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

ARTERIOSCLEROSIS A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES J AM...

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ARTERIOSCLEROSIS A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES

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., 1960Arteriosclerosis: 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: 0-597-84338-4 1. Arteriosclerosis-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 arteriosclerosis. 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 ARTERIOSCLEROSIS ................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Arteriosclerosis ............................................................................. 4 E-Journals: PubMed Central ....................................................................................................... 55 The National Library of Medicine: PubMed ................................................................................ 56 CHAPTER 2. NUTRITION AND ARTERIOSCLEROSIS ......................................................................... 59 Overview...................................................................................................................................... 59 Finding Nutrition Studies on Arteriosclerosis ............................................................................ 59 Federal Resources on Nutrition ................................................................................................... 60 Additional Web Resources ........................................................................................................... 61 CHAPTER 3. ALTERNATIVE MEDICINE AND ARTERIOSCLEROSIS ................................................... 63 Overview...................................................................................................................................... 63 National Center for Complementary and Alternative Medicine.................................................. 63 Additional Web Resources ........................................................................................................... 64 General References ....................................................................................................................... 66 CHAPTER 4. DISSERTATIONS ON ARTERIOSCLEROSIS ..................................................................... 67 Overview...................................................................................................................................... 67 Dissertations on Arteriosclerosis ................................................................................................. 67 Keeping Current .......................................................................................................................... 67 CHAPTER 5. CLINICAL TRIALS AND ARTERIOSCLEROSIS ............................................................... 69 Overview...................................................................................................................................... 69 Recent Trials on Arteriosclerosis ................................................................................................. 69 Keeping Current on Clinical Trials ............................................................................................. 86 CHAPTER 6. PATENTS ON ARTERIOSCLEROSIS................................................................................ 89 Overview...................................................................................................................................... 89 Patents on Arteriosclerosis .......................................................................................................... 89 Patent Applications on Arteriosclerosis..................................................................................... 106 Keeping Current ........................................................................................................................ 138 CHAPTER 7. BOOKS ON ARTERIOSCLEROSIS ................................................................................. 141 Overview.................................................................................................................................... 141 Book Summaries: Online Booksellers......................................................................................... 141 Chapters on Arteriosclerosis ...................................................................................................... 142 CHAPTER 8. PERIODICALS AND NEWS ON ARTERIOSCLEROSIS ................................................... 145 Overview.................................................................................................................................... 145 News Services and Press Releases.............................................................................................. 145 Academic Periodicals covering Arteriosclerosis......................................................................... 147 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 151 Overview.................................................................................................................................... 151 NIH Guidelines.......................................................................................................................... 151 NIH Databases........................................................................................................................... 153 Other Commercial Databases..................................................................................................... 155 The Genome Project and Arteriosclerosis .................................................................................. 155 APPENDIX B. PATIENT RESOURCES ............................................................................................... 159 Overview.................................................................................................................................... 159 Patient Guideline Sources.......................................................................................................... 159 Finding Associations.................................................................................................................. 166 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 169 Overview.................................................................................................................................... 169 Preparation................................................................................................................................. 169

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Finding a Local Medical Library................................................................................................ 169 Medical Libraries in the U.S. and Canada ................................................................................. 169 ONLINE GLOSSARIES................................................................................................................ 175 Online Dictionary Directories ................................................................................................... 177 ARTERIOSCLEROSIS DICTIONARY...................................................................................... 179 INDEX .............................................................................................................................................. 261

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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 arteriosclerosis 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 arteriosclerosis, 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 arteriosclerosis, 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 arteriosclerosis. 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 arteriosclerosis, 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 arteriosclerosis. 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 ARTERIOSCLEROSIS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on arteriosclerosis.

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

Diabetes and Arteriosclerosis Source: IDF Bulletin. 42(Special Issue). November 1997. Contact: Available from International Diabetes Federation. 1 rue Defacqz, 1000 Brussels, Belgium. Phone (32) 2 538-5511. Fax (32) 2 538-5114. E-mail: [email protected]. Summary: This special issue of 'IDF Bulletin', published by the International Diabetes Federation, includes seven articles that address diabetes and arteriosclerosis. The issue defines arteriosclerosis as the condition that results from the formation of fat and mineral deposits in the walls of an artery. Atherosclerosis is the actual process involving the build-up of the fat and mineral deposits. The first three articles provide information about diabetes and lipid management, the impact of the Scandinavian Simvastatin Survival Study in reducing cardiovascular risk in people with diabetes, and

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secondary intervention. The remaining four articles address the growing burden of diabetes in the world population, cardiovascular disease in people with diabetes, risk factors for coronary heart disease in people with diabetes, and dyslipidemia in type 2 diabetes. Sidebars address the Framingham Heart Study and provide definitions for diabetes mellitus, lipoproteins, atherosclerosis, arteriosclerosis, and the Diabetes Control and Complications Trial. Several scientific studies have shown that an increase in physical activity and the reduction of overweight will reduce risk factors for cardiovascular diseases. Smoking cessation and avoiding excessive alcohol intake further reduce the overall risk. Most of the articles include glossaries. An International Diabetes Federation membership form and a fact sheet about the IDF's regional development plan conclude the issue. This issue will also be published in French, Italian, and Spanish. 2 figures. 2 tables. 59 references. (AA-M).

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

Project Title: ACTIN ASSEMBLY DURING YEAST POLARIZED CELL GROWTH Principal Investigator & Institution: Li, Rong; Associate Professor; Cell Biology; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 01-JAN-1998; Project End 31-DEC-2006 Summary: (provided by applicant): Cell polarization is fundamentally important for many physiological processes such as embryonic development, cell motility and cell differentiation. Elucidation of the mechanism underlying cell polarity establishment is important for understanding developmental abnormalities and diseases such as invasive tumor and arteriosclerosis. Identification of the molecules that are specialized in cell polarity generation may reveal novo therapeutic targets for these diseases. In addition, how cells break symmetry and establish a polarity is a profound problem in cell biology. Understanding cell's intrinsic ability to polarize may lead to fundamental insights into the physical principles that govern cellular organization and morphogenesis. A key regulator of cell polarity in many eukaryotic cell types is the Rhofamily GTPase Cdc42. During cell polarization, Cdc42 is activated in a localized manner

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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and induces downstream events, most importantly, the generation of localized actin cytoskeletal elements. The goal of this proposal is to understand how Cdc42 induces polarized polymerization of actin filaments. We will continue our ongoing work studying how actin filaments are nucleated at cell cortex and how Cdc42 defines the site of actin nucleation during cell polarization. We will also investigate the mechanism by which the activated form of Cdc42 drives the initial breakage of cell symmetry. The specific aims are: 1) Biochemical characterization of the Bee1/Vrp1/myosin-I complex;2) Studying the regulation of the Bee1/Vrp1/myosin-I complex during cell polarization;3) Understanding the mechanism by which the Arp2/3 complex nucleate actin polymerization;4) Investigating the Intrinsic mechanism that drives cell polarity generation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADENOVIRAL/LENTIVIRAL MODIFICATION

