Lyme disease vaccine Source: Centers for Disease Control and Prevention - Federal Government Agency [U.S.]; 1999 June; 30 pages http://www.guideline.gov/summary/summary.aspx?doc_id=1978&nbr=1204&a mp;string=Lyme+AND+disease Healthfinder™

Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: •

Lyme Disease Research Efforts of NIAID Summary: NIAID is committed to research on Lyme borreliosis or Lyme disease. Basic and clinical research efforts funded by the this Institute encompass many different aspects of this disease. Source: National Institute of Allergy and Infectious Diseases, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=231

•

Lyme Disease; The facts, The Challenge Summary: In the early 1970s, a mysterious clustering of arthritis occured among children in Lyme, Connecticut, and surrounding towns. Source: National Institute of Allergy and Infectious Diseases, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=131

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Spotlight on Lyme Disease Summary: This page provides information about this tick-borne disease for consumers and health care professionals. Includes consumer information fact sheet and brochure and case studies. Source: National Center for Infectious Diseases, Centers for Disease Control and Prevention http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=2402

•

The Neurological Sequelae Of Lyme Disease Summary: A general overview of neurological sequelae of lyme disease that includes a description of the disorder, treatment, prognosis and research information. Source: National Institute of Neurological Disorders and Stroke, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=3799 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 Lyme disease. 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. PEDBASE Similar to NORD, PEDBASE covers relatively rare disorders, limited mainly to pediatric conditions. PEDBASE was designed by Dr. Alan Gandy. To access the database, which is more oriented to researchers than patients, you can view the current list of health topics covered at the following Web site: http://www.icondata.com/health/pedbase/pedlynx.htm. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats

•

Family Village: http://www.familyvillage.wisc.edu/specific.htm

•

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

•

Med Help International: http://www.medhelp.org/HealthTopics/A.html

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•

Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/

•

Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/

•

WebMDHealth: http://my.webmd.com/health_topics

Associations and Lyme Disease The following is a list of associations that provide information on and resources relating to Lyme disease: •

American Lyme Disease Foundation, Inc Telephone: (914) 277-6970 Toll-free: (800) 876-5963 Fax: (914) 277-6974 Email: [email protected] Web Site: http://www.aldf.com Background: The American Lyme Disease Foundation, Inc. (ALDF) is a nonprofit organization that is dedicated to advancing treatment, research, prevention, and public awareness of Lyme disease and other tickborne illnesses. Lyme disease is an infectious tick-transmitted disease characterized by an early skin lesion and, subsequently, a growing red area on the skin (i.e., 'bull's eye' rash). In some cases, later symptoms may include joint, neurological, and/or heart problems. Established in 1990, the Foundation's work focuses on public and professional education and support of research. ALDF produces several brochures, including 'A Quick Guide to Lyme Disease,' 'Understanding Ticks and Lyme Disease (new in 2003, a 'Tick Identification Card' (which helps identify different types of ticks and proper removal of them)and a 'National Clinical Conference on Lyme Disease' supplement to the American Journal of Medicine (April 1995). Other educational materials include reports, videos, and a selection of audiovisual aids. The Foundation provides a toll-free informational number and a national physician referral service. The ALDF also supports peer-revied research into the prevention and control of tick-borne infections, and, in collaboration with the Dutchess County Department of Health and the Institute of Ecosystem Studies in Millbrook, NY, has been awarded a 3-year $300,000/yr. grant from the Centers for Disease Control and Prevention (CDC) to develop and implement innovative new programs to reduce tick habitat and populations at selected sites in the county to reduce disease risk. Relevant area(s) of interest: Lyme Arthritis, Lyme Borreliosis, Lyme Disease

•

Lyme Disease Foundation Telephone: (860) 525-2000 Toll-free: (800) 886-5963 Fax: (860) 525-8425 Email: [email protected] Web Site: http://www.lyme.org Background: The Lyme Disease Foundation, Inc. (LDF) is a voluntary not-for-profit organization dedicated to finding the solutions to Lyme Disease and other tick-borne disorders. Established in 1988, the Lyme Disease Foundation funds research on Lyme Disease (LD), conducts international scientific conferences, and publishes a peerreviewed scientific journal. It has successfully lobbied Congress for federal funds

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dedicated to Lyme Disease education and research. In addition, the Lyme Disease Foundation provides appropriate referrals, promotes patient advocacy, and supports the development of educational programs for affected individuals, family members, the medical and scientific communities, and the public. The Lyme Disease Foundation s many educational and support materials include a monthly self-help newsletter and a Lyme Disease Awareness Pack. A Lyme Disease Scientific Pack includes reprints of medical articles, scientific slide show information, and guidelines for establishing and conducting a self-help group. In addition, the Foundation distributes educational program materials for students, workplace and community education program materials, poster sets, brochures, and videotapes. Relevant area(s) of interest: Lyme Disease

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to Lyme disease. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with Lyme disease. 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 Lyme disease. 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 “Lyme disease” (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.

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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 “Lyme disease”. 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 “Lyme disease” (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 “Lyme disease” (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.23

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

23

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)24: •

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/

24

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

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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/

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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

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Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

•

Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

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Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

•

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

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Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

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Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

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Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

•

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/

Finding Medical Libraries

225

•

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

227

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). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on Lyme disease: •

Basic Guidelines for Lyme Disease Lyme disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001319.htm Lyme disease - primary Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000670.htm Lyme disease - secondary Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000625.htm Lyme disease - tertiary Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000669.htm Lyme disease antibody Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003554.htm

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•

Signs & Symptoms for Lyme Disease Behavior, unusual or strange Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003255.htm Blurred vision Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003029.htm Confusion Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003205.htm Consciousness, decreased Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003202.htm Depression Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003213.htm Erythema Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003220.htm Eyelid drooping Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003035.htm Facial paralysis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003028.htm Fainting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003092.htm Fatigue Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Fever Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003090.htm Hallucinations Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003258.htm Headache Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003024.htm Heart palpitations Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003081.htm Itching, overall Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003217.htm Joint inflammation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003261.htm Joint stiffness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003261.htm

Online Glossaries 229

Lethargy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Malaise Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003089.htm Memory loss Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003257.htm Mood changes Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003213.htm Movement, dysfunctional Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003203.htm Muscle Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003193.htm Muscle pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003178.htm Muscle pains Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003178.htm Myalgia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003178.htm Nausea and vomiting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003117.htm Neck pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003025.htm Numbness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003206.htm Numbness and tingling Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003206.htm Paralysis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003190.htm Rash Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003220.htm Sensitivity to light Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003041.htm Skin lesions Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003220.htm

230 Lyme Disease

Skin rash Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003220.htm Speech impairment Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003204.htm Stiff neck Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003261.htm Tingling Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003206.htm Weakness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003174.htm •

Diagnostics and Tests for Lyme Disease Biopsy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003416.htm Blood pressure Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003398.htm Chest X-ray Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm CT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm ECG Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003868.htm Echocardiogram Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm ELISA Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003332.htm Immunofluorescence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003521.htm MRI Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003335.htm Nuclear ventriculography Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003822.htm Serology Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003511.htm Skin biopsy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003840.htm

Online Glossaries 231

Venipuncture Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003423.htm Western blot Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003538.htm •

Background Topics for Lyme Disease Lyme disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001319.htm Acute Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002215.htm Adolescent test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002054.htm Antibodies Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002223.htm Antibody Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002223.htm Bleeding Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000045.htm Central nervous system Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002311.htm Chronic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002312.htm Incidence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002387.htm Infant test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002055.htm Lyme disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001319.htm Physical examination Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002274.htm Preschooler test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002057.htm Schoolage test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002058.htm Tick Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002856.htm

232 Lyme Disease

Tick bite Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000033.htm Tick bite Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002856.htm Ticks Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002856.htm Titer Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002328.htm Toddler test or procedure preparation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002056.htm

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

•

MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

•

Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

•

Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

233

LYME DISEASE 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] Ablate: In surgery, is to remove. [NIH] Abscess: Accumulation of purulent material in tissues, organs, or circumscribed spaces, usually associated with signs of infection. [NIH] Acrodermatitis: Inflammation involving the skin of the extremities, especially the hands and feet. Several forms are known, some idiopathic and some hereditary. The infantile form is called Gianotti-Crosti syndrome. [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] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adduct: Complex formed when a carcinogen combines with DNA or a protein. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adsorption: The condensation of gases, liquids, or dissolved substances on the surfaces of solids. It includes adsorptive phenomena of bacteria and viruses as well as of tissues treated with exogenous drugs and chemicals. [NIH] Adsorptive: It captures volatile compounds by binding them to agents such as activated carbon or adsorptive resins. [NIH] 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]

234 Lyme Disease

Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]

Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Affinity Chromatography: In affinity chromatography, a ligand attached to a column binds specifically to the molecule to be purified. [NIH] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]

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] A-HA: First enzyme in the biosynthetic pathway of branched-chain amino acids. [NIH] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Airway Obstruction: Any hindrance to the passage of air into and out of the lungs. [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] 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] Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. [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]

Dictionary 235

Allergic Rhinitis: Inflammation of the nasal mucous membrane associated with hay fever; fits may be provoked by substances in the working environment. [NIH] Allogeneic: Taken from different individuals of the same species. [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] Alveoli: Tiny air sacs at the end of the bronchioles in the lungs. [NIH] 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] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amoxicillin: A broad-spectrum semisynthetic antibiotic similar to ampicillin except that its resistance to gastric acid permits higher serum levels with oral administration. [NIH] Ampicillin: Semi-synthetic derivative of penicillin that functions as an orally active broadspectrum antibiotic. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] 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] Anaplasia: Loss of structural differentiation and useful function of neoplastic cells. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH]

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Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] 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] Angioplasty: Endovascular reconstruction of an artery, which may include the removal of atheromatous plaque and/or the endothelial lining as well as simple dilatation. These are procedures performed by catheterization. When reconstruction of an artery is performed surgically, it is called endarterectomy. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]

Anomalies: Birth defects; abnormalities. [NIH] Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] 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]

Dictionary 237

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] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiproliferative: Counteracting a process of proliferation. [EU] Antipruritic: Relieving or preventing itching. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] 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] Approximate: Approximal [EU] Aqueous: Having to do with water. [NIH] Aromatic: Having a spicy odour. [EU] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arteriolar: Pertaining to or resembling arterioles. [EU] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arthropod Vectors: Arthropods, other than insects and arachnids, which transmit infective organisms from one host to another or from an inanimate reservoir to an animate host. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Asystole: Cardiac standstill or arrest; absence of a heartbeat; called also Beau's syndrome. [EU]

Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atopic: Pertaining to an atopen or to atopy; allergic. [EU]

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Attenuated: Strain with weakened or reduced virulence. [NIH] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Audiovisual Aids: Auditory and visual instructional materials. [NIH] Auditory: Pertaining to the sense of hearing. [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] Autodigestion: Autolysis; a condition found in disease of the stomach: the stomach wall is digested by the gastric juice. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autonomic Nervous System: The enteric, parasympathetic, and sympathetic nervous systems taken together. Generally speaking, the autonomic nervous system regulates the internal environment during both peaceful activity and physical or emotional stress. Autonomic activity is controlled and integrated by the central nervous system, especially the hypothalamus and the solitary nucleus, which receive information relayed from visceral afferents; these and related central and sensory structures are sometimes (but not here) considered to be part of the autonomic nervous system itself. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Babesiosis: A group of tick-borne diseases of mammals including zoonoses in humans. They are caused by protozoans of the genus babesia, which parasitize erythrocytes, producing hemolysis. In the U.S., the organism's natural host is mice and transmission is by the deer tick ixodes scapularis. [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] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Adhesion: Physicochemical property of fimbriated and non-fimbriated bacteria of attaching to cells, tissue, and nonbiological surfaces. It is a factor in bacterial colonization and pathogenicity. [NIH] Bacterial Infections: Infections by bacteria, general or unspecified. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bacterial Proteins: Proteins found in any species of bacterium. [NIH] Bacterial Vaccines: Suspensions of attenuated or killed bacteria administered for the prevention or treatment of infectious bacterial disease. [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]

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Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Bewilderment: Impairment or loss of will power. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Pigments: Pigments that give a characteristic color to bile including: bilirubin, biliverdine, and bilicyanin. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biliary Tract: The gallbladder and its ducts. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioassays: Determination of the relative effective strength of a substance (as a vitamin, hormone, or drug) by comparing its effect on a test organism with that of a standard preparation. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Bioengineering: The application of engineering principles to the solution of biological problems, for example, remote-handling devices, life-support systems, controls, and displays. [NIH] Biological Markers: Measurable and quantifiable biological parameters (e.g., specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, environmental exposure and its effects, disease diagnosis, metabolic processes, substance abuse, pregnancy, cell line development, epidemiologic studies, etc. [NIH]

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Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biopsy specimen: Tissue removed from the body and examined under a microscope to determine whether disease is present. [NIH] 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] Biotic: Pertaining to living organisms in their ecological rather than their physiological relations. [NIH] Biotin: Hexahydro-2-oxo-1H-thieno(3,4-d)imidazole-4-pentanoic acid. Growth factor present in minute amounts in every living cell. It occurs mainly bound to proteins or polypeptides and is abundant in liver, kidney, pancreas, yeast, and milk.The biotin content of cancerous tissue is higher than that of normal tissue. [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] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood transfusion: The administration of blood or blood products into a blood vessel. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Blotting, Western: Identification of proteins or peptides that have been electrophoretically separated by blotting and transferred to strips of nitrocellulose paper. The blots are then detected by radiolabeled antibody probes. [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 scan: A technique to create images of bones on a computer screen or on film. A small

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amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [NIH] Borrelia: A genus of gram-negative, anaerobic, helical bacteria; various species of which produce relapsing fever in man and other animals. [NIH] Borrelia burgdorferi: Gram-negative helical bacteria that are the etiologic agents of Lyme disease. These spirochetes are generally transmitted by several species of ixodid ticks. [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] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [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] 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] 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] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [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

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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] Castor Bean: Common name for Ricinus communis, a species in the family Euphorbiaceae. It is the source of castor oil. [NIH] Castor Oil: Oil obtained from seeds of Ricinus communis that is used as a cathartic and as a plasticizer. [NIH] Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ, or body cavity for injecting or withdrawing fluids for diagnostic or therapeutic purposes. It differs from intubation in that the tube here is used to restore or maintain patency in obstructions. [NIH] Causal: Pertaining to a cause; directed against a cause. [EU] Ceftriaxone: Broad-spectrum cephalosporin antibiotic with a very long half-life and high penetrability to usually inaccessible infections, including those involving the meninges, eyes, inner ears, and urinary tract. [NIH] Cefuroxime: Broad-spectrum cephalosporin antibiotic resistant to beta-lactamase. It has been proposed for infections with gram-negative and gram-positive organisms, gonorrhea, and haemophilus. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Count: A count of the number of cells of a specific kind, usually measured per unit volume of sample. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell Movement: The movement of cells from one location to another. [NIH] Cellular Structures: Components of a cell. [NIH] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Central Nervous System Infections: Pathogenic infections of the brain, spinal cord, and meninges. DNA virus infections; RNA virus infections; bacterial infections; mycoplasma infections; Spirochaetales infections; fungal infections; protozoan infections; helminthiasis;