VECTORS

FOR

GENETIC

Principal Investigator & Institution: Mc Gregor, Christopher G.; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2003 Summary: The broad long-term objectives of this proposal are to achieve targeted, efficient and durable gene transfer to the transplanted heart and, using biologically relevant genes for isoforms of nitric oxide synthase (NOS), to normalize coronary arterial vasoreactivity and reduce cardiac allograft vasculopathy (CAV) after allotransplantation in both a small and large animal model. The central hypotheses of this proposal are that, using the unique transplant setting, targeted, efficient and durable gene transduction of blood vessels of the heart or the myocardium can be achieved and that abnormalities in coronary vascular relaxation and the development of CAV after heart transplantation can be reduced by efficient cardiac transduction with endothelial or inducible NOS (eNOS or iNOS). CAV is the greatest obstacle to long-term patient survival after cardiac transplantation. Gene therapy may be particularly applicable in the setting of transplantation as the donor organ is uniquely available for genetic modification ex vivo prior to implantation into a recipient. Major challenges to successful clinical gene genetic modification ex vivo prior to implantation into a recipient. Major challenges to successful clinical gene therapy include the need for optimal vectors and delivery systems to transfer genetic material to tissues in vivo. Recently, for the first time, physical and chemical conditions of gene delivery to the heart have been shown to allow selective targeting of the vector to the media of the coronary arteries of the myocardium. Using a normothermic perfusion system, the usual period of storage of the donor heart before transplantation can be transformed into a period for optimal gene delivery without affecting the viability of the graft. The first aim of transformed into a period for optimal gene delivery without affecting the viability of the graft. The first aim of the current proposal is to identify the most suitable vector (adenovirus or lentivirus) and delivery system using chemical modification of a normothermic perfusion system for efficient, targeted and durable gene delivery in the heterotopic rat heart transplant model. The second aim is to study, using the most suitable vector and same delivery system from Specific Aim 1, the effects of eNOS or iNOS gene transfer to either the coronary vasculature or myocardium of the donor heart on coronary arterial vascular reactivity and on CAV after heterotopic pig heart allotransplantation. NOS will be studied as the gene of choice as reduced nitric oxide bioavailability is characteristic of vessels undergoing CAV. Abnormal endothelium dependent relaxation precedes CAV, so that successful NOS gene transfer might be

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expected to impact on the early stages of the disease. Before gene transfer technology to the transplanted heart can progress to the clinic, satisfactory experience in a large animal model will be necessary. The porcine model is particular suitable from a physiological and pathological viewpoint and is also the animal of choice for future clinical xenotransplantation. Success in achieving the specific aims of this proposal opens up the potential for clinical gene therapy to avoid CAV after heart transplantation. Implications also exist for the application of these techniques for the modification of non-allograft arteriosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALLOGRAFT INFLAMMATORY FACTOR IN TRANSPLANT VASCULOPATHY Principal Investigator & Institution: Sibinga, Nicholas E.; Assistant Professor; Medicine; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2006 Summary: Transplant arteriosclerosis is the major cause of graft organ failure after the first year of transplantation. Although its detailed pathogenesis remains unclear, clinical and laboratory studies indicate that transplant arteriosclerosis stems from a local, immune-mediated process involving interactions between the recipient's mononuclear cells, with critical roles for macrophages and B and T lymphocytes, and cells of the donor organ's vascular system. Allograft inflammatory factor (aif-1), a 17 kD protein bearing an EF hand Ca++-binding motif, is barely detectable in most normal tissues. However, its expression by cells of macrophage lineage increases markedly in both alloand autoimmune reactions, including perivascular inflammation in transplanted hearts, experimental autoimmune neuritis, and the inflamed pancreas of prediabetic BB rats. Very little is known about the function of aif-1 in macrophage activation or its specific role in the pathogenesis of transplant arteriosclerosis or other inflammatory conditions. This proposal has three major goals: to delineate the molecular basis for the discrete disease-associated pattern of expression of aif-1, to define the role of aif-1 in macrophage biology, and to assess its importance in the pathogenesis of transplant arteriosclerosis. Molecular genetic techniques such as adenoviral transduction and gene targeting of embryonic stem cells will be used to produce macrophages with substantially different levels of aif-1 expression. Function of these cells will be tested both in vitro and in vivo. The importance of aif-1 in transplant arteriosclerosis will be assessed in allograft transplantation studies with mice lacking aif-1. This work may lead to improved longterm outcomes for organ transplantation. The genetic elements controlling aif-1 expression may be useful to direct expression of immunoregulatory gene products to sites of inflammation in transplanted organs. The functional significance of aif-1 likely resides in macrophages, or in their regulation of other inflammatory cells; how aif-1 expression affects the immune response may point to new regulatory pathways involved in the development of transplant arteriosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: ANALYSIS OF A NOVEL FAMILY OF LIPID RECEPTORS Principal Investigator & Institution: Xu, Yan; Associate Professor; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2006 Summary: (provided by applicant) Four G protein coupled receptor, OGR1, GPR4, G2A and TDAG8, belong to a novel subfamily of receptors. We have recently identified that

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7

these receptors are the first and only receptors for sphingosylphosphorylcholine (SPC) and lysophosphatidyicholine (LPC), which are important bioactive lipid signaling molecules. Each of these receptors, share some similar, but distinct, binding and activating features. We propose that the specific amino acid residues reside in 7TMs are responsible for ligand binding and the different intracellular domains in OGR1 family receptors that are required for their shared as well as specific signaling activities. This hypothesis will be tested in three specific aims. Specific Aim 1: Identify the amino acids required for SPC and LPC binding in OGR1 subfamily genes and construct threedimensional (3D) models of OGR1 and G2A. Mutational and functional analyses (binding and activity assays) will be performed to identify the structural determinants for ligand binding. Molecular models of OGR1 and G2A will be constructed based on structure-function data generated. Specific Aim 2: Determine the amino acid residues required for antagonist binding in TDAG8 and the mechanisms of PMA-induced OGR1 desensitization. The structural determinants for antagonist binding in TDAG8 will be identified using mutational studies. The mechanism for PMA-induced desensitization will be determined through mutational and functional studies. Specific Aim 3: Determine the structural requirements for activating the calcium and MAP kinase signaling pathways in OGR1 subfamily genes. Chimeric receptors will be made between OGR1 and other receptors to determine the structural element(s) that is required for differential coupling to Gi and Gq proteins, leading to the increase in intracellular calcium; the structural elements responsible for the lack of coupling to the calcium pathway and which are essential for MAP kinase activation. The involvement of SPC and LPC in many diseases, such as arteriosclerosis, inflammatory diseases and cancers makes these receptors highly attractive targets for the treatment of these diseases. The structure-function relationship data to be obtained through proposed studies will lay the foundation for future development of new agonist(s) and/or antagonist(s) for OGR1 family receptors, which are crucial for establishing the physiological and pathological roles and functions of these receptors, and eventually the development of drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANGIOGENESIS AND MECHANISMS OF EXERCISE TRAINING IN PAD Principal Investigator & Institution: Annex, Brian H.; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2003; Project Start 25-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Peripheral arterial disease (PAD) impairs arterial blood flow to the legs & is a major indicator of systemic atherosclerosis. PAD affects 5% of the US population over 50. Approx 1/3 of patients with PAD have typical claudication, defined as pain in one or both legs on walking that is relieved by rest. Patients with claudication have a marked impairment in exercise performance similar to patients with NYHA class III heart failure. Goals of treatment for PAD patients include risk-factor modification & antiplatelet drug therapy to address increased cardiovascular mortality risk. Supervised exercise training is the most efficacious treatment to improve walking capacity, demonstrated in many (small) randomized trials. Neither the pathophysiology of claudication nor the mechanism(s) by which exercise training improves walking times in persons with IC are completely understood. It is unknown how long-term exercise training affects skeletal muscle or to what extent skeletal muscle abnormalities in PAD are reversible. Women have been largely underrepresented in mechanistic studies of IC and exercise training. There is an urgent need for clinical research directed towards defining the basis of the exercise training changes induced in

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PAD patients in order to: 1) provide insights into the general pathophysiology of the exercise impairment in PAD; 2) permit scientifically plausible & testable modifications to currently prescribed exercise regimens to better employ this critical therapeutic modality &, 3) identify novel targets from pharmacotherapy that are capable of inducing the repertoire of molecular responses induced by exercise training. In this RFA (HL-03003) (AMNESTI in PAD), men & women (n=160), over 40 years, with IC & an ankle/brachial systolic blood pressure ratio (ABI) <0.8 at rest, will be recruited from Duke University Medical Center and the University of Colorado Health Science Center. Patients will be randomized to a supervised or home-based exercise program. Evaluations will be at baseline, 3-weeks (supervised exercise) and 3-months. Age-gender matched healthy controls (n=66) will be tested at base line. The central hypothesis is that the beneficial effects of exercise training are primarily mediated through an angiogenic effect. Sp Aim 1 will establish the baseline vascular abnormalities present in patients. Sp Aim 2 will establish the ability of the selected vascular abnormalities in Sp Aim I to predict peak oxygen consumption in PAD using a prediction model. Sp Aim 3 will establish the ability of exercise training to modify the vascular abnormalities in PAD. Sp Aim 4 will examine the gender specificity of the results obtained in Sp Aim 1-3. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIMHC ANTIBODY EFFECTS ON ENDOTHELIUM AND MUSCLE Principal Investigator & Institution: Reed, Elaine F.; Professor; Pathology and Laboratory Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 01-JAN-1999; Project End 31-DEC-2007 Summary: (provided by applicant): Accelerated transplant arteriosclerosis (TA), a manifestation of chronic rejection, is the leading cause of graft failure. The development of anti-HLA antibodies to donor HLA antigens is a major risk factor associated with TA. The overall goal of this proposal is to elucidate the signal transduction pathways that mediate HLA class I induced cell proliferation and the development of TA. Under specific aim #1, we will establish whether anti-HLA antibodies induce tyrosine phoshphorylation of focal adhesion proteins and assembly of signaling complexes via an actin cytoskeleton dependent pathway in endothelium and smooth muscle. For this, we will establish whether exposure of cultured endothelial cells (EC) and smooth muscle cells (SMC) to monoclonal anti-HLA antibodies and anti-HLA antibodies from transplant patients with chronic rejection is accompanied by FAK phosphorylation and the generation of FAK/Src/Paxillin signaling complexes. We will determine if the phosphorylation of focal adhesion proteins is accompanied by alterations in the organization of the actin cytoskeleton and in the assembly of focal adhesions. We will explore the role of ROK, MLC phosphatase and ERK as upstream components of the class I signaling pathway. We will also determine if class I signaling stimulates antiapoptotic signals by inducing tyrosine phosphorylation of PI3-kinase, Akt and Bad. Under specific aim #2, we will identify the signaling pathways leading to MHC class I induced FGF receptor translocation in EC and SMC. For this, we will determine the role of the actin cytoskeleton, phosphorylation of FAK, Src, paxillin and assembly of focal adhesions in class I mediated FGFR translocation to distinct subcellular locations using flow cytometry and confocal microscopy. We will also assess the importance of ROK, ERK, MLC phosphatase in class I mediated FGF receptor translocation. The contribution of the FGF receptor tyrosine kinase activity and ERK phosphorylation to class I induced cell proliferation will be established. Under aim #3, we will assess the expression of class

Studies

9

I induced tyrosine phosphorylation, FGF receptors and anti-apoptotic proteins in clinical biopsy specimens from cardiac allografts with and without evidence of transplant arteriosclerosis. We will determine the correlation between protein phosphorylation events and protein expression with the incidence and time of onset of transplant arteriosclerosis and development of anti-HLA antibodies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: APCS IN CHRONIC HEART REJECTION Principal Investigator & Institution: Rosengard, Bruce R.; Assistant Professor; Surgery; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-MAY-2001; Project End 30-APR-2004 Summary: (Verbatim from the Applicant's Abstract): Cardiac transplantation is established therapy for the treatment of end-stage heart failure. However, chronic rejection in the form of accelerated arteriosclerosis remains the primary cause of late death after heart transplantation. Despite the development of several new drugs to combat rejection, the incidence of this form of chronic rejection has not changed. We have hypothesized that endothelial cells, which line coronary arteries, are capable of directly activating CD8+ T cells, which may play an important role in the development of graft vascular disease. We have established both in vitro and in vivo mouse models to study this process. The broad objective of this grant proposal is to define the differences in the ability of murine endothelium to activate CD4+ and CD8+ T cells in vitro and then to use analogous in vivo models to define the allorecognition pathways and effector mechanisms responsible for graft vascular disease. To achieve this goal, we will: 1. Test the hypothesis that endothelium activates both unprimed and primed CD8t T cells preferentially due to a less stringent requirement for costimulation. 2. Test the hypothesis that endothelium is a suitable target for CD8+ T cell cytotoxicity predominantly via the Fas/FasL pathway. 3. Test the hypothesis that graft vascular disease is a CDK about-dependent process. In summary, this proposal will determine whether endothelium has the capacity to stimulate CD8F T cells and the ability to act as targets for CD8+ cytotoxic T cells, which is sufficient to induce graft vasculopathy in a mouse model. Insights from this study will undoubtedly provide information that will lead to rational strategies to help prevent this lethal complication of human heart transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: ARTERIOSCLEROSIS: VASCULAR AND NUTRITIONAL ASPECTS Principal Investigator & Institution: Phillips, Michael C.; Professor; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-JUL-1979; Project End 30-JUN-2005 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: AUTOMATION OF THE VITRO MICRONUCLEUS ASSAY Principal Investigator & Institution: Dertinger, Stephen D.; Litron Laboratories, Ltd. 1351 Mount Hope Ave Rochester, Ny 14620 Timing: Fiscal Year 2003; Project Start 01-JUN-2002; Project End 31-AUG-2005 Summary: (provided by applicant): The induction of DNA damage and the resulting sequelae of mutations and chromosomal rearrangements are primary mechanisms by

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which cancers arise. DNA damage has also been implicated in arteriosclerosis and certain birth defects. Thus, there is an important need for sensitive methods for identifying compounds that mutate or otherwise damage DNA. The very high cost of long-term animal studies dictates that short- and medium-term mutagenicity assays must be relied on to eliminate potentially hazardous chemicals from development, and to prioritize chemicals for further study. Furthermore, as new chemicals and therapeutic drugs are being developed ever more rapidly, the need for short-term tests with high throughput capabilities increases. The aim of this Phase II research effort is to refine, standardize, and validate an automated system for scoring chromosome damage in cultured mammalian cells. Specifically, a flow cytometric method for enumerating genotoxicant-induced micronuclei will be developed and vigorously tested. This system will be extremely valuable as an early screening test for identifying genotoxicants, and is expected to prove particularly valuable to the Chemical Manufacturing and Pharmaceutical Industries which are required to assess compounds' DNA-damaging potential. The automated scoring systems' commercial potential will be realized through: 1) fee-for-service contract testing, and 2) bundling dyes and other reagents required to perform these analyses into commercially available kits. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SIGNALING