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and prion diseases may involve the central nervous system as a primary or secondary process. [NIH] Central retinal artery: The blood vessel that carries blood into eye; supplies nutrition to the retina. [NIH] Central retinal vein: The blood vessel that carries blood from the retina. [NIH] Cephalexin: A semisynthetic cephalosporin antibiotic with antimicrobial activity similar to that of cephaloridine or cephalothin, but somewhat less potent. It is effective against both gram-positive and gram-negative organisms. [NIH] Cephaloridine: A cephalosporin antibiotic. [NIH] Cephalothin: A cephalosporin antibiotic. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Palsy: Refers to a motor disability caused by a brain dysfunction. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Chemokines: Class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. They can be divided into at least three structural branches: C (chemokines, C), CC (chemokines, CC), and CXC (chemokines, CXC), according to variations in a shared cysteine motif. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotaxis: The movement of cells or organisms toward or away from a substance in response to its concentration gradient. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chlamydia: A genus of the family Chlamydiaceae whose species cause a variety of diseases in vertebrates including humans, mice, and swine. Chlamydia species are gram-negative and produce glycogen. The type species is Chlamydia trachomatis. [NIH] Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [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] Cholestyramine: Strongly basic anion exchange resin whose main constituent is polystyrene trimethylbenzylammonium as Cl(-) anion. It exchanges chloride ions with bile salts, thus decreasing their concentration and that of cholesterol. It is used as a hypocholesteremic in diarrhea and biliary obstruction and as an antipruritic. [NIH]

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Chorioretinitis: Inflammation of the choroid in which the sensory retina becomes edematous and opaque. The inflammatory cells and exudate may burst through the sensory retina to cloud the vitreous body. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic Fatigue Syndrome: Fatigue caused by the combined effects of different types of prolonged fatigue. [NIH] Chronic lymphocytic leukemia: A slowly progressing disease in which too many white blood cells (called lymphocytes) are found in the body. [NIH] Chronic myelogenous leukemia: CML. A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myeloid leukemia or chronic granulocytic leukemia. [NIH] Chronic Obstructive Pulmonary Disease: Collective term for chronic bronchitis and emphysema. [NIH] Chronic 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] Circulatory system: The system that contains the heart and the blood vessels and moves blood throughout the body. This system helps tissues get enough oxygen and nutrients, and it helps them get rid of waste products. The lymph system, which connects with the blood system, is often considered part of the circulatory system. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Clarithromycin: A semisynthetic macrolide antibiotic derived from erythromycin that is active against a variety of microorganisms. It can inhibit protein synthesis in bacteria by reversibly binding to the 50S ribosomal subunits. This inhibits the translocation of aminoacyl transfer-RNA and prevents peptide chain elongation. [NIH] 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 Medicine: The study and practice of medicine by direct examination of the patient. [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]

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Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]

Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Clot Retraction: Retraction of a clot resulting from contraction of platelet pseudopods attached to fibrin strands that is dependent on the contractile protein thrombosthenin. Used as a measure of platelet function. [NIH] 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] Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever (periodic disease). [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] Collagen disease: A term previously used to describe chronic diseases of the connective tissue (e.g., rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis), but now is thought to be more appropriate for diseases associated with defects in collagen, which is a component of the connective tissue. [NIH] Colloidal: Of the nature of a colloid. [EU] 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

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pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] 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] 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] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Conduction: The transfer of sound waves, heat, nervous impulses, or electricity. [EU] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Conjunctivitis: Inflammation of the conjunctiva, generally consisting of conjunctival hyperaemia associated with a discharge. [EU]

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Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Constriction: The act of constricting. [NIH] Contact dermatitis: Inflammation of the skin with varying degrees of erythema, edema and vesinculation resulting from cutaneous contact with a foreign substance or other exposure. [NIH]

Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Contrast Sensitivity: The ability to detect sharp boundaries (stimuli) and to detect slight changes in luminance at regions without distinct contours. Psychophysical measurements of this visual function are used to evaluate visual acuity and to detect eye disease. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]

Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Corpus: The body of the uterus. [NIH] Corpus Luteum: The yellow glandular mass formed in the ovary by an ovarian follicle that has ruptured and discharged its ovum. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Corticosteroids: Hormones that have antitumor activity in lymphomas and lymphoid leukemias; in addition, corticosteroids (steroids) may be used for hormone replacement and for the management of some of the complications of cancer and its treatment. [NIH] Coumarin: A fluorescent dye. [NIH] Cowpox: A mild, eruptive skin disease of milk cows caused by cowpox virus, with lesions occurring principally on the udder and teats. Human infection may occur while milking an infected animal. [NIH]

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Cowpox Virus: A species of orthopoxvirus that is the etiologic agent of cowpox. It is closely related to but antigenically different from vaccina virus. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Cues: Signals for an action; that specific portion of a perceptual field or pattern of stimuli to which a subject has learned to respond. [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] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cytogenetics: A branch of genetics which deals with the cytological and molecular behavior of genes and chromosomes during cell division. [NIH] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] 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] Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [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] Databases, Bibliographic: Extensive collections, reputedly complete, of references and citations to books, articles, publications, etc., generally on a single subject or specialized subject area. Databases can operate through automated files, libraries, or computer disks. The concept should be differentiated from factual databases which is used for collections of data and facts apart from bibliographic references to them. [NIH] Defense Mechanisms: Unconscious process used by an individual or a group of individuals in order to cope with impulses, feelings or ideas which are not acceptable at their conscious level; various types include reaction formation, projection and self reversal. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH]

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Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dendritic cell: A special type of antigen-presenting cell (APC) that activates T lymphocytes. [NIH]

Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dermal: Pertaining to or coming from the skin. [NIH] Dermatitis: Any inflammation of the skin. [NIH] Dermatology: A medical specialty concerned with the skin, its structure, functions, diseases, and treatment. [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] Diagnostic procedure: A method used to identify a disease. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diathesis: A constitution or condition of the body which makes the tissues react in special ways to certain extrinsic stimuli and thus tends to make the person more than usually susceptible to certain diseases. [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] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Dilatation: The act of dilating. [NIH] Dilution: A diluted or attenuated medicine; in homeopathy, the diffusion of a given quantity of a medicinal agent in ten or one hundred times the same quantity of water. [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] Disease Transmission: The transmission of infectious disease or pathogens. When transmission is within the same species, the mode can be horizontal (disease transmission, horizontal) or vertical (disease transmission, vertical). [NIH]

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Disease Transmission, Horizontal: The transmission of infectious disease or pathogens from one individual to another in the same generation. [NIH] Disease Transmission, Vertical: The transmission of infectious disease or pathogens from one generation to another. It includes transmission in utero or intrapartum by exposure to blood and secretions, and postpartum exposure via breastfeeding. [NIH] Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [EU] 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] Dizziness: An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. [NIH] Domesticated: Species in which the evolutionary process has been influenced by humans to meet their needs. [NIH] Doxycycline: A synthetic tetracycline derivative with a range of antimicrobial activity and mode of action similar to that of tetracycline, but more effective against many species. Animal studies suggest that it may cause less tooth staining than other tetracyclines. [NIH] Dreams: A series of thoughts, images, or emotions occurring during sleep which are dissociated from the usual stream of consciousness of the waking state. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [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] 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] Dysphoria: Disquiet; restlessness; malaise. [EU] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most

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commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [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] Ehrlichiosis: A tick-borne disease characterized by fever, headache, myalgias, anorexia, and occasionally rash. In humans the disease is caused by Ehrlichia chaffeensis, in dogs it is caused by E. canis, and in horses, E. equi. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] 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]

Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Encephalitis: Inflammation of the brain due to infection, autoimmune processes, toxins, and other conditions. Viral infections (see encephalitis, viral) are a relatively frequent cause of this condition. [NIH] Encephalitis, Viral: Inflammation of brain parenchymal tissue as a result of viral infection. Encephalitis may occur as primary or secondary manifestation of Togaviridae infections; Herpesviridae infections; Adenoviridae infections; Flaviviridae infections; Bunyaviridae infections; Picornaviridae infections; Paramyxoviridae infections; Orthomyxoviridae infections; Retroviridae infections; and Arenaviridae infections. [NIH] Encephalopathy: A disorder of the brain that can be caused by disease, injury, drugs, or chemicals. [NIH] Endarterectomy: Surgical excision, performed under general anesthesia, of the atheromatous tunica intima of an artery. When reconstruction of an artery is performed as an endovascular procedure through a catheter, it is called atherectomy. [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] Endometrial: Having to do with the endometrium (the layer of tissue that lines the uterus). [NIH]

Endometriosis: A condition in which tissue more or less perfectly resembling the uterine mucous membrane (the endometrium) and containing typical endometrial granular and stromal elements occurs aberrantly in various locations in the pelvic cavity. [NIH] Endometrium: The layer of tissue that lines the uterus. [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]

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Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] 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] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme-Linked Immunosorbent Assay: An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed. [NIH] Eosinophilia: Abnormal increase in eosinophils in the blood, tissues or organs. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [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 Factors: Events, characteristics, or other definable entities that have the potential to bring about a change in a health condition or other defined outcome. [NIH] 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] Episcleritis: Inflammation of the episclera and/or the outer layers of the sclera itself. [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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Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]

Erythema: Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of causes. [NIH] Erythema Chronicum Migrans: A deep type of gyrate erythema that follows a bite by an ixodid tick; it is a stage-1 manifestation of Lyme disease. The site of the bite is characterized by a red papule that expands peripherally as a nonscaling, palpable band that clears centrally. This condition is often associated with systemic symptoms such as chills, fever, headache, malaise, nausea, vomiting, fatigue, backache, and stiff neck. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythromycin: A bacteriostatic antibiotic substance produced by Streptomyces erythreus. Erythromycin A is considered its major active component. In sensitive organisms, it inhibits protein synthesis by binding to 50S ribosomal subunits. This binding process inhibits peptidyl transferase activity and interferes with translocation of amino acids during translation and assembly of proteins. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Evoked Potentials: The electric response evoked in the central nervous system by stimulation of sensory receptors or some point on the sensory pathway leading from the receptor to the cortex. The evoked stimulus can be auditory, somatosensory, or visual, although other modalities have been reported. Event-related potentials is sometimes used synonymously with evoked potentials but is often associated with the execution of a motor, cognitive, or psychophysiological task, as well as with the response to a stimulus. [NIH] Excipient: Any more or less inert substance added to a prescription in order to confer a suitable consistency or form to the drug; a vehicle. [EU] Exhaustion: The feeling of weariness of mind and body. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exotoxin: Toxic substance excreted by living bacterial cells. [NIH] Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [NIH]

Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the

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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] Extraction: The process or act of pulling or drawing out. [EU] Extravasation: A discharge or escape, as of blood, from a vessel into the tissues. [EU] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Exudate: Material, such as fluid, cells, or cellular debris, which has escaped from blood vessels and has been deposited in tissues or on tissue surfaces, usually as a result of inflammation. An exudate, in contrast to a transudate, is characterized by a high content of protein, cells, or solid materials derived from cells. [EU] Facial: Of or pertaining to the face. [EU] Facial Nerve: The 7th cranial nerve. The facial nerve has two parts, the larger motor root which may be called the facial nerve proper, and the smaller intermediate or sensory root. Together they provide efferent innervation to the muscles of facial expression and to the lacrimal and salivary glands, and convey afferent information for taste from the anterior two-thirds of the tongue and for touch from the external ear. [NIH] Facial Pain: Pain in the facial region including orofacial pain and craniofacial pain. Associated conditions include local inflammatory and neoplastic disorders and neuralgic syndromes involving the trigeminal, facial, and glossopharyngeal nerves. Conditions which feature recurrent or persistent facial pain as the primary manifestation of disease are referred to as facial pain syndromes. [NIH] False Positive Reactions: Area that the program rates as suspicious but that the radiologist ultimately decides does not represent a possible malignancy. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Far East: A geographic area of east and southeast Asia encompassing China, Hong Kong, Japan, Korea, Macao, Mongolia, and Taiwan. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatal Outcome: Death resulting from the presence of a disease in an individual, as shown by 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] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Febrile: Pertaining to or characterized by fever. [EU] Fetal Death: Death of the young developing in utero. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three non-

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identical 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] Fibrinolytic: Pertaining to, characterized by, or causing the dissolution of fibrin by enzymatic action [EU] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Flagellin: A protein with a molecular weight of 40,000 isolated from bacterial flagella. At appropriate pH and salt concentration, three flagellin monomers can spontaneously reaggregate to form structures which appear identical to intact flagella. [NIH] Flagellum: A whiplike appendage of a cell. It can function either as an organ of locomotion or as a device for moving the fluid surrounding the cell. [NIH] Fleas: Parasitic, blood-sucking, wingless insects comprising the order Siphonaptera. [NIH] Flexor: Muscles which flex a joint. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Foramen: A natural hole of perforation, especially one in a bone. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Frameshift: A type of mutation which causes out-of-phase transcription of the base sequence; such mutations arise from the addition or delection of nucleotide(s) in numbers other than 3 or multiples of 3. [NIH] Frameshift Mutation: A type of mutation in which a number of nucleotides not divisible by three is deleted from or inserted into a coding sequence, thereby causing an alteration in the reading frame of the entire sequence downstream of the mutation. These mutations may be induced by certain types of mutagens or may occur spontaneously. [NIH] Fructose: A type of sugar found in many fruits and vegetables and in honey. Fructose is used to sweeten some diet foods. It is considered a nutritive sweetener because it has calories. [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] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a

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aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] 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] Gas exchange: Primary function of the lungs; transfer of oxygen from inhaled air into the blood and of carbon dioxide from the blood into the lungs. [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Acid: Hydrochloric acid present in gastric juice. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastrointestinal: Refers to the stomach and intestines. [NIH] Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [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] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Order: The sequential location of genes on a chromosome. [NIH] Gene Pool: The total genetic information possessed by the reproductive members of a population of sexually reproducing organisms. [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 Screening: Searching a population or individuals for persons possessing certain genotypes or karyotypes that: (1) are already associated with disease or predispose to disease; (2) may lead to disease in their descendants; or (3) produce other variations not known to be associated with disease. Genetic screening may be directed toward identifying phenotypic expression of genetic traits. It includes prenatal genetic screening. [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] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genomics: The systematic study of the complete DNA sequences (genome) of organisms.

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[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] 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] Gliosis: The production of a dense fibrous network of neuroglia; includes astrocytosis, which is a proliferation of astrocytes in the area of a degenerative lesion. [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] Glossopharyngeal Nerve: The 9th cranial nerve. The glossopharyngeal nerve is a mixed motor and sensory nerve; it conveys somatic and autonomic efferents as well as general, special, and visceral afferents. Among the connections are motor fibers to the stylopharyngeus muscle, parasympathetic fibers to the parotid glands, general and taste afferents from the posterior third of the tongue, the nasopharynx, and the palate, and afferents from baroreceptors and chemoreceptors of the carotid sinus. [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] Glucuronic Acid: Derivatives of uronic acid found throughout the plant and animal kingdoms. They detoxify drugs and toxins by conjugating with them to form glucuronides in the liver which are more water-soluble metabolites that can be easily eliminated from the body. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycan: A type of long, unbranched polysaccharide molecule. Glycosaminoglycans are major structural components of cartilage and are also found in the cornea of the eye. [NIH] Gonorrhea: Acute infectious disease characterized by primary invasion of the urogenital tract. The etiologic agent, Neisseria gonorrhoeae, was isolated by Neisser in 1879. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]

Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the

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recipient. [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-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] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Grasses: A large family, Gramineae, of narrow-leaved herbaceous monocots. Many grasses produce highly allergenic pollens and are hosts to cattle parasites and toxic fungi. [NIH] Groin: The external junctural region between the lower part of the abdomen and the thigh. [NIH]

Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [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] Haemophilus: A genus of Pasteurellaceae that consists of several species occurring in animals and humans. Its organisms are described as gram-negative, facultatively anaerobic, coccobacillus or rod-shaped, and nonmotile. [NIH] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] 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] Headache Disorders: Common conditions characterized by persistent or recurrent headaches. Headache syndrome classification systems may be based on etiology (e.g., vascular headache, post-traumatic headaches, etc.), temporal pattern (e.g., cluster headache, paroxysmal hemicrania, etc.), and precipitating factors (e.g., cough headache). [NIH] Health Resources: Available manpower, facilities, revenue, equipment, and supplies to produce requisite health care and services. [NIH] Health Services: Services for the diagnosis and treatment of disease and the maintenance of health. [NIH] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [NIH]

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Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heartbeat: One complete contraction of the heart. [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] Hematogenous: Originating in the blood or spread through the bloodstream. [NIH] Hemicrania: An ache or a pain in one side of the head, as in migraine. [NIH] Hemolysis: The destruction of erythrocytes by many different causal agents such as antibodies, bacteria, chemicals, temperature, and changes in tonicity. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]

Heparin: Heparinic acid. A highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. [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] Heterodimers: Zippered pair of nonidentical proteins. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]

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] 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] Horseradish Peroxidase: An enzyme isolated from horseradish which is able to act as an antigen. It is frequently used as a histochemical tracer for light and electron microscopy. Its antigenicity has permitted its use as a combined antigen and marker in experimental immunology. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain

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hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hybridoma: A hybrid cell resulting from the fusion of a specific antibody-producing spleen cell with a myeloma cell. [NIH] 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] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hyperaemia: An excess of blood in a part; engorgement. [EU] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hypercapnia: A clinical manifestation of abnormal increase in the amount of carbon dioxide in arterial blood. [NIH] 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] Hypesthesia: Absent or reduced sensitivity to cutaneous stimulation. [NIH] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Illusion: A false interpretation of a genuine percept. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [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] Immune Tolerance: The specific failure of a normally responsive individual to make an immune response to a known antigen. It results from previous contact with the antigen by

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an immunologically immature individual (fetus or neonate) or by an adult exposed to extreme high-dose or low-dose antigen, or by exposure to radiation, antimetabolites, antilymphocytic serum, etc. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] 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] Immunoblotting: Immunologic methods for isolating and quantitatively measuring immunoreactive substances. When used with immune reagents such as monoclonal antibodies, the process is known generically as western blot analysis (blotting, western). [NIH]

Immunocompromised: Having a weakened immune system caused by certain diseases or treatments. [NIH] Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunogen: A substance that is capable of causing antibody formation. [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] 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] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU]

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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] Incompetence: Physical or mental inadequacy or insufficiency. [EU] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [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] Infantile: Pertaining to an infant or to infancy. [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]

Infectious Mononucleosis: A common, acute infection usually caused by the Epstein-Barr virus (Human herpesvirus 4). There is an increase in mononuclear white blood cells and other atypical lymphocytes, generalized lymphadenopathy, splenomegaly, and occasionally hepatomegaly with hepatitis. [NIH] Infestation: Parasitic attack or subsistence on the skin and/or its appendages, as by insects, mites, or ticks; sometimes used to denote parasitic invasion of the organs and tissues, as by helminths. [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 severe, often generalized, myalgia. [NIH] Information Systems: Integrated set of files, procedures, and equipment for the storage, manipulation, and retrieval of information. [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

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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] Inner ear: The labyrinth, comprising the vestibule, cochlea, and semicircular canals. [NIH] Innervation: 1. The distribution or supply of nerves to a part. 2. The supply of nervous energy or of nerve stimulus sent to a part. [EU] Insect Repellents: Substances causing insects to turn away from them or reject them as food. [NIH]

Insect Vectors: Insects that transmit infective organisms from one host to another or from an inanimate reservoir to an animate host. [NIH] Insertional: A technique in which foreign DNA is cloned into a restriction site which occupies a position within the coding sequence of a gene in the cloning vector molecule. Insertion interrupts the gene's sequence such that its original function is no longer expressed. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insomnia: Difficulty in going to sleep or getting enough sleep. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Integrins: A family of transmembrane glycoproteins consisting of noncovalent heterodimers. They interact with a wide variety of ligands including extracellular matrix glycoproteins, complement, and other cells, while their intracellular domains interact with the cytoskeleton. The integrins consist of at least three identified families: the cytoadhesin receptors, the leukocyte adhesion receptors, and the very-late-antigen receptors. Each family contains a common beta-subunit combined with one or more distinct alpha-subunits. These receptors participate in cell-matrix and cell-cell adhesion in many physiologically important processes, including embryological development, hemostasis, thrombosis, wound healing, immune and nonimmune defense mechanisms, and oncogenic transformation. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are

264 Lyme Disease

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-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] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intervention Studies: Epidemiologic investigations designed to test a hypothesized causeeffect relation by modifying the supposed causal factor(s) in the study population. [NIH] Intestines: The section of the alimentary canal from the stomach to the anus. It includes the large intestine and small intestine. [NIH] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intracranial Pressure: Pressure within the cranial cavity. It is influenced by brain mass, the circulatory system, CSF dynamics, and skull rigidity. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intrathecal: Describes the fluid-filled space between the thin layers of tissue that cover the brain and spinal cord. Drugs can be injected into the fluid or a sample of the fluid can be removed for testing. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Intrinsic Factor: A glycoprotein secreted by the cells of the gastric glands that is required for the absorption of vitamin B 12. Deficiency of intrinsic factor results in pernicious anemia. [NIH]

Introns: Non-coding, intervening sequences of DNA that are transcribed, but are removed from within the primary gene transcript and rapidly degraded during maturation of messenger RNA. Most genes in the nuclei of eukaryotes contain introns, as do mitochondrial and chloroplast genes. [NIH] 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]

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] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isoelectric: Separation of amphoteric substances, dissolved in water, based on their

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isoelectric behavior. The amphoteric substances are a mixture of proteins to be separated and of auxiliary "carrier ampholytes". [NIH] Isoelectric Point: The pH in solutions of proteins and related compounds at which the dipolar ions are at a maximum. [NIH] Isozymes: The multiple forms of a single enzyme. [NIH] Ixodes: A large, widely distributed genus of ticks consisting of approximately 245 species. Many infest man and other mammals and several are vectors of diseases such as Lyme disease, tick-borne encephalitis (encephalitis, tick-borne), and Kyasanur forest disease. [NIH] Ixodid: A tick of the genus Ixodes. [NIH] Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH]

Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Keratitis: Inflammation of the cornea. [NIH] Kilobase: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [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] Lacrimal: Pertaining to the tears. [EU] Lactate Dehydrogenase: A tetrameric enzyme that, along with the coenzyme NAD+, catalyzes the interconversion of lactate and pyruvate. In vertebrates, genes for three different subunits (LDH-A, LDH-B and LDH-C) exist. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] 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] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] 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] Leptospirosis: Infections with bacteria of the genus Leptospira. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethargy: Abnormal drowsiness or stupor; a condition of indifference. [EU] Leukapheresis: The preparation of leukocyte concentrates with the return of red cells and

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leukocyte-poor plasma to the donor. [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] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Lice: A general name for small, wingless, parasitic insects, previously of the order Phthiraptera. Though exact taxonomy is still controversial, they can be grouped in the orders Anoplura (sucking lice), Mallophaga (biting lice), and Rhynchophthirina (elephant lice). [NIH] Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Ligaments: Shiny, flexible bands of fibrous tissue connecting together articular extremities of bones. They are pliant, tough, and inextensile. [NIH] Ligands: A RNA simulation method developed by the MIT. [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 A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [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] 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] Litter: Appliance consisting of an oblong frame over which is stretched a canvas or other material, used for carrying an injured or disabled person. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver scan: An image of the liver created on a computer screen or on film. A radioactive substance is injected into a blood vessel and travels through the bloodstream. It collects in the liver, especially in abnormal areas, and can be detected by the scanner. [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]

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Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] 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] Lumbar: Pertaining to the loins, the part of the back between the thorax and the pelvis. [EU] Lumbar puncture: A procedure in which a needle is put into the lower part of the spinal column to collect cerebrospinal fluid or to give anticancer drugs intrathecally. Also called a spinal tap. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lyme Disease: An infectious disease caused by a spirochete, Borrelia burgdorferi, which is transmitted chiefly by Ixodes dammini and pacificus ticks in the United States and Ixodes ricinis in Europe. It is a disease with early and late cutaneous manifestations plus involvement of the nervous system, heart, eye, and joints in variable combinations. The disease was formerly known as Lyme arthritis and first discovered at Old Lyme, Connecticut. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphadenopathy: Disease or swelling of the lymph nodes. [NIH] Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] 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 Subsets: A classification of lymphocytes based on structurally or functionally different populations of cells. [NIH] Lymphocytic: Referring to lymphocytes, a type of white blood cell. [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

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cells, primarily those involved in cellular immunity. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [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] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] 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] Malaise: A vague feeling of bodily discomfort. [EU] Malaria: A protozoan disease caused in humans by four species of the genus Plasmodium (P. falciparum (malaria, falciparum), P. vivax (malaria, vivax), P. ovale, and P. malariae) and transmitted by the bite of an infected female mosquito of the genus Anopheles. Malaria is endemic in parts of Asia, Africa, Central and South America, Oceania, and certain Caribbean islands. It is characterized by extreme exhaustion associated with paroxysms of high fever, sweating, shaking chills, and anemia. Malaria in animals is caused by other species of plasmodia. [NIH] Malaria, Falciparum: Malaria caused by Plasmodium falciparum. This is the severest form of malaria and is associated with the highest levels of parasites in the blood. This disease is characterized by irregularly recurring febrile paroxysms that in extreme cases occur with acute cerebral, renal, or gastrointestinal manifestations. [NIH] Malaria, Vivax: Malaria caused by Plasmodium vivax. This form of malaria is less severe than malaria, falciparum, but there is a higher probability for relapses to occur. Febrile paroxysms often occur every other day. [NIH] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] 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] 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] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [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

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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] 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] 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] Menstrual Cycle: The period of the regularly recurring physiologic changes in the endometrium occurring during the reproductive period in human females and some primates and culminating in partial sloughing of the endometrium (menstruation). [NIH] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] 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] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiological: Pertaining to microbiology : the science that deals with microorganisms, including algae, bacteria, fungi, protozoa and viruses. [EU] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] 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] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH]

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Microwaves: That portion of the electromagnetic spectrum lying between UHF (ultrahigh frequency) radio waves and heat (infrared) waves. Microwaves are used to generate heat, especially in some types of diathermy. They may cause heat damage to tissues. [NIH] Migrans: Infestation of the dermis by various larvae, characterized by bizarre red irregular lines which are broad at one end and fade at the other, produced by burrowing larvae. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [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] Mobility: Capability of movement, of being moved, or of flowing freely. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular mass: The sum of the atomic masses of all atoms in a molecule, based on a scale in which the atomic masses of hydrogen, carbon, nitrogen, and oxygen are 1, 12, 14, and 16, respectively. For example, the molecular mass of water, which has two atoms of hydrogen and one atom of oxygen, is 18 (i.e., 2 + 16). [NIH] Molecular Probes: A group of atoms or molecules attached to other molecules or cellular structures and used in studying the properties of these molecules and structures. Radioactive DNA or RNA sequences are used in molecular genetics to detect the presence of a complementary sequence by molecular hybridization. [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. 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] Mononuclear: A cell with one nucleus. [NIH] Mononucleosis: The presence of an abnormally large number of mononuclear leucocytes (monocytes) in the blood. The term is often used alone to refer to infectious mononucleosis. [EU]

Monophosphate: So called second messenger for neurotransmitters and hormones. [NIH] Morphological: Relating to the configuration or the structure of live organs. [NIH] Motility: The ability to move spontaneously. [EU] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH]

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Mucocutaneous: Pertaining to or affecting the mucous membrane and the skin. [EU] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Musculoskeletal System: Themuscles, bones, and cartilage of the body. [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] Myalgia: Pain in a muscle or muscles. [EU] Mycobacterium: A genus of gram-positive, aerobic bacteria. Most species are free-living in soil and water, but the major habitat for some is the diseased tissue of warm-blooded hosts. [NIH]

Myelin: The fatty substance that covers and protects nerves. [NIH] Myelitis: Inflammation of the spinal cord. Relatively common etiologies include infections; autoimmune diseases; spinal cord; and ischemia (see also spinal cord vascular diseases). Clinical features generally include weakness, sensory loss, localized pain, incontinence, and other signs of autonomic dysfunction. [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] Myositis: Inflammation of a voluntary muscle. [EU] Naive: Used to describe an individual who has never taken a certain drug or class of drugs (e. g., AZT-naive, antiretroviral-naive), or to refer to an undifferentiated immune system cell. [NIH] Nasal Mucosa: The mucous membrane lining the nasal cavity. [NIH] Natural Disasters: Sudden calamitous events producing great material damage, loss, and distress. They are the result of natural phenomena such as earthquakes, floods, etc. [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

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swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Needs Assessment: Systematic identification of a population's needs or the assessment of individuals to determine the proper level of services needed. [NIH] Neoplasms: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] 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] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neuritis: A general term indicating inflammation of a peripheral or cranial nerve. Clinical manifestation may include pain; paresthesias; paresis; or hypesthesia. [NIH] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neuroglia: The non-neuronal cells of the nervous system. They are divided into macroglia (astrocytes, oligodendroglia, and schwann cells) and microglia. They not only provide physical support, but also respond to injury, regulate the ionic and chemical composition of the extracellular milieu, participate in the blood-brain and blood-retina barriers, form the myelin insulation of nervous pathways, guide neuronal migration during development, and exchange metabolites with neurons. Neuroglia have high-affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitters, but their role in signaling (as in many other functions) is unclear. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] Neurologic Manifestations: Clinical signs and symptoms caused by nervous system injury or dysfunction. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuroretinitis: Inflammation of the optic nerve head and adjacent retina. [NIH] Neurosyphilis: A late form of syphilis that affects the brain and may lead to dementia and death. [NIH] Neurotoxin: A substance that is poisonous to nerve tissue. [NIH] Neurotransmitters: Endogenous signaling molecules that alter the behavior of neurons or effector cells. Neurotransmitter is used here in its most general sense, including not only messengers that act directly to regulate ion channels, but also those that act through second messenger systems, and those that act at a distance from their site of release. Included are neuromodulators, neuroregulators, neuromediators, and neurohumors, whether or not acting at synapses. [NIH]