CADHERINS,

INTEGRINS,

AND

MECHANOCHEMICAL

Principal Investigator & Institution: Chen, Christopher S.; Assistant Professor; Biomedical Engineering; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): This project focuses on the mechanisms by which cadherins, integrins and the cytoskeleton cooperate to regulate proliferation in endothelial and smooth muscle (vascular) cells. Aberrant proliferation of vascular cells plays a major role in the pathophysiology of atherosclerosis and arteriosclerosis, and likely is triggered by inflammatory changes in the local tissue microstructure. Understanding the molecular basis for how cues within the tissue microenvironment are integrated within cells to regulate proliferation is hence a priority in the development of rational strategies to interrupt progression of vascular disease. It is proposed that Rhomediated tension generated in the actin cytoskeleton couples signals from cadherins and integrins in an integrated mechanochemical signaling system to regulate proliferation in both endothelial and smooth muscle cells. Preliminary results suggest that cadherin-mediated cell-cell contact causes cell spreading against extracellular matrix to decrease, and thereby, inhibits cell proliferation. Controlling for changes in cell spreading revealed a novel cadherin-dependent stimulatory signal for proliferation. Both the spreading and cadherin-mediated proliferative signals require Rho-mediated changes in cytoskeletal tension. Specific Aim 1 will be to investigate the cooperative role of vascular cadherins and integrin-mediated cell spreading in the positive and negative regulation of cell proliferation. The investigator has developed a micropatterning tool to independently manipulate cell-cell contact and cell-substrate adhesion for this study, and will combine this tool with molecular approaches to probe the specific role of VEcadherin and N-cadherin in proliferative signaling. Specific Aim 2 will be to examine the role of RhoA and cytoskeletal tension in the regulation of proliferation by cadherins and cell spreading. A novel cellular tension microsensor will be combined with microinjection and transfection approaches to distinguish the importance of RhoA and cytoskeletal tension in proliferation. Specific Aim 3 will be to examine the role of focal

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adhesions and cadherin-based contacts in the transduction of cytoskeletal tension into proliferative signals. This project will lead to an integrated molecular understanding of how endothelial and smooth muscle cells coordinate signals from cadherins, integrins, and cytoskeletal tension into a proliferative response, and may suggest new therapeutic strategies to interrupt the progression of atherosclerosis and arteriosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CALCIFICATION OF ELASTIN-- MECHANISMS AND PREVENTION Principal Investigator & Institution: Vyavahare, Naren R.; Associate Professor; Bioengineering; Clemson University 300 Brackett Hall Clemson, Sc 296345702 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2004 Summary: (Adapted from Investigator's Abstract): Cardiovascular diseases are the leading cause of morbidity and mortality worldwide and the estimated costs of current treatments are 260 billion dollars. Pathologic calcification occurs in a variety of cardiovascular diseases as an end-stage process. The mechanisms of this type of calcification are incompletely understood and no therapy is available to prevent calcification. Elastin, one of the major structural proteins present in the ECM or arterial walls, is prone to calcification in a number of diseases such as advanced atherosclerosis, age related arterial hardening, and bioprosthetic heart valve (BPHV) clacification. The overall objectives of this research are the following: (A) Understanding the basic mechanism of elastin calcification as it has important implications in arteriosclerosis and BPHV calcification. (B) To discover therapies for preventing calcification based on the basic understanding of the mechanism. (C) Understanding ECM function in cardiovascular calcification using elastin as a model structural protein. The PI has developed a rat subdermal implant model, where a purified elastin implant undergoes severe pathologic calcification within 21 days. He has shown that such elastin calcification also occurs in a circulatory rat aortic allograft model. The following hypotheses will be studied using these two animal models. I: Post-implant extracellular matrix (ECM) remodeling events have a mechanistic role is elastin oriented calcification. II: Blocking of specific ECM signaling events in elastin calcification process will inhibit calcification. This will include site-specific delivery of lactose (to supress elastin receptor activation), MMP inhibitor (to suppress general MMP activity), adenovirus AdCMV.hTIMP-2 (to overexpress tissue inhibitor of matrix metalloproteinase-2 or TIMP-2), and anti-sense oligonuclotide for translation initiation site of tenascin mRNA (to suppress tenascin expression). III: Aluminum ions bind to elastin and alter its structure such that post-implant ECM remodeling events are modulated leading to inhibition of calcification. The experiments will include rat subdermal implantation of purified elastin (extracted from porcine aorta) and rat aortic allograft implants. The time-specific ECM remodeling events will be studied from 1 day to 90 days in terms of MMP activity (MMP-2 and MMP-9 by immunohistochemistry and zymography) TN-C expression (by immunohistochemistry, western blots and RNAase protection assays), and alkaline phosphatase activity and elastin degradation. The in vitro studies will include elastin conformational studies with FT-IR, NMR and circular dichroism spectroscopies, study of elastin-MMP interactions by surface plasmon resonance analysis and elastolysis experiments with MMPS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Arteriosclerosis

Project Title: CCR2 AND CCR5--ATHEROSCLEROSIS AND CONTROL OF EXPRESSION Principal Investigator & Institution: Charo, Israel F.; Professor of Medicine; J. David Gladstone Institutes 365 Vermont St San Francisco, Ca 94103 Timing: Fiscal Year 2002; Project Start 15-JUL-1994; Project End 30-JUN-2003 Summary: (Adapted from the application) The overall goal of this proposal is to determine the role of chemokine receptors in vascular disease. Chemokines (chemotatic cytokines) specifically attract leukocytes by activating G-protein-coupled receptors. The investigators have focused their efforts on two of these receptors, CCR2 and CCR5, which were cloned in this laboratory and which are the major chemokine receptors on monocytes. During the first funding period, the investigators examined the structure/activity relationships of these two receptors with regard to ligand binding and signaling. The work proposed in the current application will extend these in vitro studies to in vivo models, taking advantage of our recent creation of a CCR2 knockout mouse. The first goal of the proposal is to determine the role of CCR2 in two forms of vascular disease: atherosclerosis and the accelerated arteriosclerosis of allogeneic cardiac transplants. The investigators will cross the CCR2-/- mice with apoE-/- mice and perform detailed atherosclerosis studies. The investigators will also perform heterotopic transplants of allogeneic hearts into the CCR2-/- mice and determine whether CCR2 plays a role in chronic myocardial rejection and transplant arteriosclerosis. The second goal is creating CCR2/CCR5 double-knockout mice. The investigators will selectively delete these receptors and simultaneously "knock in" lacZ under the control of the CCR2 promoter and green fluorescent protein (GFP) under the control of the CCR5 promoter. This approach will generate chemokine receptor knockout animals, as well as provide a sensitive means for detecting the endogenous in vivo expression of CCR2 and CCR5. Differential regulation of chemokine receptors clustered on chromosome 3 (3p21.3-24) may provide specificity in inflammation and immunity. The third goal is to determine the tissue-specific expression and transcriptional regulation if selected CC receptors. The investigators will use the hemizygous CCR2/CCR5 double-knockout mice (CCR2+/LacZ, CCR5=/GfP), as well as transgenic mice created with large fragments of human genomic DNA, to follow the expression of these two receptors in models of human disease. the experiments proposed in this grant will utilize novel and complementary approaches to provide the first detailed information on the role of chemokines and chemokine receptors in vascular disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CELL MEDIATED IMMUNE MECHANISMS IN ACCELERATED GRAFT ARTERIOSCLEROSIS (AGA) Principal Investigator & Institution: Hess, Allan D.; Professor; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002 Summary: The principal objective of project 5 is to define the cell-mediated immune mechanisms responsible for the development of accelerated graft arteriosclerosis (AGA). One of the central tenets to be tested in this project is that the association of AGA with CsA treatment is due to or exacerbated by the aberrant "autoimmune" recognition of MHC Class II antigens. The "autoreactive" T cells that mediate this chronic inflammatory response are the direct result of CsA treatment which inhibits the clonal deletion of a unique subset of T cells that promiscuously recognize both auto and