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Neutropenia: An abnormal decrease in the number of neutrophils, a type of white blood cell. [NIH] Neutrophils: Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. [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] 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 Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleic Acid Probes: Nucleic acid which complements a specific mRNA or DNA molecule, or fragment thereof; used for hybridization studies in order to identify microorganisms and for genetic studies. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Occupational Health: The promotion and maintenance of physical and mental health in the work environment. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Odour: A volatile emanation that is perceived by the sense of smell. [EU] 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] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] Only Child: Child who has no siblings. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Ophthalmic: Pertaining to the eye. [EU] Ophthalmic Artery: Artery originating from the internal carotid artery and distributing to the eye, orbit and adjacent facial structures. [NIH]

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Opsin: A visual pigment protein found in the retinal rods. It combines with retinaldehyde to form rhodopsin. [NIH] Optic Disk: The portion of the optic nerve seen in the fundus with the ophthalmoscope. It is formed by the meeting of all the retinal ganglion cell axons as they enter the optic nerve. [NIH]

Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Optic Nerve Diseases: Conditions which produce injury or dysfunction of the second cranial or optic nerve, which is generally considered a component of the central nervous system. Damage to optic nerve fibers may occur at or near their origin in the retina, at the optic disk, or in the nerve, optic chiasm, optic tract, or lateral geniculate nuclei. Clinical manifestations may include decreased visual acuity and contrast sensitivity, impaired color vision, and an afferent pupillary defect. [NIH] Optic nerve head: The circular area (disc) where the optic nerve connects to the retina. [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] Orofacial: Of or relating to the mouth and face. [EU] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

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] Pachymeningitis: Inflammation of the dura mater of the brain, the spinal cord or the optic nerve. [NIH] Paediatric: Of or relating to the care and medical treatment of children; belonging to or concerned with paediatrics. [EU] Palladium: A chemical element having an atomic weight of 106.4, atomic number of 46, and the symbol Pd. It is a white, ductile metal resembling platinum, and following it in abundance and importance of applications. It is used in dentistry in the form of gold, silver, and copper alloys. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Palsy: Disease of the peripheral nervous system occurring usually after many years of increased lead absorption. [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

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gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatitis: Acute or chronic inflammation of the pancreas, which may be asymptomatic or symptomatic, and which is due to autodigestion of a pancreatic tissue by its own enzymes. It is caused most often by alcoholism or biliary tract disease; less commonly it may be associated with hyperlipaemia, hyperparathyroidism, abdominal trauma (accidental or operative injury), vasculitis, or uraemia. [EU] Papilla: A small nipple-shaped elevation. [NIH] Papilledema: Swelling around the optic disk. [NIH] Papilloedema: Choked disk, edema of the optic disk (papilla), most commonly due to increased intracranial pressure, malignant hypertension, or thrombosis of the central retinal vein : called also choke disk. [EU] Papule: A small circumscribed, superficial, solid elevation of the skin. [EU] 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] Parasitic Diseases: Infections or infestations with parasitic organisms. They are often contracted through contact with an intermediate vector, but may occur as the result of direct exposure. [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] Paresis: A general term referring to a mild to moderate degree of muscular weakness, occasionally used as a synonym for paralysis (severe or complete loss of motor function). In the older literature, paresis often referred specifically to paretic neurosyphilis. "General paresis" and "general paralysis" may still carry that connotation. Bilateral lower extremity paresis is referred to as paraparesis. [NIH] Paresthesias: Abnormal touch sensations, such as burning or prickling, that occur without an outside stimulus. [NIH] Parotid: The space that contains the parotid gland, the facial nerve, the external carotid artery, and the retromandibular vein. [NIH] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Advocacy: Promotion and protection of the rights of patients, frequently through a legal process. [NIH]

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Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Pediatrics: A medical specialty concerned with maintaining health and providing medical care to children from birth to adolescence. [NIH] Pelvic: Pertaining to the pelvis. [EU] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide Chain Elongation: The process whereby an amino acid is joined through a substituted amide linkage to a chain of peptides. [NIH] Peptide Mapping: Analysis of peptides generated from the digestion of a protein by a specific protease for the purpose of indentifing the protein or to look for polymorphisms. [NIH]

Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [NIH] Perception: The ability quickly and accurately to recognize similarities and differences among presented objects, whether these be pairs of words, pairs of number series, or multiple sets of these or other symbols such as geometric figures. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]

Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [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] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peripheral Neuropathy: Nerve damage, usually affecting the feet and legs; causing pain, numbness, or a tingling feeling. Also called "somatic neuropathy" or "distal sensory polyneuropathy." [NIH] 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] 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

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layer of the bowel wall. [NIH] Pernicious: Tending to a fatal issue. [EU] Pernicious anemia: A type of anemia (low red blood cell count) caused by the body's inability to absorb vitamin B12. [NIH] Peroneal Nerve: The lateral of the two terminal branches of the sciatic nerve. The peroneal (or fibular) nerve provides motor and sensory innervation to parts of the leg and foot. [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] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Pharmacokinetics: Dynamic and kinetic mechanisms of exogenous chemical and drug absorption, biotransformation, distribution, release, transport, uptake, and elimination as a function of dosage, and extent and rate of metabolic processes. It includes toxicokinetics, the pharmacokinetic mechanism of the toxic effects of a substance. [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] Pheromone: A substance secreted externally by certain animal species, especially insects, to affect the behavior or development of other members of the species. [NIH] Phosphoglycerate Kinase: An enzyme catalyzing the transfer of a phosphate group from 3phospho-D-glycerate in the presence of ATP to yield 3-phospho-D-glyceroyl phosphate and ADP. EC 2.7.2.3. [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] 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] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] 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] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other

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nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Plague: An acute infectious disease caused by Yersinia pestis that affects humans, wild rodents, and their ectoparasites. This condition persists due to its firm entrenchment in sylvatic rodent-flea ecosystems throughout the world. Bubonic plague is the most common form. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [NIH] Plasmin: A product of the lysis of plasminogen (profibrinolysin) by plasminogen activators. It is composed of two polypeptide chains, light (B) and heavy (A), with a molecular weight of 75,000. It is the major proteolytic enzyme involved in blood clot retraction or the lysis of fibrin and quickly inactivated by antiplasmins. EC 3.4.21.7. [NIH] Plasminogen: Precursor of fibrinolysin (plasmin). It is a single-chain beta-globulin of molecular weight 80-90,000 found mostly in association with fibrinogen in plasma; plasminogen activators change it to fibrinolysin. It is used in wound debriding and has been investigated as a thrombolytic agent. [NIH] Plasminogen Activators: A heterogeneous group of proteolytic enzymes that convert plasminogen to plasmin. They are concentrated in the lysosomes of most cells and in the vascular endothelium, particularly in the vessels of the microcirculation. EC 3.4.21.-. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] 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]

Plexus: A network or tangle; a general term for a network of lymphatic vessels, nerves, or veins. [EU] Polyarthritis: An inflammation of several joints together. [EU] Polyethylene: A vinyl polymer made from ethylene. It can be branched or linear. Branched or low-density polyethylene is tough and pliable but not to the same degree as linear polyethylene. Linear or high-density polyethylene has a greater hardness and tensile

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strength. Polyethylene is used in a variety of products, including implants and prostheses. [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 stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same population. [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] Population Density: Number of individuals in a population relative to space. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Post-traumatic: Occurring as a result of or after injury. [EU] Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiating: 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] Precipitating Factors: Factors associated with the definitive onset of a disease, illness, accident, behavioral response, or course of action. Usually one factor is more important or more obviously recognizable than others, if several are involved, and one may often be regarded as "necessary". Examples include exposure to specific disease; amount or level of an infectious organism, drug, or noxious agent, etc. [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]

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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] 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] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Promyelocytic leukemia: A type of acute myeloid leukemia, a quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. [NIH]

Prone: Having the front portion of the body downwards. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Proportional: Being in proportion : corresponding in size, degree, or intensity, having the same or a constant ratio; of, relating to, or used in determining proportions. [EU] 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] Protective Clothing: Clothing designed to protect the individual against possible exposure to known hazards. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein 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] Proteoglycan: A molecule that contains both protein and glycosaminoglycans, which are a type of polysaccharide. Proteoglycans are found in cartilage and other connective tissues. [NIH]

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Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] 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] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Pseudotumor Cerebri: A condition marked by raised intracranial pressure and characterized clinically by headaches; nausea; papilledema, peripheral constriction of the visual fields, transient visual obscurations, and pulsatile tinnitus. Obesity is frequently associated with this condition, which primarily affects women between 20 and 44 years of age. Chronic papilledema may lead to optic nerve injury (optic nerve diseases) and visual loss (blindness). [NIH] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychogenic: Produced or caused by psychic or mental factors rather than organic factors. [EU]

Psychosomatic: Pertaining to the mind-body relationship; having bodily symptoms of psychic, emotional, or mental origin; called also psychophysiologic. [EU] 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 Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to 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]

Purifying: Respiratory equipment whose function is to remove contaminants from otherwise wholesome air. [NIH]

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Purulent: Consisting of or containing pus; associated with the formation of or caused by pus. [EU] Pyruvate Kinase: ATP:pyruvate 2-O-phosphotransferase. A phosphotransferase that catalyzes reversibly the phosphorylation of pyruvate to phosphoenolpyruvate in the presence of ATP. It has four isozymes (L, R, M1, and M2). Deficiency of the enzyme results in hemolytic anemia. EC 2.7.1.40. [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] Radio Waves: That portion of the electromagnetic spectrum beyond the microwaves, with wavelengths as high as 30 KM. They are used in communications, including television. Short Wave or HF (high frequency), UHF (ultrahigh frequency) and VHF (very high frequency) waves are used in citizen's band communication. [NIH] Radioactive: Giving off radiation. [NIH] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiologist: A doctor who specializes in creating and interpreting pictures of areas inside the body. The pictures are produced with x-rays, sound waves, or other types of energy. [NIH]

Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] 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] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombinant Proteins: Proteins prepared by recombinant DNA technology. [NIH] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Reconstitution: 1. A type of regeneration in which a new organ forms by the rearrangement

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of tissues rather than from new formation at an injured surface. 2. The restoration to original form of a substance previously altered for preservation and storage, as the restoration to a liquid state of blood serum or plasma that has been dried and stored. [EU] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] 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] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Reliability: Used technically, in a statistical sense, of consistency of a test with itself, i. e. the extent to which we can assume that it will yield the same result if repeated a second time. [NIH]

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] Resolving: The ability of the eye or of a lens to make small objects that are close together, separately visible; thus revealing the structure of an object. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respiratory Physiology: Functions and activities of the respiratory tract as a whole or of any of its parts. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinal Artery: Central retinal artery and its branches. It arises from the ophthalmic artery,

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pierces the optic nerve and runs through its center, enters the eye through the porus opticus and branches to supply the retina. [NIH] Retinal Artery Occlusion: Occlusion or closure of the central retinal artery causing sudden, usually nearly complete, loss of vision in one eye. Occlusion of the branch retinal artery causes sudden visual loss in only a portion of the visual field. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retrospective: Looking back at events that have already taken place. [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] Rheumatic Diseases: Disorders of connective tissue, especially the joints and related structures, characterized by inflammation, degeneration, or metabolic derangement. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Rheumatology: A subspecialty of internal medicine concerned with the study of inflammatory or degenerative processes and metabolic derangement of connective tissue structures which pertain to a variety of musculoskeletal disorders, such as arthritis. [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] Ricin: A protein phytotoxin from the seeds of Ricinus communis, the castor oil plant. It agglutinates cells, is proteolytic, and causes lethal inflammation and hemorrhage if taken internally. [NIH] Ricinus: An euphorbiaceous plant with very toxic seeds. The castor bean, castor oil, ricin, and other lectins are its most important products. [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] Sagittal: The line of direction passing through the body from back to front, or any vertical plane parallel to the medial plane of the body and inclusive of that plane; often restricted to the medial plane, the plane of the sagittal suture. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Salivary Proteins: Proteins found in saliva and the salivary glands. These proteins show some enzymatic activity, but their composition varies in different individuals. [NIH] Saponin: A substance found in soybeans and many other plants. Saponins may help lower cholesterol and may have anticancer effects. [NIH] Sarcoidosis: An idiopathic systemic inflammatory granulomatous disorder comprised of

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epithelioid and multinucleated giant cells with little necrosis. It usually invades the lungs with fibrosis and may also involve lymph nodes, skin, liver, spleen, eyes, phalangeal bones, and parotid glands. [NIH] Satellite: Applied to a vein which closely accompanies an artery for some distance; in cytogenetics, a chromosomal agent separated by a secondary constriction from the main body of the chromosome. [NIH] Scans: Pictures of structures inside the body. Scans often used in diagnosing, staging, and monitoring disease include liver scans, bone scans, and computed tomography (CT) or computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) scans. In liver scanning and bone scanning, radioactive substances that are injected into the bloodstream collect in these organs. A scanner that detects the radiation is used to create pictures. In CT scanning, an x-ray machine linked to a computer is used to produce detailed pictures of organs inside the body. MRI scans use a large magnet connected to a computer to create pictures of areas inside the body. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Sciatic Nerve: A nerve which originates in the lumbar and sacral spinal cord (L4 to S3) and supplies motor and sensory innervation to the lower extremity. The sciatic nerve, which is the main continuation of the sacral plexus, is the largest nerve in the body. It has two major branches, the tibial nerve and the peroneal nerve. [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] Scleritis: Refers to any inflammation of the sclera including episcleritis, a benign condition affecting only the episclera, which is generally short-lived and easily treated. Classic scleritis, on the other hand, affects deeper tissue and is characterized by higher rates of visual acuity loss and even mortality, particularly in necrotizing form. Its characteristic symptom is severe and general head pain. Scleritis has also been associated with systemic collagen disease. Etiology is unknown but is thought to involve a local immune response. Treatment is difficult and includes administration of anti-inflammatory and immunosuppressive agents such as corticosteroids. Inflammation of the sclera may also be secondary to inflammation of adjacent tissues, such as the conjunctiva. [NIH] Scleroderma: A chronic disorder marked by hardening and thickening of the skin. Scleroderma can be localized or it can affect the entire body (systemic). [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Segmental: Describing or pertaining to a structure which is repeated in similar form in successive segments of an organism, or which is undergoing segmentation. [NIH] Segmentation: The process by which muscles in the intestines move food and wastes through the body. [NIH] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH]

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Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Sensory loss: A disease of the nerves whereby the myelin or insulating sheath of myelin on the nerves does not stay intact and the messages from the brain to the muscles through the nerves are not carried properly. [NIH] Sepsis: The presence of bacteria in the bloodstream. [NIH] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU] Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serologic Tests: Diagnostic procedures involving immunoglobulin reactions. [NIH] Serology: The study of serum, especially of antigen-antibody reactions in vitro. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skin Tests: Epicutaneous or intradermal application of a sensitizer for demonstration of either delayed or immediate hypersensitivity. Used in diagnosis of hypersensitivity or as a test for cellular immunity. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [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] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Sound wave: An alteration of properties of an elastic medium, such as pressure, particle

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displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] Spastic: 1. Of the nature of or characterized by spasms. 2. Hypertonic, so that the muscles are stiff and the movements awkward. 3. A person exhibiting spasticity, such as occurs in spastic paralysis or in cerebral palsy. [EU] Spasticity: A state of hypertonicity, or increase over the normal tone of a muscle, with heightened deep tendon reflexes. [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] Species Specificity: Restriction of a characteristic or response to the members of one species; it usually refers to that property of the immune response which differentiates one species from another on the basis of antigen recognition, but the concept is not limited to immunology and is used loosely at levels higher than the species. [NIH] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] 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] 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 Cord Vascular Diseases: Hypoxic-ischemic and hemorrhagic disorders of the spinal cord. Arteriosclerosis, emboli, and vascular malformations are potential causes of these conditions. [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] Spinal tap: A procedure in which a needle is put into the lower part of the spinal column to collect cerebrospinal fluid or to give anticancer drugs intrathecally. Also called a lumbar puncture. [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] Spondylitis: Inflammation of the vertebrae. [EU] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

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Standardize: To compare with or conform to a standard; to establish standards. [EU] Steady state: Dynamic equilibrium. [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] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Streptavidin: A 60kD extracellular protein of Streptomyces avidinii with four high-affinity biotin binding sites. Unlike AVIDIN, streptavidin has a near neutral isoelectric point and is free of carbohydrate side chains. [NIH] Streptococcal: Caused by infection due to any species of streptococcus. [NIH] Streptococcus: A genus of gram-positive, coccoid bacteria whose organisms occur in pairs or chains. No endospores are produced. Many species exist as commensals or parasites on man or animals with some being highly pathogenic. A few species are saprophytes and occur in the natural environment. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stupor: Partial or nearly complete unconsciousness, manifested by the subject's responding only to vigorous stimulation. Also, in psychiatry, a disorder marked by reduced responsiveness. [EU] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] 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] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synovial: Of pertaining to, or secreting synovia. [EU] Synovial Fluid: The clear, viscous fluid secreted by the synovial membrane. It contains mucin, albumin, fat, and mineral salts and serves to lubricate joints. [NIH] Synovial Membrane: The inner membrane of a joint capsule surrounding a freely movable joint. It is loosely attached to the external fibrous capsule and secretes synovial fluid. [NIH]

Dictionary 289

Syphilis: A contagious venereal disease caused by the spirochete Treponema pallidum. [NIH]

Systemic: Affecting the entire body. [NIH] Systemic disease: Disease that affects the whole body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Tendonitis: Inflammation of tendons attached to the biceps muscle, i. e. the main flexor muscle of the upper arm. [NIH] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thiamphenicol: A methylsulfonyl analog of chloramphenicol. It is an antibiotic and immunosuppressive agent. [NIH] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH] Thorax: A part of the trunk between the neck and the abdomen; the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thrombocytopenia: A decrease in the number of blood platelets. [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] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and

290 Lyme Disease

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] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroiditis: Inflammation of the thyroid gland. [NIH] Tibial Nerve: The medial terminal branch of the sciatic nerve. The tibial nerve fibers originate in lumbar and sacral spinal segments (L4 to S2). They supply motor and sensory innervation to parts of the calf and foot. [NIH] Tick Paralysis: Paralysis caused by a neurotropic toxin secreted by the salivary glands of ticks. [NIH] Tick-Borne Diseases: Bacterial, viral, or parasitic diseases transmitted to humans and animals by the bite of infected ticks. The families Ixodidae and Argasidae contain many bloodsucking species that are important pests of man and domestic birds and mammals and probably exceed all other arthropods in the number and variety of disease agents they transmit. Many of the tick-borne diseases are zoonotic. [NIH] Ticks: Blood-sucking arachnids of the order Acarina. [NIH] Tin: A trace element that is required in bone formation. It has the atomic symbol Sn, atomic number 50, and atomic weight 118.71. [NIH] Tinnitus: Sounds that are perceived in the absence of any external noise source which may take the form of buzzing, ringing, clicking, pulsations, and other noises. Objective tinnitus refers to noises generated from within the ear or adjacent structures that can be heard by other individuals. The term subjective tinnitus is used when the sound is audible only to the affected individual. Tinnitus may occur as a manifestation of cochlear diseases; vestibulocochlear nerve diseases; intracranial hypertension; craniocerebral trauma; and other conditions. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue 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] Titre: The quantity of a substance required to produce a reaction with a given volume of another substance, or the amount of one substance required to correspond with a given amount of another substance. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] 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] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of

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toxic manifestations. [NIH] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] 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] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] 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]

Trigeminal: Cranial nerve V. It is sensory for the eyeball, the conjunctiva, the eyebrow, the skin of face and scalp, the teeth, the mucous membranes in the mouth and nose, and is motor to the muscles of mastication. [NIH] Tropism: Directed movements and orientations found in plants, such as the turning of the sunflower to face the sun. [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] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tubulin: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from sperm flagella, cilia, and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to colchicine, vincristine, and vinblastine. [NIH] Tularemia: A plague-like disease of rodents, transmissible to man. It is caused by Francisella tularensis and is characterized by fever, chills, headache, backache, and weakness. [NIH] Typhimurium: Microbial assay which measures his-his+ reversion by chemicals which cause base substitutions or frameshift mutations in the genome of this organism. [NIH]

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Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Uracil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Uraemia: 1. An excess in the blood of urea, creatinine, and other nitrogenous end products of protein and amino acids metabolism; more correctly referred to as azotemia. 2. In current usage the entire constellation of signs and symptoms of chronic renal failure, including nausea, vomiting anorexia, a metallic taste in the mouth, a uraemic odour of the breath, pruritus, uraemic frost on the skin, neuromuscular disorders, pain and twitching in the muscles, hypertension, edema, mental confusion, and acid-base and electrolyte imbalances. [EU]

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] Urinate: To release urine from the bladder to the outside. [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] Urine Testing: Checking urine to see if it contains glucose (sugar) and ketones. Special strips of paper or tablets (called reagents) are put into a small amount of urine or urine plus water. Changes in the color of the strip show the amount of glucose or ketones in the urine. Urine testing is the only way to check for the presence of ketones, a sign of serious illness. However, urine testing is less desirable then blood testing for monitoring the level of glucose in the body. [NIH] Urokinase: A drug that dissolves blood clots or prevents them from forming. [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] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vaccine adjuvant: A substance added to a vaccine to improve the immune response so that less vaccine is needed. [NIH] Vaccinia: The cutaneous and occasional systemic reactions associated with vaccination using smallpox (variola) vaccine. [NIH] Vaccinia Virus: The type species of Orthopoxvirus, related to cowpox virus, but whose true origin is unknown. It has been used as a live vaccine against smallpox. It is also used as a vector for inserting foreign DNA into animals. Rabbitpox virus is a subspecies of vaccinia virus. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH]

Dictionary 293

Varicella: Chicken pox. [EU] 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] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venereal: Pertaining or related to or transmitted by sexual contact. [EU] Venous: Of or pertaining to the veins. [EU] Ventilation: 1. In respiratory physiology, the process of exchange of air between the lungs and the ambient air. Pulmonary ventilation (usually measured in litres per minute) refers to the total exchange, whereas alveolar ventilation refers to the effective ventilation of the alveoli, in which gas exchange with the blood takes place. 2. In psychiatry, verbalization of one's emotional problems. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vertigo: An illusion of movement; a sensation as if the external world were revolving around the patient (objective vertigo) or as if he himself were revolving in space (subjective vertigo). The term is sometimes erroneously used to mean any form of dizziness. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. [NIH] Vinca Alkaloids: A class of alkaloids from the genus of apocyanaceous woody herbs including periwinkles. They are some of the most useful antineoplastic agents. [NIH] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] 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] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH]

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Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Visual Acuity: Acuteness or clearness of vision, especially of form vision, which is dependent mainly on the sharpness of the retinal focus. [NIH] Visual field: The entire area that can be seen when the eye is forward, including peripheral vision. [NIH] 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] Void: To urinate, empty the bladder. [NIH] Walkers: Walking aids generally having two handgrips and four legs. [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 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] Yellow Fever: An acute infectious disease primarily of the tropics, caused by a virus and transmitted to man by mosquitoes of the genera Aedes and Haemagogus. [NIH] Zoonoses: Diseases of non-human animals that may be transmitted to man or may be transmitted from man to non-human animals. [NIH] Zoonosis: Disease of animals, e. g. rabies, that can be transmitted to humans. A risk in major disasters; any disease and/or infection which is likely to be naturally transmitted from animals to man; disease caused by animal parasites. [NIH] Zoster: A virus infection of the Gasserian ganglion and its nerve branches, characterized by discrete areas of vesiculation of the epithelium of the forehead, the nose, the eyelids, and the cornea together with subepithelial infiltration. [NIH] 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]

295

INDEX A Abdominal, 233, 274, 275, 276 Ablate, 172, 233 Abscess, 37, 233 Acrodermatitis, 150, 159, 233 Acute myeloid leukemia, 233, 280 Adaptability, 233, 242 Adaptation, 7, 31, 45, 233 Adduct, 32, 233 Adjustment, 233 Adjuvant, 11, 118, 123, 142, 233, 256 Adolescence, 233, 276 Adrenal Cortex, 233, 280 Adsorption, 122, 143, 233 Adsorptive, 233 Adverse Effect, 142, 233, 286 Aerobic, 233, 271 Aerosol, 153, 234 Afferent, 234, 254, 274 Affinity, 7, 21, 234, 237, 272, 288 Affinity Chromatography, 7, 234 Agar, 234, 248, 278 Agarose, 37, 234 A-HA, 96, 130, 234 Airway, 171, 234 Airway Obstruction, 171, 234 Albumin, 234, 288 Algorithms, 234, 240 Alimentary, 234, 264, 275 Alkylating Agents, 234, 292 Alleles, 33, 38, 234 Allergic Rhinitis, 164, 235 Allogeneic, 235, 257 Alternative medicine, 177, 193, 235 Alveoli, 235, 293 Amino Acid Sequence, 144, 145, 174, 235, 236, 256 Amino Acids, 48, 165, 234, 235, 245, 253, 256, 276, 279, 280, 284, 291, 292 Amoxicillin, 4, 85, 235 Ampicillin, 235 Amplification, 122, 158, 172, 235 Anaerobic, 235, 241, 258 Anaesthesia, 235, 262 Anal, 235, 252, 267 Analog, 235, 289 Analogous, 54, 235, 250, 291 Analytes, 210, 235

Anaphylatoxins, 235, 246 Anaplasia, 235, 272 Anatomical, 235, 261, 285 Anemia, 235, 268, 277, 282 Anesthesia, 234, 236, 251 Angiogenesis, 236, 268 Angioplasty, 171, 236 Animal model, 17, 26, 41, 54, 57, 89, 236 Annealing, 236, 279 Anomalies, 193, 236 Anorexia, 236, 251, 292 Anthrax, 48, 101, 179, 236 Antibacterial, 236, 287 Anticoagulant, 50, 56, 236, 280 Antigen, 6, 8, 9, 10, 15, 17, 23, 33, 34, 39, 43, 48, 57, 59, 61, 62, 64, 65, 67, 68, 71, 76, 77, 86, 91, 94, 99, 106, 108, 109, 143, 146, 150, 153, 154, 155, 156, 157, 161, 166, 173, 191, 215, 234, 236, 237, 245, 249, 252, 257, 259, 260, 261, 262, 263, 269, 286, 287 Antigen-Antibody Complex, 236, 245 Antigen-presenting cell, 237, 249 Anti-infective, 32, 237 Anti-inflammatory, 29, 237, 285 Antimicrobial, 63, 65, 90, 115, 237, 243, 250 Antioxidant, 237, 274 Antiproliferative, 32, 237 Antipruritic, 237, 243 Antiviral, 237, 263, 276 Apolipoproteins, 237, 266 Approximate, 165, 237 Aqueous, 237, 239, 248, 265 Aromatic, 171, 237 Arterial, 28, 237, 243, 260, 280 Arteries, 165, 237, 240, 247, 267, 269 Arteriolar, 46, 237 Arterioles, 237, 240 Arthropod Vectors, 174, 237 Astrocytes, 237, 257, 272 Asymptomatic, 4, 237, 275 Asystole, 94, 237 Ataxia, 84, 237, 289 Atopic, 164, 237 Attenuated, 72, 238, 249 Attenuation, 122, 238 Audiovisual Aids, 218, 238 Auditory, 238, 253

296 Lyme Disease

Autoantibodies, 238 Autoantigens, 192, 238 Autodigestion, 238, 275 Autoimmune disease, 18, 43, 53, 156, 238, 271 Autoimmunity, 54, 61, 101, 106, 164, 238 Autonomic, 238, 257, 271, 276 Autonomic Nervous System, 238, 276 Axons, 238, 274, 276 B Babesiosis, 18, 27, 28, 41, 47, 57, 63, 69, 88, 116, 130, 178, 238 Bacillus, 36, 236, 238 Bacterial Adhesion, 147, 238 Bacterial Infections, 54, 164, 238, 242 Bacterial Physiology, 233, 238 Bacterial Proteins, 14, 163, 173, 238 Bacterial Vaccines, 142, 238 Bacteriophage, 238, 278, 293 Bacterium, 7, 11, 28, 36, 42, 50, 142, 162, 213, 238, 239, 259 Basal Ganglia, 237, 239, 255 Basal Ganglia Diseases, 237, 239 Base, 53, 198, 215, 239, 241, 249, 255, 256, 265, 289, 291, 292 Basement Membrane, 239, 253 Basophils, 239, 258, 266 Benign, 239, 255, 258, 272, 285 Bewilderment, 239, 246 Bile, 239, 243, 255, 259, 265, 266 Bile Pigments, 239, 265 Biliary, 81, 239, 243, 275 Biliary Tract, 239, 275 Binding Sites, 239, 288 Bioassays, 157, 239 Biochemical, 6, 15, 37, 44, 50, 56, 234, 239, 256, 265 Bioengineering, 11, 204, 239 Biological Markers, 137, 239 Biological response modifier, 240, 263 Biopsy, 45, 81, 129, 139, 162, 166, 230, 240, 276 Biopsy specimen, 162, 166, 240 Biosynthesis, 32, 240 Biotechnology, 60, 77, 89, 183, 193, 205, 240 Biotic, 33, 240 Biotin, 122, 240, 273, 288 Bladder, 32, 240, 262, 271, 292, 294 Blast phase, 240, 244 Blood Platelets, 240, 289 Blood pressure, 194, 230, 240, 260, 270