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allo MHC Class Il determinants. This hypothesis is supported by the findings that: 1) AGA is positively correlated with the use of CsA; 2) CsA induced "autoreactive" T cells mediate an inflammatory process consistent with chronic rejection; and 3) "autoreactive" T cells can be detected within he graft during CsA treatment. Moreover, strains of animals that differ in their susceptibility also exhibit a differential effect of CsA on the induction of AGA. The production and localization of this unique autoreactive cell population to the graft promotes the development of AGA due to recognition of MHC Class II determinants upregulated on endothelial cells within the graft. Several factors contribute to the upregulation of MHC Class II determinants and include initial allorecognition and the release of v- interferon, ischemia and infection with cytomegalovirus. The factors also contribute to the development of AGA independent of CsA treatment indicating that other immune mechanisms contribute to this chronic inflammatory process. Therefore, the specific aims of this project are to 1) define the cellmediated allo and autoimmune mechanisms leading to AG particularly examining the role of CsA induced MHC Class II reactive T cells, 2) dissect the intragraft cellular immune mechanisms responsible for AGA and 3) define the requirements for autoimmune recognition of vascular endothelial cells in AGA in order to develop novel therapeutic strategies. The development of these strategies is based, in part, on the recent demonstration that the autoreactive T cells induced by CsA recognize a peptide from the MHC Class Il invariant chain presented by MHC Class Il determinants. Antibodies to the peptide that block recognition and divalent soluble MHC Class Il antigens complexed to the peptide will be assessed for their efficacy in preventing AGA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHRONIC ARTERIOSCLEROS*

DTH

AND

IFN-GAMMA

IN

HUMAN

GRAFT

Principal Investigator & Institution: Pober, Jordan S.; Professor; Pathology; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 20-SEP-2001; Project End 31-AUG-2006 Summary: Chronic DTH and IFN-gamma in Human Graft Arteriosclerosis. Graft arteriosclerosis (GA) is a host anti-graft immune-mediated lesion characterized by intimal expansion, vessel construction (pathological remodeling) and abnormal vasoregulation. GA is the underlying basis of chronic cardiac allograft rejection and the leading cause of allograft failure. There is currently no effective therapy or means of early diagnosis of this inexorably progressive disease. The immunopathogenetic mechanism(s) of GA is unknown. Our early immunocytochemical analysis of cardiac allograft allograft arteries suggested the presence of a chronic delayed type hypersensitivity (DTH) reaction mediated by non-cytolytic T cells within the arterial intima that appeared to be reacting to alloantigens expressed on persistent graft endothelial cells (EC). Since interactions of rodent T cells with EC are profoundly different from those that occur in humans, rodent transplant models may be of limited us in exploring immune pathogenetic mechanisms. Our more recent work has suggested that IFN-gamma, a cytokine made by T cells that mediate DTH (I.e. TH1 cells) can cause intimal expansion of human arteries. In this program project we will employ human artery cell and organ culture models as well as human arteries xenografted into SCID mice (produced by Core B) to investigate the development of anti-EC DTH and effects of chronic DTH on human vessels (Project 1) and to elucidate the mechanisms by which IFN-gamma induces intimal expansion and other changes of human arteries (Project 2). We will validate these models by comparisons to human GA specimens (analyzed by Core D) using conventional morphology (including immunofluorescence,

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Arteriosclerosis

immunocytochemistry and in situ hybridization) as well as laser capture microscopy/reverse transcription- polymerase chain reaction. These studies will be complemented with morphometry to assess both vascular remodeling and intimal chain reaction. These studies will be complemented with morphometry to assess both vascular remodeling and intimal hyperplasia (conducted by Core C) and physiological assessment of vessel function (conducted by Core C) and molecular expression profiling (via peptide phage display, SELDI/ProteinChip analysis and RNA array analysis (conducted by Project 3, Core D and Core, respectively). Finally, we will use our human artery xenografts and other models to develop new approaches for early non-invasive of GA based upon pathophysiologic processes rather than end stage structural changes (Project 3). The results of this thematically integrated program will provide a scientific basis for new and more effective approaches to address the problem of chronic allograft rejection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLINICAL MORPHOLOGY

IMPLICATIONS

OF

PERIPHERAL

PLAQUE

Principal Investigator & Institution: Ouriel, Kenneth; Surgery; Cleveland Clinic Lerner Col/Med-Cwru Cleveland, Oh 44195 Timing: Fiscal Year 2003; Project Start 22-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Peripheral arterial disease (PAD) is found in almost 20% of the population aged 55 and older. It is responsible for incapacitating symptoms of leg pain when walking, culminating in amputation in a small proportion of patients. Further, the presence of PAD is a strong marker for future cardiovascular events such as myocardial infarction and stroke. Despite the clinical significance of PAD, it is under diagnosed and its pathobiology remains ill defined. While imaging studies play an integral role in the study of most disease processes, angiography, standard ultrasound examination, and even magnetic resonance imaging do not provide adequate resolution of the arterial wall to quantify and characterize the extent of vascular wall abnormalities or to track changes over time. Intravascular ultrasound (IVUS) technology is associated with spatial resolution of 80-100 fm radially and 150-200 fm circumferentially. As such, IVUS appears ideally suited to the quantification of vascular wall changes. Our group has studied IVUS in the characterization of coronary artery plaque morphology, correlating clinical signs and symptoms with atheroma burden and content. We propose similar studies in the peripheral arterial bed, quantifying the amount and composition of lower extremity arterial atheroma and relating these findings to the patients' clinical presentation and subsequent course. This goal will be accomplished through the completion of three separate but concurrent studies: (1) Histologic sections of fresh arterial segments from cadaver limbs and amputation specimens will be correlated with IVUS-derived radiofrequency data to quantify arterial plaque burden and composition (calcium, collagen, fibro-lipidic and necrotic components). (2) Patients undergoing standard lower extremity angiography for PAD will be studied with IVUS at the same sitting. IVUS findings will be correlated with demographic factors (age, gender, race) and symptom severity (claudication, rest pain, tissue loss). Patients will be followed for up to five years, and the occurrence of ischemic events (worsening of leg ischemia, need for intervention and re-intervention, and distant complications such as Mi and stroke) will be reconciled with the arterial wall content at the baseline examination. (3) A randomized, blinded clinical trial of high-dose atorvastatin vs. placebo will be performed in patients with intermittent claudication, based on our hypothesis that statin therapy will result in stabilization or regression of femoral artery plaque, differences

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best assessed with high resolution imaging studies. IVUS data will be collected at baseline and at 24 months. The primary endpoint will be the change in femoral arterial plaque volume; baseline arterial wall parameters will be assessed in the subgroup of stain responders vs. non-responders. The completion of these three investigations should yield a validated, high resolution, real time imaging study with which to assess risk and base treatment decisions in patients with PAD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CMV AND DYSREGULATION OF THE NOS PATHWAY Principal Investigator & Institution: Cooke, John P.; Associate Professor; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002 Summary: (provided by applicant): Impairment of eNOS contributes to the pathological alterations in vascular reactivity and structure that are observed in atherosclerosis. The premise of the current proposal is that impairment of the NOS pathway also plays a major role in the development of TA. We propose that in transplant recipients, the endothelial NOS pathway is impaired by two major insults: 1) increases in vascular superoxide anion (O2-), and 2) increases in ADMA. These abnormalities increase NO degradation and reduce NO synthesis. We further hypothesize that CMV infection augments these abnormalities via cytokine induced alterations in oxidative stress and ADMA accumulation. Accordingly, we propose to characterize the derangement of the NOS pathway in TA. We will assess the activity of the NOS pathway in transplant recipients using coronary vascular reactivity studies, coronary arteriovenous gradients and tissue biopsy studies using markers, which reflect NOS activity and oxidative stress. Genomic DNA obtained from the biopsy material will be used to characterize polymorphisms of the NOS pathway that may be associated with specific phenotypes. In addition, biochemical and physiological measurements of traditional and nontraditional risk factors, viral load and strain identification of CMV will be performed. These studies should provide insights into the mechanisms by which the NOS pathway is disturbed, and the role of CMV in these perturbations. However, cardiac transplant recipients have multiple metabolic disturbances that may impair the NOS pathway. Furthermore, CMV infection may have indirect effects on endothelial function by activation of the immune response. Therefore, to determine if there are direct effects of CMV infection on endothelial NOS, and to delineate mechanisms, additional studies of the CMV/NOS interaction will be conducted in endothelial cell cultures to determine the role of ADMA and oxidative stress in CMV-induced alterations in endothelial NOS and determinants of endothelial-mononuclear cell interaction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COMPLEMENT AND ANTIBODY IN THE PATHOGENESIS OF AGA Principal Investigator & Institution: Sanfilippo, Fred P.; Professor and Chairman; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002 Summary: The overall working hypothesis of this project is that there are multiple stages at which activation of complement (C) and evoked antibody (Ab) responses can contribute to the pathogenesis of AGA. The first specific aim is to investigate donor heart warm ischemia, which is an independent risk factor for C activation -- as well as AGA. Preliminary findings, which demonstrate that C deposition in perioperative endomyocardial biopsies correlates with ischemic damage, will be extended by yearly

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Arteriosclerosis

coronary angiography to identify potential associations with the subsequent development of AGA. The second specific aim focuses on those classes and subclasses of Ab that can activate C. Our passive transfer studies demonstrating that alloantisera can cause AGA in rats will be extended by using monoclonal Ab of different specificities to known MHC class I epitopes and Ab elicited to synthetic heat shock protein (HSP) peptides, or combinations of these (HSP peptides in autologous or allogeneic MHC), to identify their ability to augment AGA through C activation. These results will be correlated with studies inhibiting particular alloAb subclass production using CTLAR4Ig to block the development of AGA. Our recent finding that cardiac transplants in C6 deficient rats sustain profound, reversible endothelialitis which does not progress onto AGA indicates a potential critical role for the membrane attack complex (MAC) of C. Thus, our third specific aim is to assess the role of C components involved in this initial phase of AGA, while the fourth specific aim is to identify mediators between C6 deposition and smooth muscle proliferation in the subsequent phase of AGA. sCR1, which inhibits the C3 and C5 convertases, and inhibitory anti-C3a and C5a Ab, will be used to assess the contribution of specific C components to the first phase of AGA. Based on in vitro evidence that C5b-C9 (MAC) deposition on endothelial cells causes its release, platelet derived growth factor (PDGF) will be examined as a potential mediator in the second phase of AGA. These aims are feasible in the highly interactive setting of this program project. Morphological analysis of different stages of AGA lesions will be augmented with physiological assessments by Dr. Flavahan (Project l). Studies on C mediated PDGF production will be extended to CMV induction of PDGF with Drs. Hayward (Project 2), and in vitro studies with Dr. Ballermann (Project 3). Studies of antibody responses to autoantigens (HSP) will be supplemented with studies of cellular autoimmunity by Dr. Hess (Project 5). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOLOGY

CONFERENCE

ON

ARTERIOSCLEROSIS

AND

VASCULAR

Principal Investigator & Institution: Forte, Trudy M.; Molecular and Nuclear Medicine; University of Calif-Lawrenc Berkeley Lab Lawrence Berkeley National Laboratory Berkeley, Ca 94720 Timing: Fiscal Year 2002; Project Start 10-JUL-2000; Project End 30-JUN-2005 Summary: The Conference on Arteriosclerosis, Thrombosis and Vascular Biology is a two and one-half day meeting, May 20-22, 2000, to be held in Broomfield/Denver, Colorado. This meeting is designed to be an annual meeting that will focus on new emerging research in the areas of arteriosclerosis (lipids and lipoproteins), thrombosis and vascular biology. The meeting is sponsored by the Council on Arteriosclerosis, Thrombosis and Vascular Biology of the American Heart Association and in its first year is co- sponsored by the North American Vascular Biology Organization. The major goal of this conference is to bring together diverse disciplines within the Arteriosclerosis, Thrombosis and Vascular Biology research communities to allow investigators to exchange and disseminate information and to explore areas of cross- disciplinary interest. These disciplines have long been treated as separate entities yet in reality lipid and lipoprotein functions are interwoven with thrombotic and vascular wall events and vice versa. The program is designed to encourage cross- fertilization between these disciplines by examining new and emerging areas in lipids and lipoproteins, thrombosis and vascular biology in an informal setting. Hot Topics and Plenary sessions have been designed to stimulate interdisciplinary discussions and interactions in the areas angiogenesis, PPARs in atherosclerosis, nitric oxide function, abc1 gene in HDL

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metabolism, molecular genetics of vascular disease, and cell biology of the vessel wall. Special sessions planned by each of the representative areas, i.e., arteriosclerosis, thrombosis and vascular biology, will provide an opportunity for oral presentations of abstracts and each session begins with a keynote talk on the topic to be given by an expert in the field. The arteriosclerosis sessions cover the areas of transgenic and adenovirus models to study lipoprotein metabolism, HDL in atherosclerosis, diet and gene contribution to dyslipidemias, and lipases in atherosclerosis. The thrombosis sessions address the areas of protein C pathways, integrin biology, platelet signaling, and humoral and cellular factors in fibrinolysis. The vascular biology sessions include endothelial cell function, smooth muscle cell pathobiology, vascular autoregulation and remodeling, and inflammation in vascular disease. The conference will foster stronger links between arteriosclerosis, thrombosis and vascular biology and provide an opportunity for investigators to discuss newly breaking information. Because of the importance for developing well-rounded new investigators in the areas of lipids and lipoproteins, thrombosis and vascular biology, a major objective is to encourage young scientists to attend the conference. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--HUMAN CARDIAC TISSUE REPOSITORY Principal Investigator & Institution: Rodriguez, E Rene.; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2003 Summary: Human Cardiac Tissue Repository Core. To study the immunopathogenesis of human cardiac allograft arteriosclerosis (GA), the Human Cardiovascular Tissue Repository will continue to build on the highly successful existing tissue bank established at Hopkins. The functions of the core will be: 1. To banked fresh-frozen tissues include sections of myocardium and coronary arteries. The number of hears from patients undergoing a re-transplantation have steadily been in the range of 5-15% of all hearts transplanted (average 30 hearts per year) at Hopkins during the last 10 years. The infrastructure in place for this core allows for procurement of human hearts at the time of surgery. Cardiac tissues are triaged and processed immediately as needed by the different projects in this proposal (e.e. freezing, cell culture, organ culture) by a cardiac pathologist as part of the evaluation of the specimen. In addition to the fresh and frozen tissue repository, there is formalin-fixed paraffin- embedded tissue from human heart transplant recipients, which currently includes over 6,000 heart biopsies, 54 autopsies and 223 explanted hearts, including 24 explanted from heart transplant recipients who were re- transplanted because of allograft vasculopathy in their first grafts. 2. Another function of this core be to provide clinical data striped from any identifies to individual investigators. These database is supported by departmental funds and are provided free to the Core. 3. Comprehensive pathologic examination of the tissues will be performed with advanced pathologic techniques in our facilities at Hopkins Molecular Pathology, tissues will be performed with advanced pathologic techniques in our facilities at Hopkins Molecular Pathology, Research Immunohistochemistry, and Research Histology laboratories. 4. Cardiac allograft arteriosclerosis lesions will be microdissected and analyzed with an array of ProteinChips/TM to identify protein expression alterations in the allograft important mechanism in the pathogenesis of cardiac allograft arteriosclerosis. Accordingly, the proteomics core will focus on the role of IFN-gamma and the molecules that both, regulate IFN-gamma and are regulated by IFN-gamma, leading to proliferation of TH1 cells. The proteomics core will correlate expression of molecules identified in projects 1, 2 and 3 taking advantage of phage-