Blood transfusion, 41, 240 Blot, 4, 7, 34, 52, 63, 110, 118, 120, 157, 215, 231, 240, 261, 273 Blotting, Western, 240, 261 Body Fluids, 14, 143, 155, 158, 165, 169, 240, 241, 250 Bone Marrow, 233, 240, 244, 261, 267, 280, 288 Bone scan, 82, 240, 285 Bowel, 235, 241, 249, 276 Bowel Movement, 241, 249 Branch, 67, 83, 186, 187, 225, 241, 248, 267, 275, 281, 284, 287, 289, 290 Breeding, 19, 241 Broad-spectrum, 235, 241, 242 Bronchitis, 241, 244 Bypass, 36, 241 C Calcium, 241, 245, 268 Canonical, 145, 241 Carbohydrate, 241, 279, 288 Carbon Dioxide, 241, 256, 260, 278, 283 Carcinogen, 233, 241 Carcinogenic, 234, 241, 263, 273, 280 Cardiac, 83, 144, 146, 152, 154, 160, 162, 163, 172, 173, 184, 193, 237, 241, 271 Cardiovascular, 30, 59, 241 Carotene, 241, 283 Carrier Proteins, 148, 241 Case report, 79, 107, 109, 177, 241, 254 Case-Control Studies, 55, 242, 252 Castor Bean, 242, 284 Castor Oil, 242, 284 Catheterization, 236, 242 Causal, 242, 252, 259, 264 Ceftriaxone, 46, 138, 242 Cefuroxime, 63, 85, 242 Cell, 6, 7, 9, 10, 14, 17, 22, 24, 25, 26, 27, 29, 30, 33, 34, 37, 38, 43, 44, 45, 50, 52, 61, 62, 65, 67, 71, 75, 76, 86, 92, 99, 100, 106, 114, 124, 137, 146, 156, 163, 164, 166, 169, 173, 181, 235, 237, 238, 239, 240, 241, 242, 244, 246, 248, 249, 252, 253, 255, 256, 257, 258, 260, 261, 262, 263, 264, 265, 268, 270, 271, 272, 274, 277, 278, 282, 283, 285, 288, 289, 290, 291, 294 Cell Adhesion, 242, 263 Cell Count, 17, 242, 277 Cell Death, 25, 242, 257, 272 Cell Differentiation, 156, 242 Cell Division, 238, 242, 248, 278, 285 Cell membrane, 241, 242, 277

Index 297

Cell Movement, 37, 242 Cellular Structures, 242, 270 Cellulose, 242, 255, 278 Central Nervous System Infections, 242, 258 Central retinal artery, 243, 283, 284 Central retinal vein, 243, 275 Cephalexin, 93, 243 Cephaloridine, 243 Cephalothin, 243 Cerebellar, 84, 237, 243, 283 Cerebral, 46, 84, 113, 131, 237, 239, 243, 253, 268, 287 Cerebral Palsy, 243, 287 Cerebrospinal, 14, 16, 20, 40, 45, 86, 138, 166, 243, 267, 287 Cerebrospinal fluid, 14, 16, 20, 40, 45, 86, 138, 166, 243, 267, 287 Cerebrovascular, 53, 239, 243, 289 Cerebrum, 243 Chemokines, 23, 243 Chemotactic Factors, 108, 243, 246 Chemotaxis, 6, 243 Chemotherapy, 32, 90, 101, 127, 243 Chlamydia, 53, 243 Chlorophyll, 243, 255 Cholesterol, 239, 243, 244, 266, 267, 284 Cholesterol Esters, 243, 266 Cholestyramine, 171, 243 Chorioretinitis, 106, 244 Choroid, 244, 283, 292 Chromatin, 244, 252, 273 Chromosomal, 49, 51, 154, 235, 244, 256, 278, 285 Chromosome, 19, 244, 256, 266, 285 Chronic Disease, 17, 138, 244, 245 Chronic Fatigue Syndrome, 170, 177, 244 Chronic lymphocytic leukemia, 244 Chronic myelogenous leukemia, 240, 244 Chronic Obstructive Pulmonary Disease, 171, 244 Chronic phase, 17, 244 Chylomicrons, 244, 266 Circulatory system, 159, 244, 264 CIS, 44, 244, 283 Clarithromycin, 63, 90, 244 Clear cell carcinoma, 244, 249 Clinical Medicine, 244, 279 Clinical trial, 5, 25, 44, 79, 80, 137, 139, 164, 205, 244, 247, 281, 282 Clone, 17, 43, 52, 245 Cloning, 39, 50, 144, 163, 240, 245, 263

Clot Retraction, 245, 278 Codon, 36, 245, 256 Coenzyme, 245, 265 Cofactor, 245, 280, 289 Colchicine, 245, 291 Collagen, 149, 239, 245, 254, 256, 268, 280, 285 Collagen disease, 245, 285 Colloidal, 234, 245, 251 Complement, 34, 36, 50, 59, 64, 65, 74, 78, 83, 85, 88, 93, 127, 128, 235, 245, 246, 256, 263, 268 Complementary and alternative medicine, 127, 134, 246 Complementary medicine, 127, 246 Complementation, 7, 246 Computational Biology, 205, 246 Computed tomography, 246, 285 Computerized axial tomography, 246, 285 Conception, 246, 254 Concomitant, 32, 81, 187, 246 Conduction, 83, 246 Cones, 246, 283 Confusion, 152, 171, 191, 228, 246, 250, 292 Congestion, 246, 253 Congestive heart failure, 171, 246 Conjunctiva, 246, 262, 285, 291 Conjunctivitis, 80, 122, 164, 246 Connective Tissue, 165, 240, 245, 247, 255, 256, 267, 276, 280, 284, 289 Connective Tissue Cells, 247 Consciousness, 228, 247, 249, 250 Constitutional, 152, 247 Constriction, 247, 264, 281, 285 Contact dermatitis, 164, 247 Contraindications, ii, 247 Contrast Sensitivity, 171, 247, 274 Control group, 20, 247 Controlled study, 78, 247 Coordination, 20, 247, 271 Cornea, 247, 257, 265, 285, 292, 294 Coronary, 171, 247, 269 Coronary Thrombosis, 247, 269 Corpus, 247, 280 Corpus Luteum, 247, 280 Cortex, 237, 247, 253, 283 Cortical, 46, 247, 286, 289 Corticosteroids, 70, 198, 247, 285 Coumarin, 68, 122, 247 Cowpox, 247, 248, 292 Cowpox Virus, 247, 248, 292

298 Lyme Disease

Cranial, 114, 248, 254, 257, 258, 264, 272, 274, 276, 291 Craniocerebral Trauma, 239, 248, 258, 289, 290 Crossing-over, 248, 282 Cues, 7, 26, 31, 50, 248 Culture Media, 169, 234, 248 Cultured cells, 26, 248 Curative, 184, 248, 289 Cutaneous, 92, 100, 104, 119, 186, 236, 247, 248, 260, 265, 267, 292 Cysteine, 243, 248 Cytogenetics, 248, 285 Cytokine, 11, 17, 24, 29, 30, 35, 44, 45, 66, 100, 171, 248, 264 Cytoplasm, 239, 242, 248, 252, 258, 273, 284 Cytoskeleton, 248, 263 Cytotoxic, 164, 166, 248, 261 D Data Collection, 20, 21, 248 Databases, Bibliographic, 205, 248 Defense Mechanisms, 248, 263 Degenerative, 248, 257, 284 Deletion, 7, 21, 56, 248 Dementia, 46, 249, 272 Denaturation, 249, 279 Dendrites, 249 Dendritic, 24, 249 Dendritic cell, 24, 249 Density, 27, 36, 163, 249, 266, 273, 278, 287 Dermal, 53, 149, 249 Dermatitis, 249 Dermatology, 6, 80, 82, 83, 90, 92, 100, 102, 117, 132, 249 DES, 160, 235, 249 Diagnostic procedure, 141, 193, 249, 286 Diarrhea, 171, 243, 249 Diathesis, 55, 249 Diffusion, 249, 262 Digestion, 234, 239, 241, 249, 266, 276, 288 Digestive system, 140, 249 Dilatation, 236, 249, 280 Dilution, 10, 249 Diploid, 246, 249, 278 Discrimination, 67, 68, 249 Disease Transmission, 13, 57, 249, 250 Disease Transmission, Horizontal, 249, 250 Disease Transmission, Vertical, 249, 250 Disorientation, 246, 250 Dissociation, 234, 250

Distal, 23, 250, 276, 281 Dizziness, 250, 293 Domesticated, 250, 258 Doxycycline, 4, 63, 190, 198, 250 Dreams, 94, 250 Drive, ii, vi, 3, 121, 156, 178, 250 Drug Design, 32, 250 Drug Interactions, 199, 250 Duct, 242, 250, 274, 284 Dura mater, 250, 269, 274 Dyes, 239, 250, 273 Dysphoria, 40, 250 E Edema, 38, 247, 250, 275, 292 Effector, 51, 156, 245, 251, 272 Efficacy, 4, 18, 22, 23, 33, 34, 46, 55, 66, 90, 129, 250, 251, 291 Ehrlichiosis, 18, 26, 27, 28, 41, 47, 57, 63, 68, 69, 73, 88, 93, 96, 178, 251 Elastin, 245, 251, 254 Elective, 114, 251 Electrons, 237, 239, 251, 264, 274, 282 Electrophoresis, 36, 50, 251 Embryo, 242, 251, 262 Emphysema, 244, 251 Encephalitis, 38, 93, 135, 178, 179, 183, 251, 265 Encephalitis, Viral, 251 Encephalopathy, 17, 39, 46, 131, 152, 184, 251 Endarterectomy, 236, 251 Endometrial, 251 Endometriosis, 171, 251 Endometrium, 251, 269 Endothelium, 23, 53, 251, 252, 278 Endothelium, Lymphatic, 251, 252 Endothelium, Vascular, 251, 252 Endotoxic, 252, 266 Endotoxins, 246, 252 Environmental Exposure, 239, 252 Environmental Health, 78, 84, 85, 86, 204, 206, 252 Enzymatic, 241, 246, 252, 255, 279, 283, 284 Eosinophilia, 164, 252 Eosinophils, 252, 258, 266 Epidemic, 5, 166, 252, 287 Epidemiologic Factors, 33, 252 Epidemiologic Studies, 239, 252 Epidemiological, 10, 109, 150, 252, 254 Episcleritis, 122, 252, 285 Epithelial, 10, 252, 253 Epithelial Cells, 10, 252, 253

Index 299

Epithelium, 239, 251, 253, 294 Epitope, 17, 33, 56, 68, 69, 73, 92, 99, 123, 146, 147, 166, 253 Erythema Chronicum Migrans, 71, 83, 152, 159, 165, 253 Erythrocytes, 235, 238, 240, 253, 259 Erythromycin, 244, 253 Esophagus, 249, 253, 277, 288 Eukaryotic Cells, 253, 262 Evoke, 253, 288 Evoked Potentials, 112, 253 Excipient, 166, 253 Exhaustion, 253, 268 Exogenous, 29, 233, 253, 277 Exotoxin, 35, 253 Extensor, 253, 281 Extracellular, 50, 149, 237, 247, 253, 254, 263, 268, 272, 288 Extracellular Matrix, 50, 149, 247, 253, 263, 268 Extracellular Matrix Proteins, 253, 268 Extracellular Space, 253, 254 Extraction, 45, 163, 254 Extravasation, 23, 254 Extremity, 254, 275, 285 Exudate, 244, 254 F Facial, 3, 79, 92, 93, 102, 120, 194, 228, 254, 273, 275 Facial Nerve, 79, 102, 194, 254, 275 Facial Pain, 3, 254 False Positive Reactions, 143, 254 Family Planning, 205, 254 Far East, 70, 73, 254 Fat, 240, 241, 254, 266, 271, 284, 288 Fatal Outcome, 254, 282 Fatigue, 40, 82, 133, 148, 171, 174, 179, 214, 228, 244, 253, 254, 259 Febrile, 28, 254, 268 Fetal Death, 184, 254 Fetus, 215, 254, 261, 277, 279, 292 Fibrin, 245, 254, 255, 278, 289 Fibrinogen, 254, 278, 289 Fibrinolytic, 15, 255 Fibrosis, 255, 285 Flagellin, 61, 62, 66, 69, 74, 97, 123, 143, 149, 166, 167, 168, 255 Flagellum, 37, 143, 255 Fleas, 48, 255 Flexor, 253, 255, 289 Fold, 145, 168, 255 Foramen, 255, 276

Forearm, 240, 255 Frameshift, 255, 291 Frameshift Mutation, 255, 291 Fructose, 167, 168, 255 Fungi, 255, 258, 269, 294 Fungus, 169, 255 G Gallbladder, 233, 239, 249, 255 Ganglia, 239, 255, 272, 276 Ganglion, 255, 274, 294 Gas, 241, 249, 256, 260, 273, 293 Gas exchange, 256, 293 Gastric, 235, 238, 256, 264 Gastric Acid, 235, 256 Gastrin, 256, 259 Gastrointestinal, 164, 214, 215, 256, 268, 288 Gelatin, 248, 256, 289 Gels, 163, 256 Gene Expression, 7, 13, 25, 30, 31, 35, 36, 37, 39, 43, 49, 50, 57, 65, 88, 164, 256 Gene Order, 70, 256 Gene Pool, 19, 256 Genetic Code, 256, 273 Genetic Engineering, 240, 245, 256 Genetic Markers, 37, 256 Genetic Screening, 154, 256 Genetic Techniques, 34, 256 Genetic testing, 256, 279 Genetics, 7, 11, 12, 14, 21, 27, 45, 123, 187, 248, 256, 270 Genomics, 19, 50, 256 Genotype, 42, 92, 257, 277 Giant Cells, 257, 285 Gland, 50, 56, 57, 84, 233, 257, 267, 274, 275, 285, 288, 290 Gliosis, 46, 257 Glomerular, 164, 257 Glomerulus, 257, 272 Glossopharyngeal Nerve, 254, 257 Glucose, 242, 257, 263, 292 Glucuronic Acid, 257, 259 Glutamate, 36, 257 Glycogen, 243, 257 Glycoprotein, 254, 257, 264, 289 Glycosaminoglycan, 75, 122, 257 Gonorrhea, 242, 257 Governing Board, 257, 279 Gp120, 257, 276 Graft, 164, 257, 259, 261 Graft Rejection, 164, 257, 261 Gram-negative, 241, 242, 243, 252, 258