18

Arteriosclerosis

peptide-display libraries and candidate gene sequences identified in core E (RNA microarrays). Core D will microdissect cells from human coronary arteries. Microdissection will allow the comparison of the proliferative cell component present in the intima of GA vessels with musculopathy and smooth muscle cells from the media of transplant arteries and controls. The power of the proteomics analysis with the ProteinChipTM technology is that femtomolar amounts of proteins can be identified, thus requiring only a few hundred to a few thousand cells from human arteries to obtain protein expression information. The integration of this core with the projects in this proposal will provide scientific basis to develop effective approaches to early diagnosis of GA and provide information of possible targets for early therapeutic intervention, which is crucial to lengthen the longevity of the allograft. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--MORPHOMETRY AND PHYSIOLOGY Principal Investigator & Institution: Sessa, William C.; Professor; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2003 Summary: Morphometry and Physiology Core. The purposes of Core C are to evaluate the morphometric changes that occur during graft arteriosclerosis (GA) that culminate in constrictive remodeling and to assess the vasomotor function during the progression of GA in vitro. The combination of histological assessment and morphometric evaluation in conjunction with vessel physiology will allow us to dissect when vasomotor function contributes to GA remodeling. Core C will interface with Projects 1, 2 and 3 to assess the degree of remodeling and function in vessels undergoing GA in vitro and vessels modified in organ culture. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--PATHOLOGY/CLINICAL Principal Investigator & Institution: Hruban, r; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002 Summary: All of the projects in this program will use the Pathology/Clinical Core. This core iwll serve several broad functions: (1) tissue Banking; (2) Clinical Data; (3) Pathologic Evaluation of Tissues; (4) Quantitative Stereology; (5) In vitro Assays; (6) Consent Procedure. This core will serve all projects as a central facility for maintenance of a clinical database, banking of tissues (human and animal), and performance and unbiased interpretation of standard histology, immunohistochemistry, electron microscopy, and in situ hybridization. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DECREASED PERLECAN IN EXPERIMENTAL MODELS OF DIABETES Principal Investigator & Institution: Shachter, Neil S.; Assistant Professor; Medicine; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 11-MAR-2002; Project End 28-FEB-2006 Summary: (Provided by applicant): Decreased heparan sulfate proteoglycans (HSPG) may be a central contributor to the nephropathy, retinopathy, neuropathy and early atherosclerosis of diabetes mellitus (DM). Decreased HSPG has been shown (including

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our own work on diabetic dyslipidemia) specifically to involve decreased perlecan, the most abundant basement-membrane HSPG. The objective of this proposal is to support the role of perlecan in DM complications, specifically dyslipidemia and atherosclerosis, and to define mechanisms for its decrease. Three hypotheses are proposed, corresponding to each aim of the proposal. Hypothesis 1. Decreased expression of perlecan, independent of diabetes, will impair the clearance of remnant apoB48 lipoprotein and will aggravate the impaired clearance of such lipoproteins resulting from DM, leading to increased atherosclerosis. Heterozygous perlecan gene-knock-out (PKO) mice and control mice will be studied in the presence and absence of streptozotocin-induced DM. The lipoprotein phenotype will be extensively characterized and kinetic studies will define its mechanism. Similar studies will be performed with PKO mice in the apoE-null and human apoB transgenic backgrounds. Hypothesis 2. DM causes a generalized decrease in perlecan independent of organ or cell type that will lead to increased atherosclerosis. The propensity of different mouse strains to exhibit such a decrease will correlate with their described propensity to develop increased arteriosclerosis with diabetes. Analysis of perlecan protein levels will be conducted in tissues from diabetic and non-diabetic mice from the C57BL/6 as well as the BALB/c strains, both on a "chow" diet and on a high-cholesterol diet (to assess possible interactions of diabetes and diet on perlecan levels). Quantitative arteriosclerosis studies will be conducted in WT and PKO mice both in the C57BL/6 and BALB/c backgrounds and in the apoE-null and human apoB transgenic contexts. In addition, cultured cells representative of tissues affected by complications of diabetes will be exposed to high glucose levels. These experiments will provide an appropriate model for the molecular studies in aim 3 as well as providing the basis for future studies of molecular pathologies related to diabetes. Hypothesis 3. The decrease in perlecan core protein in diabetes mellitus is a result of reduced GAG incorporation into PG. Changes in glycosaminoglycan (GAG) chain size and charge affect proteoglycan function and, likely, synthetic rates and stability. A systematic study of the synthesis and intracellular processing of the perlecan core protein and of the sequence of enzymes involved in GAG synthesis and modification will be performed. This will include characterizing the GAG chains present in HSPG. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIABETES AND ENDOCRINOLOGY RESEARCH CENTER Principal Investigator & Institution: Accili, Domenico; Professor of Medicine; Medicine; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 31-JAN-2008 Summary: (provided by applicant): We seek to establish a Diabetes and Endocrinology Research Center at Columbia University. The DERC will promote interactions among research groups in diabetes, immunology, transplantation and obesity at the Naomi Berrie Diabetes Center, The New York Obesity Research Center, and the historically strong groups in arteriosclerosis/lipid research at Columbia University. We envision that these interactions will extend to groups currently pursuing basic research in structural biology, genomics, complications, cell biology and clinical investigators in the areas of body composition, energy expenditure, genetic epidemiology of type 2 diabetes in adolescents, islet transplantation and prevention of diabetes complications. The DERC will strengthen existing NIH training grants in Endocrinology, Metabolism, Pediatrics, Arterioeclerosis, Immunology, Genetics and Obesity by broadening the pool of mentors and laboratories for the trainees' benefit. To meet these goals, the DERC will provide core services in six areas of research: Hormone/metabolite, Protein expression,