300 Lyme Disease

Gram-positive, 242, 243, 258, 271, 288 Granulocytes, 166, 258, 294 Grasses, 5, 170, 258 Groin, 214, 258 Guinea Pigs, 57, 258 H Habitat, 111, 218, 258, 271 Haemophilus, 242, 258 Half-Life, 242, 258 Haplotypes, 38, 258 Haptens, 234, 258 Headache, 3, 17, 97, 133, 171, 194, 198, 214, 228, 251, 253, 258, 262, 291 Headache Disorders, 4, 258 Health Resources, iv, 5, 53, 258 Health Services, 31, 258 Health Status, 31, 258 Heart failure, 259 Heartbeat, 237, 259 Helminths, 259, 262 Hematogenous, 42, 259 Hemicrania, 258, 259 Hemolysis, 238, 259 Hemolytic, 259, 282 Hemorrhage, 248, 258, 259, 284, 288 Hemostasis, 259, 263 Heparin, 21, 259 Hereditary, 233, 259, 277 Heredity, 256, 259 Heterodimers, 50, 259, 263 Heterogeneity, 61, 62, 69, 84, 110, 234, 259 Homologous, 18, 33, 49, 54, 56, 59, 71, 76, 234, 248, 259, 285 Hormone, 97, 171, 239, 247, 249, 256, 259, 263, 269, 280, 284, 290 Horseradish Peroxidase, 252, 259 Humoral, 8, 15, 34, 62, 68, 98, 155, 156, 257, 259 Humour, 259 Hybrid, 245, 260, 273 Hybridization, 13, 158, 260, 270, 273 Hybridoma, 156, 260 Hydrogen, 239, 241, 249, 253, 260, 266, 270, 273, 274 Hydrolysis, 32, 260, 279, 281 Hydrophobic, 260, 266 Hydroxylysine, 245, 260 Hydroxyproline, 245, 260 Hyperaemia, 246, 260 Hyperbilirubinemia, 260, 265 Hypercapnia, 46, 260 Hypersensitivity, 148, 260, 284, 286

Hypertension, 258, 260, 275, 290, 292 Hypesthesia, 260, 272 I Id, 124, 132, 216, 217, 224, 226, 260 Idiopathic, 233, 260, 284 Illusion, 260, 293 Imidazole, 240, 260 Immune response, 8, 10, 15, 17, 23, 34, 35, 50, 56, 58, 59, 62, 66, 98, 139, 143, 144, 147, 156, 160, 161, 162, 164, 166, 173, 174, 233, 236, 237, 238, 257, 258, 260, 261, 268, 285, 287, 288, 292, 293 Immune Sera, 260, 261 Immune system, 30, 138, 142, 161, 213, 215, 237, 238, 260, 261, 267, 268, 271, 277, 292, 294 Immune Tolerance, 39, 260 Immunization, 12, 52, 57, 58, 59, 66, 70, 78, 147, 159, 164, 165, 261 Immunoassay, 4, 252, 261 Immunoblotting, 61, 68, 74, 87, 261 Immunocompromised, 41, 261 Immunofluorescence, 152, 230, 261 Immunogen, 12, 22, 166, 261 Immunogenic, 15, 23, 59, 72, 110, 144, 146, 150, 160, 163, 167, 174, 261, 266 Immunoglobulin, 69, 76, 77, 93, 98, 111, 119, 123, 236, 261, 270, 286 Immunohistochemistry, 53, 261 Immunologic, 30, 59, 154, 181, 243, 261 Immunosuppressive, 32, 51, 261, 285, 289 Immunosuppressive Agents, 261, 285 Immunosuppressive therapy, 261 Immunotherapy, 164, 174, 261 Impairment, 31, 46, 171, 230, 237, 239, 261, 269 In situ, 23, 34, 35, 261 In Situ Hybridization, 35, 262 In vivo, 8, 11, 15, 26, 35, 36, 49, 51, 54, 56, 63, 90, 146, 149, 259, 262 Incision, 262, 264 Incompetence, 150, 262 Incontinence, 262, 271 Indicative, 178, 262, 275, 293 Induction, 25, 66, 70, 71, 262 Infantile, 233, 262 Infarction, 247, 262, 269 Infectious Mononucleosis, 262, 270 Infestation, 22, 262, 270 Infiltration, 262, 294 Influenza, 53, 103, 179, 185, 262 Information Systems, 34, 53, 262

Index 301

Ingestion, 236, 262 Inhalation, 171, 198, 234, 262 Initiation, 58, 262 Initiator, 263, 264 Inner ear, 242, 263 Innervation, 254, 263, 277, 285, 290 Insect Repellents, 151, 263 Insect Vectors, 47, 263 Insertional, 22, 37, 263 Insight, 7, 24, 25, 30, 59, 263 Insomnia, 152, 263 Insulator, 263, 271 Insulin, 164, 263 Insulin-dependent diabetes mellitus, 263 Integrins, 10, 28, 50, 69, 263 Interferon, 44, 64, 65, 67, 95, 263, 264 Interferon-alpha, 263 Interleukin-1, 61, 66, 171, 263, 264 Interleukin-12, 61, 264 Interleukin-2, 264 Interleukin-4, 64, 67, 264 Internal Medicine, 6, 13, 15, 31, 35, 42, 53, 56, 85, 89, 96, 103, 106, 107, 110, 264, 284 Interstitial, 254, 264, 272 Intervention Studies, 11, 264 Intestines, 233, 256, 264, 285 Intracellular, 36, 164, 256, 262, 263, 264, 269 Intracellular Membranes, 264, 269 Intracranial Pressure, 264, 275, 281 Intramuscular, 264, 275 Intrathecal, 17, 264 Intravenous, 33, 264, 275 Intrinsic, 33, 234, 239, 264 Intrinsic Factor, 33, 264 Introns, 38, 264 Invasive, 7, 59, 261, 264, 268 Ions, 239, 243, 250, 260, 264, 265 Ischemia, 264, 271 Isoelectric, 264, 265, 288 Isoelectric Point, 265, 288 Isozymes, 265, 282 Ixodid, 13, 123, 148, 152, 154, 159, 163, 241, 253, 265 J Jaundice, 131, 260, 265 Joint, 3, 17, 32, 33, 38, 45, 54, 101, 146, 160, 165, 172, 173, 213, 214, 218, 228, 255, 265, 288, 289 K Kb, 204, 265 Keratitis, 81, 122, 265

Kilobase, 61, 68, 265 Kinetic, 29, 32, 114, 265, 277 L Labile, 144, 245, 265 Lacrimal, 254, 265 Lactate Dehydrogenase, 167, 168, 265 Large Intestine, 249, 264, 265, 283, 286 Lectin, 265, 269 Leishmaniasis, 52, 164, 265 Lens, 265, 283, 294 Leprosy, 142, 164, 265 Leptospirosis, 143, 265 Lesion, 4, 16, 23, 34, 45, 71, 83, 148, 152, 154, 160, 162, 163, 172, 218, 257, 265, 266 Lethargy, 148, 229, 265 Leukapheresis, 138, 139, 265 Leukemia, 233, 244, 266 Leukocytes, 23, 239, 240, 243, 252, 258, 263, 266, 273, 277 Library Services, 224, 266 Lice, 48, 266 Life cycle, 26, 31, 42, 54, 56, 178, 255, 266 Ligaments, 247, 266 Ligands, 26, 263, 266 Ligation, 24, 266 Linkage, 256, 266, 276 Lipid, 15, 142, 237, 263, 266, 271, 274 Lipid A, 142, 266 Lipid Peroxidation, 266, 274 Lipopolysaccharides, 266 Lipoprotein, 4, 15, 22, 31, 42, 58, 62, 84, 118, 142, 146, 258, 266, 267 Liposomes, 59, 266 Litter, 34, 266 Liver, 76, 149, 161, 214, 215, 233, 234, 239, 240, 249, 255, 257, 259, 266, 285 Liver scan, 266, 285 Localization, 34, 49, 61, 261, 266 Localized, 4, 5, 150, 168, 178, 184, 262, 266, 271, 278, 285 Locomotion, 255, 267, 278 Longitudinal study, 27, 267 Low-density lipoprotein, 266, 267 Lumbar, 138, 267, 285, 287, 290 Lumbar puncture, 138, 267, 287 Lupus, 267, 289 Lymph, 174, 214, 244, 251, 252, 259, 262, 267, 285 Lymph node, 214, 267, 285 Lymphadenopathy, 174, 262, 267 Lymphatic, 252, 262, 267, 278, 287, 289 Lymphatic system, 267, 287, 289

302 Lyme Disease

Lymphocyte, 30, 33, 79, 86, 106, 164, 215, 236, 267, 268, 269 Lymphocyte Subsets, 79, 267 Lymphocytic, 34, 159, 267 Lymphoid, 30, 236, 247, 267, 268 Lymphokines, 156, 267 Lymphoma, 92, 100, 268 Lysine, 145, 148, 260, 268 Lytic, 24, 268, 286, 293 M Macrophage, 11, 264, 268 Magnetic Resonance Imaging, 268, 285 Major Histocompatibility Complex, 258, 264, 268 Malaise, 174, 229, 250, 253, 268 Malaria, 41, 151, 179, 185, 268 Malaria, Falciparum, 268 Malaria, Vivax, 268 Malignancy, 254, 268 Malignant, 53, 268, 272, 275 Manifest, 154, 155, 159, 268 Mannans, 255, 268 Matrix metalloproteinase, 114, 268 Medial, 268, 284, 290 Mediate, 9, 30, 45, 50, 59, 64, 69, 128, 144, 156, 171, 268 Mediator, 44, 264, 268 MEDLINE, 205, 269 Membrane Proteins, 34, 144, 266, 269 Memory, 17, 21, 40, 137, 171, 229, 236, 249, 269 Meninges, 242, 248, 250, 269 Meningitis, 5, 133, 269 Menstrual Cycle, 269, 280 Mental Disorders, 55, 140, 269, 281 Mental Health, iv, 5, 140, 204, 206, 269, 273, 281 Meta-Analysis, 106, 269 Metastasis, 268, 269, 272 MI, 36, 169, 232, 269 Microbe, 269, 290 Microbiological, 8, 138, 269 Microorganism, 145, 164, 245, 269, 275, 294 Microscopy, 34, 37, 145, 239, 259, 269 Microwaves, 270, 282 Migration, 24, 84, 270, 272 Mitochondrial Swelling, 270, 272 Mobility, 36, 270 Modeling, 11, 250, 270 Molecular mass, 173, 270 Molecular Probes, 53, 270

Molecule, 14, 15, 28, 146, 159, 166, 234, 236, 239, 245, 250, 251, 253, 257, 260, 263, 265, 270, 273, 274, 278, 280, 282, 293 Monitor, 18, 20, 26, 270, 273 Monoclonal, 10, 60, 61, 62, 71, 97, 109, 156, 159, 161, 261, 270 Monoclonal antibodies, 10, 60, 62, 109, 161, 261, 270 Monocyte, 14, 270 Mononuclear, 29, 64, 166, 262, 270 Mononucleosis, 5, 270 Monophosphate, 32, 270 Morphological, 12, 101, 251, 255, 270 Motility, 6, 37, 270 Mucins, 270, 284 Mucocutaneous, 265, 271 Multiple sclerosis, 5, 106, 107, 123, 138, 164, 169, 271 Musculoskeletal System, 9, 154, 161, 271 Mutagenesis, 32, 37, 271 Mutagens, 255, 271 Myalgia, 229, 262, 271 Mycobacterium, 142, 265, 271, 291 Myelin, 271, 272, 286 Myelitis, 116, 271 Myeloma, 260, 271 Myocarditis, 159, 271 Myocardium, 269, 271 Myositis, 109, 271 N Naive, 9, 31, 69, 99, 271 Nasal Mucosa, 262, 271 Natural Disasters, 47, 271 Natural killer cells, 264, 271 Nausea, 229, 253, 271, 281, 292 NCI, 1, 140, 203, 244, 271 Necrosis, 44, 171, 262, 269, 271, 285 Needs Assessment, 53, 272 Neoplasms, 53, 272, 289 Neoplastic, 235, 254, 268, 272 Nephritis, 164, 272 Nerve, 92, 103, 105, 114, 137, 165, 236, 237, 238, 249, 254, 255, 257, 263, 269, 271, 272, 274, 276, 277, 285, 287, 288, 290, 291, 294 Neural, 234, 259, 272 Neuritis, 101, 272 Neuroblastoma, 61, 97, 166, 272 Neuroglia, 257, 272 Neurologic Manifestations, 154, 272 Neuronal, 272, 276 Neuropathy, 61, 97, 105, 109, 272, 276

Index 303

Neuroretinitis, 81, 272 Neurosyphilis, 105, 272, 275 Neurotoxin, 170, 171, 272 Neurotransmitters, 270, 272 Neutropenia, 28, 273 Neutrophils, 28, 35, 44, 258, 266, 273 Nitrogen, 234, 253, 270, 273, 291 Nuclear, 38, 82, 84, 230, 239, 251, 253, 255, 272, 273 Nuclei, 251, 256, 264, 268, 273, 274 Nucleic acid, 147, 152, 158, 162, 164, 168, 172, 173, 174, 256, 260, 262, 271, 273 Nucleic Acid Hybridization, 260, 273 Nucleic Acid Probes, 158, 273 Nucleus, 238, 239, 244, 248, 252, 253, 270, 273, 288, 289 O Occupational Health, 183, 273 Ocular, 122, 123, 273 Odour, 237, 273, 292 Oligonucleotide Probes, 157, 273 Oncogenic, 263, 273 Only Child, 142, 273 Opacity, 249, 273 Operon, 36, 37, 64, 273, 283 Ophthalmic, 198, 273, 283 Ophthalmic Artery, 273, 283 Opsin, 274, 283 Optic Disk, 274, 275 Optic Nerve, 272, 274, 281, 283, 284, 285 Optic Nerve Diseases, 274, 281 Optic nerve head, 272, 274 Organ Culture, 274, 290 Orofacial, 3, 254, 274 Ovum, 247, 266, 274, 280 Oxidation, 237, 266, 274 Oxidative Stress, 36, 274 P Pachymeningitis, 269, 274 Paediatric, 87, 132, 274 Palladium, 154, 274 Palliative, 274, 289 Palsy, 79, 92, 93, 102, 120, 133, 194, 274 Pancreas, 233, 240, 249, 263, 274, 275 Pancreatic, 275 Pancreatitis, 171, 275 Papilla, 275 Papilledema, 275, 281 Papilloedema, 81, 275 Papule, 4, 253, 275 Paralysis, 87, 194, 228, 229, 275, 287, 290 Parasite, 41, 275

Parasitic, 22, 36, 60, 255, 259, 262, 266, 275, 290 Parasitic Diseases, 60, 275, 290 Parenteral, 12, 275 Paresis, 272, 275 Paresthesias, 272, 275 Parotid, 257, 275, 285 Paroxysmal, 258, 275 Patch, 4, 10, 275 Pathologic, 3, 30, 240, 247, 260, 275, 281 Pathophysiology, 46, 275 Patient Advocacy, 219, 275 Patient Education, 213, 222, 224, 232, 276 Pediatrics, 6, 54, 85, 88, 92, 93, 100, 102, 105, 108, 109, 131, 216, 276 Pelvic, 251, 276 Peptide Chain Elongation, 244, 276 Peptide Mapping, 47, 276 Peptide T, 142, 276 Perception, 80, 276 Percutaneous, 171, 276 Pericardium, 276, 289 Periodontal disease, 37, 276 Peripheral blood, 14, 29, 34, 64, 69, 78, 79, 263, 276 Peripheral Nerves, 165, 265, 276, 287 Peripheral Nervous System, 41, 103, 161, 274, 276, 288 Peripheral Neuropathy, 79, 184, 276 Peritoneal, 35, 54, 276 Peritoneal Cavity, 35, 276 Peritoneum, 276 Pernicious, 264, 277 Pernicious anemia, 264, 277 Peroneal Nerve, 277, 285 Peroxidase, 36, 266, 277 Peroxide, 36, 266, 277 Phagocyte, 35, 277 Pharmacokinetics, 250, 277 Pharmacologic, 236, 258, 277, 290 Pharynx, 262, 277 Phenotype, 7, 38, 239, 246, 277 Pheromone, 47, 277 Phosphoglycerate Kinase, 167, 277 Phospholipids, 254, 266, 277 Phosphorylation, 277, 282 Physical Examination, 31, 138, 139, 214, 277 Physiologic, 240, 258, 269, 277, 282 Physiology, 239, 277 Pigments, 239, 241, 277, 283 Pilot study, 63, 277

304 Lyme Disease

Placenta, 277, 280 Plague, 48, 185, 278, 291 Plants, 241, 257, 265, 277, 278, 284, 291 Plaque, 236, 278 Plasma, 64, 234, 236, 242, 243, 252, 254, 256, 259, 266, 271, 278, 283 Plasma cells, 236, 271, 278 Plasmid, 19, 29, 34, 36, 43, 59, 61, 74, 85, 146, 154, 161, 278, 293 Plasmin, 14, 278 Plasminogen, 14, 81, 278 Plasminogen Activators, 278 Platelet Activation, 28, 278 Platelets, 10, 28, 69, 278, 289 Platinum, 274, 278 Plexus, 278, 285 Polyarthritis, 174, 278 Polyethylene, 8, 278 Polymerase, 18, 42, 45, 82, 92, 131, 149, 152, 161, 166, 167, 168, 215, 279, 283 Polymerase Chain Reaction, 18, 42, 45, 82, 92, 131, 149, 152, 161, 166, 215, 279 Polymorphic, 30, 38, 279 Polymorphism, 45, 68, 71, 106, 279 Polypeptide, 37, 142, 145, 159, 163, 172, 235, 245, 255, 260, 278, 279, 280, 294 Polysaccharide, 234, 236, 242, 257, 279, 280 Population Density, 10, 279 Posterior, 111, 235, 237, 244, 257, 274, 279, 285 Post-traumatic, 258, 279 Potentiates, 263, 279 Potentiating, 15, 279 Practicability, 279, 291 Practice Guidelines, 206, 215, 279 Precipitating Factors, 258, 279 Precursor, 164, 167, 168, 251, 252, 278, 279, 291 Prenatal, 251, 256, 279 Prevalence, 10, 11, 27, 34, 73, 75, 280 Probe, 18, 44, 52, 56, 158, 161, 273, 280 Progesterone, 122, 280 Progression, 38, 40, 178, 184, 236, 280 Progressive, 157, 161, 242, 249, 258, 271, 278, 280 Proline, 245, 260, 280 Promoter, 29, 44, 146, 280 Promyelocytic leukemia, 26, 280 Prone, 30, 280 Prophylaxis, 66, 80, 88, 173, 280, 292 Proportional, 252, 280 Prospective study, 52, 267, 280

Protease, 276, 280 Protective Clothing, 213, 280 Protein C, 51, 147, 148, 155, 167, 168, 234, 235, 237, 238, 245, 266, 280 Protein Conformation, 235, 280 Protein S, 6, 87, 145, 146, 148, 156, 183, 240, 244, 253, 256, 280, 284, 289 Proteoglycan, 21, 68, 122, 149, 280 Proteolytic, 184, 245, 255, 278, 281, 284 Protocol, 50, 52, 72, 139, 281 Protozoa, 37, 265, 269, 281 Proximal, 250, 281 Pseudotumor Cerebri, 103, 281 Psoriasis, 156, 164, 281 Psychiatric, 5, 16, 112, 239, 269, 281 Psychiatry, 46, 55, 281, 288, 293 Psychic, 281, 286 Psychogenic, 85, 281 Psychosomatic, 40, 281 Public Policy, 205, 281 Publishing, 60, 281 Pulmonary, 6, 240, 281, 293 Pulmonary Artery, 240, 281, 293 Pulse, 270, 281 Purifying, 22, 144, 281 Purulent, 233, 282 Pyruvate Kinase, 167, 168, 282 R Rabies, 22, 179, 182, 282, 294 Race, 270, 282 Radiation, 252, 261, 282, 285, 294 Radio Waves, 138, 270, 282 Radioactive, 241, 258, 260, 266, 270, 273, 282, 285 Radioisotope, 273, 282 Radiological, 213, 276, 282 Radiologist, 254, 282 Randomized, 4, 55, 89, 135, 251, 282 Randomized clinical trial, 55, 282 Reagent, 157, 282 Receptor, 14, 24, 28, 43, 45, 62, 136, 156, 233, 236, 253, 257, 276, 282 Recombinant Proteins, 9, 50, 57, 68, 144, 282 Recombination, 30, 59, 71, 256, 282 Reconstitution, 30, 282 Rectum, 241, 249, 256, 262, 265, 283 Red Nucleus, 237, 283 Refer, 1, 245, 250, 255, 266, 267, 270, 271, 283 Refraction, 283, 287 Refractory, 174, 283

Index 305

Regeneration, 282, 283 Regimen, 251, 283 Relapse, 215, 283 Reliability, 42, 100, 101, 283 Repressor, 36, 273, 283 Resolving, 39, 283 Respiration, 241, 270, 283 Respiratory Physiology, 87, 283, 293 Restoration, 283, 294 Retina, 95, 243, 244, 246, 265, 272, 274, 283, 284, 292, 294 Retinal, 83, 274, 283, 284, 294 Retinal Artery, 83, 283, 284 Retinal Artery Occlusion, 83, 284 Retinol, 283, 284 Retrospective, 31, 284 Reversion, 284, 291 Rheumatic Diseases, 30, 97, 103, 104, 107, 116, 119, 184, 284 Rheumatism, 86, 108, 118, 284 Rheumatoid, 5, 21, 44, 92, 166, 210, 245, 284 Rheumatoid arthritis, 5, 21, 44, 92, 245, 284 Rheumatology, 6, 25, 31, 55, 80, 95, 101, 102, 183, 284 Ribosome, 284, 291 Ricin, 284 Ricinus, 13, 61, 130, 146, 160, 162, 172, 242, 284 Risk factor, 31, 40, 56, 113, 128, 252, 280, 284 Rod, 238, 239, 258, 284 S Sagittal, 46, 284 Saliva, 23, 34, 50, 51, 56, 99, 124, 165, 284 Salivary, 23, 50, 52, 56, 57, 84, 249, 254, 284, 290 Salivary glands, 249, 254, 284, 290 Salivary Proteins, 23, 56, 284 Saponin, 123, 284 Sarcoidosis, 164, 284 Satellite, 34, 285 Scans, 46, 285 Schizophrenia, 74, 285 Sciatic Nerve, 101, 277, 285, 290 Sclera, 244, 246, 252, 285, 292 Scleritis, 111, 285 Scleroderma, 53, 285 Sclerosis, 53, 107, 138, 245, 271, 285 Screening, 4, 39, 47, 51, 53, 58, 130, 145, 147, 154, 157, 164, 244, 256, 285

Secretion, 17, 142, 146, 156, 259, 263, 270, 285 Secretory, 171, 285 Segmental, 59, 285 Segmentation, 285 Segregation, 282, 285 Seizures, 152, 275, 286 Semisynthetic, 235, 243, 244, 286 Sensory loss, 271, 286, 289 Sepsis, 171, 286 Septic, 166, 286 Sequence Homology, 276, 286 Sequencing, 8, 18, 42, 50, 279, 286 Serologic Tests, 42, 66, 76, 118, 122, 155, 286 Serology, 41, 48, 69, 93, 112, 163, 173, 192, 230, 286 Serous, 251, 286 Shock, 97, 128, 167, 168, 286, 291 Side effect, 151, 197, 233, 286, 290 Signs and Symptoms, 5, 178, 214, 272, 283, 286, 292 Skeleton, 265, 286 Skin Tests, 20, 286 Skull, 248, 264, 286, 289 Small intestine, 244, 259, 264, 286 Smallpox, 179, 182, 286, 292 Soma, 286 Somatic, 85, 233, 257, 259, 276, 286 Sound wave, 246, 282, 286 Spastic, 81, 287 Spasticity, 287 Specialist, 219, 287 Species Specificity, 75, 124, 287 Specificity, 8, 9, 17, 43, 47, 69, 74, 99, 143, 156, 162, 163, 173, 234, 287 Spectrum, 26, 27, 30, 40, 116, 162, 163, 165, 186, 270, 282, 287 Sperm, 244, 287, 291 Spinal cord, 107, 138, 237, 242, 243, 250, 255, 264, 269, 271, 272, 274, 276, 285, 287 Spinal Cord Vascular Diseases, 271, 287 Spinal Nerves, 276, 287 Spinal tap, 138, 267, 287 Spleen, 214, 215, 260, 267, 285, 287 Spondylitis, 92, 171, 287 Sporadic, 74, 287 Staging, 285, 287 Standardize, 40, 288 Steady state, 32, 288 Stimulus, 30, 250, 253, 263, 275, 288

306 Lyme Disease

Stomach, 233, 238, 249, 253, 256, 259, 264, 271, 276, 277, 286, 287, 288 Strand, 38, 279, 288 Streptavidin, 122, 288 Streptococcal, 112, 288 Streptococcus, 288 Stress, 36, 50, 55, 238, 271, 274, 284, 288 Stroke, 137, 140, 194, 204, 211, 217, 288 Stromal, 251, 288 Stupor, 265, 288 Subacute, 262, 288 Subarachnoid, 258, 288 Subclinical, 262, 286, 288 Subcutaneous, 35, 251, 275, 288 Subspecies, 287, 288, 292 Substance P, 253, 283, 285, 288 Substrate, 36, 170, 252, 288 Symptomatic, 17, 275, 288 Synovial, 9, 18, 24, 33, 38, 42, 65, 108, 166, 288 Synovial Fluid, 9, 24, 33, 42, 108, 166, 288 Synovial Membrane, 288 Syphilis, 37, 46, 143, 145, 154, 167, 272, 289 Systemic disease, 143, 289 Systemic lupus erythematosus, 92, 245, 289 T Temporal, 8, 13, 22, 25, 42, 62, 64, 75, 84, 258, 289 Tendonitis, 38, 289 Terminator, 146, 245, 289 Tetracycline, 250, 289 Thalamic, 237, 289 Thalamic Diseases, 237, 289 Therapeutics, 11, 37, 79, 131, 145, 200, 289 Thermal, 250, 279, 289 Thiamphenicol, 168, 289 Thigh, 83, 258, 289 Thorax, 267, 289 Threonine, 276, 289 Thrombin, 254, 280, 289 Thrombocytes, 278, 289 Thrombocytopenia, 28, 289 Thrombolytic, 278, 289 Thrombomodulin, 280, 289 Thrombosis, 263, 275, 280, 288, 289 Thymus, 261, 267, 289 Thyroid, 290 Thyroid Gland, 290 Thyroiditis, 164, 290 Tibial Nerve, 285, 290 Tick Paralysis, 178, 290

Tick-Borne Diseases, 13, 18, 41, 157, 238, 290 Tin, 229, 230, 276, 278, 290 Tinnitus, 281, 290 Tissue Culture, 139, 290 Titre, 161, 290 Tomography, 37, 117, 246, 290 Tooth Preparation, 233, 290 Topical, 128, 152, 199, 290 Toxic, iv, 152, 153, 234, 252, 253, 258, 261, 272, 277, 284, 290 Toxicity, 47, 153, 250, 290 Toxicology, 206, 290 Toxins, 194, 236, 251, 252, 257, 262, 270, 291 Trace element, 290, 291 Transfection, 58, 240, 291 Transfer Factor, 261, 291 Transfusion, 291 Translation, 145, 253, 291 Translational, 15, 291 Translocation, 244, 253, 291 Transmitter, 237, 269, 272, 291 Transplantation, 261, 268, 291 Trauma, 194, 271, 275, 291 Treatment Outcome, 85, 291 Trigeminal, 254, 291 Tropism, 56, 291 Tryptophan, 245, 291 Tuberculosis, 142, 164, 185, 267, 291 Tubulin, 38, 291 Tularemia, 178, 291 Typhimurium, 72, 291 U Unconscious, 248, 260, 292 Uracil, 36, 292 Uraemia, 275, 292 Urethra, 292 Urinary, 242, 262, 292 Urinary tract, 242, 292 Urinate, 292, 294 Urine, 69, 82, 100, 101, 129, 138, 139, 158, 191, 240, 262, 292 Urine Testing, 100, 101, 292 Urokinase, 14, 81, 292 Uterus, 247, 251, 280, 292 Uvea, 292 Uveitis, 73, 134, 171, 292 V Vaccine adjuvant, 11, 292 Vaccinia, 22, 292 Vaccinia Virus, 22, 292

Index 307

Vagina, 249, 292 Varicella, 55, 93, 293 Variola, 292, 293 Vascular, 23, 28, 46, 54, 244, 252, 258, 262, 277, 278, 287, 290, 292, 293 Vasculitis, 46, 275, 293 Vein, 138, 139, 264, 273, 275, 285, 293 Venereal, 289, 293 Venous, 280, 293 Ventilation, 60, 293 Ventricle, 281, 293 Ventricular, 94, 293 Venules, 240, 252, 293 Vertebrae, 287, 293 Vertigo, 171, 293 Veterinary Medicine, 205, 293 Vinblastine, 291, 293 Vinca Alkaloids, 293 Vincristine, 127, 291, 293 Viral, 5, 27, 32, 60, 135, 164, 184, 211, 251, 257, 262, 273, 282, 290, 293 Virulence, 6, 10, 21, 22, 35, 37, 50, 161, 174, 238, 290, 293 Virulent, 7, 22, 54, 58, 293 Virus, 22, 27, 179, 182, 238, 242, 248, 256, 257, 262, 263, 278, 286, 292, 293, 294 Viscera, 286, 293

Visceral, 238, 257, 265, 276, 294 Visual Acuity, 247, 274, 285, 294 Visual field, 281, 284, 294 Vitreous Body, 244, 283, 294 Vitro, 10, 11, 15, 23, 24, 26, 30, 31, 33, 34, 35, 45, 49, 51, 54, 58, 59, 61, 63, 66, 101, 115, 145, 146, 161, 173, 259, 262, 279, 286, 290, 294 Vivo, 11, 15, 35, 49, 51, 54, 57, 101, 146, 294 Void, 13, 294 W Walkers, 170, 294 White blood cell, 138, 139, 236, 240, 244, 262, 266, 267, 268, 270, 271, 273, 278, 294 Wound Healing, 263, 268, 294 X Xenograft, 236, 294 X-ray, 32, 138, 139, 230, 246, 273, 282, 285, 294 Y Yeasts, 255, 277, 294 Yellow Fever, 185, 294 Z Zoonoses, 10, 88, 238, 282, 294 Zoonosis, 159, 162, 294 Zoster, 93, 294 Zymogen, 280, 294

308 Lyme Disease