20

Arteriosclerosis

Immunology/cell banking, Genomics, Analytical determinations of body composition and tissue metabolites, and Mouse phenotyping. Additionally, the DERC will provide opportunity and encouragement for established scientists in other research areas at Columbia University to enter the diabetes field, and will make available initial funding for young investigators through a pilot/feasibility grant program modeled after the existing Naomi Berrie Fellowship Award. The DERC will broaden the research base through program enrichment activities aimed at increasing the awareness of diabetes research in the scientific/academic community of Columbia University and New York City and through more extensive interactions with other academic institutions in the greater New York area. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECTS OF KLOTHO PROTEIN ON AGING AND METABOLISM Principal Investigator & Institution: Kuro-O, Makoto; Pathology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (Provided by applicant): With a significant increase in the average life span during last century, more and more people are facing old age and diseases associated with aging. By elucidating the mechanisms of aging, it may eventually become possible to delay the deleterious effects from old age through rational drug intervention. Because the phenotype of mice deficient in Klotho protein suggests that Klotho suppresses aging, identification of the Klotho protein function may provide new insights into the mechanisms behind aging required to achieve this long-term goal. Klotho-deficient mice exhibit a syndrome resembling human aging such as a shortened life span, arteriosclerosis, osteoporosis, skin atrophy, ectopic calcification, lipodystrophy, and pulmonary emphysema. Consequently, the klotho mouse becomes the first laboratory animal model of human aging caused by a single gene mutation. Recent evidence suggests that Klotho protein functions as a humoral factor that inhibits insulin signaling and reduces oxidative stress. Interestingly, these two effects of Klotho are identical with the two evolutionally conserved mechanisms that can suppress aging in lower animals. The proposed mechanism of Klotho action is that Klotho binds to its putative cellsurface receptor and sends a signal into the cell to inhibit insulin signaling and suppress oxidative stress, which eventually suppresses aging in mammals. The objective of this proposal is to test this hypothesis. Specific aims are to: (1) Determine the mechanism by which Klotho inhibits insulin action. Phenotypic consequence of Klotho-deficient mice whose insulin-signaling pathway is chronically inhibited is also determined. If inhibition of insulin signaling is essential to the anti-aging effect of Klotho, the aging phenotypes would be improved in these mice. (2) Determine the mechanism by which Klotho reduces oxidative stress. Phenotypic consequence of Klotho-deficient mice overexpressing an enzyme that detoxifies reactive oxygen species is also determined. If reduction in oxidative stress is essential to the anti-aging effect of Klotho, the aging phenotypes would be improved in these mice. These studies would provide the first genetic evidence for the involvement of insulin signaling and oxidative stress in mammalian aging. (3) Identify Klotho receptor. Identification of Klotho receptor is indispensable to elucidating intracellular Klotho-signaling pathway. In addition, it promises to promote better understanding of the Klotho protein function and verify its role as an anti-aging hormone, which would have a significant impact on basic research and medical practice of aging. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ENANTIOSELECTIVE TOTAL SYNTHESIS OF (+)-HALICHLORINE Principal Investigator & Institution: Andrade, Rodrigo B.; Chemistry and Biochemistry; University of Texas Austin 101 E. 27Th/Po Box 7726 Austin, Tx 78712 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2005 Summary: (provided by applicant): A strategy for the efficient, enantioselective synthesis of (+)-halichlorine, a marine natural product which inhibits VCAM-1 (vascular cell adhesion molecule-1) with an IC50 of 7 fg/mL, is proposed. Due to its critical role in the regulation of inflammation, VCAM-1 has emerged as a potential target for drug discovery. Inhibitors of this protein could have a profound impact on the treatment of arteriosclerosis, asthma, and cancer. To date there only exists one total synthesis of halichlorine. The proposed plan outlines a novel synthetic route to halichlorine which can be modified to access precursors of pinnaic acid, a related alkaloid and potent inhibitor of cytosolic phospholipase A2. The plan utilizes cress-metathesis methodology for the construction of key olefinic bonds which heretofore has not been used in alkaloid synthesis. This represents a unique opportunity to study the scope of cross-metathesis in total synthesis. An intramolecular Kishi-Nozaki reaction is also proposed as an alternative macrocyclization step. Molecular modeling suggests the reaction will take place with a high degree of diastereoselectivity in favor of the desired stereoisomer. The synthesis will furnish sufficient quantities of halichlorine to assess its potential as a candidate for the treatment of the above conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ENDOTHELIAL CELL APOPTOSIS Principal Investigator & Institution: Harlan, John M.; Professor and Head; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002 Summary: The regulation of endothelial cell survival and death is critical to vascular development and homeostatis and to processes associated with arteriosclerosis including vascular remodeling, atherogenesis, and plaque neovascularization. The proposed studies examine the molecular basis of endothelial cell survival and death, focusing on those proteins that support survival or oppose death. The underlying hypothesis of this proposal is that proteins of the Bcl-2 family determine endothelial cell survival under both basal conditions and during exposure to inflammatory and toxic stimuli. The specific aims proposed test several aspects of this hypothesis, examining the molecular basis and consequences of endothelial cell survival and apoptosis (programmed cell death) in vitro and in vivo models. The Specific Aims are: 1) to characterize the role of integrin- dependent adherence and signaling in the mechanisms of endothelial cell survival in vitro; 2) to characterize the signal transduction pathways mediated by TNF-alpha that induce the Bcl-2 homologue, A1 and that A1 inhibits; 3) to study the function of A1 in vivo by generating A1- deficient mice; and 4) to examine the mechanisms by which apoptotic endothelial cells become proadhesive for leukocytes. Insights gained from these studies may suggest new potential targets for the treatment of atherosclerosis and its complications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ENDOTHELIAL CELL DYSFUNCTION & APOPOTOSIS IN ACCELERATED GRAFT ARTERIOSCLEROSIS Principal Investigator & Institution: Flavahan, Nicholas; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218

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Timing: Fiscal Year 2002 Summary: Accelerated graft arteriosclerOsis (AGA) represents a major obstacle to long term survival of heart transplant recipients. While it has become clear that AGA is a multifactorial problem, the specific mechanisms leading to AGA remain unknown. Because of their pivotal role in the maintenance of vessel homeostasis, endothelial cells (EcS) are likely to represent prime targets in the pathogenesis of AGA. Project 1 is designed to provide in-depth characterization of the process that affects ECs in AGA, from extracellular factors to intracellular molecular pathways that transduce messages to the genome of ECs. By integrating our studies on ECs with other projects of this program, we intend to provide information that will be key to the development of specific strategies to suppress AGA. In AGA, the functional damage to the endothelium is diffuse. Morphologically, areas of endothelial erosion can be found dispersed along the coronary vessels. Several mechanisms of BC ii-jury have been implicated in AGA: (i) oxidative injury resulting from ischemia/reperfusion at the time of surgery; (ii) immunological injuries involving complement activation, processing and presentation of antigens, activation and adhesion of T.lymphocytes, in particular cytolytic Tlymphocytes (CTL), sequestration of monocytes, production of antibodies against alloor iso-antigens, and dysregulation of the immune system with Cyclosporine A; (iii) injury with CMV-infection/reactivation; and (iv) direct Cyclosporine A toxicity. These various mechanisms could contribute either independently or in concert, to the diffuse abnormalities of ECs in AGA. Particular emphasis will be placed on the following pathway, which will provide the basis for the specific aims of this project: (i) the initial injury results in uncoupling of Gi-2 from its membrane receptors; (ii) the uncoupling of Gi-2 then results in BC dysfunction and overexpression of Fas on the surface of ECs, through a pathway that requires NF-kappaB activation; (iii) overexpression of Fas, in turn, results in the "kiss of death" as CTL bind to the ECs through the interaction of Fas and Fas-ligand present on the CTL surface; (iv) increased BC apoptosis will further aggravate the dysfunctional aspect of the endothelium and promote fibrin production and deposition due to the abnormal presence of phosphatidylserine on the surface of ECs. As a result, the endothelium in these patients is not capable of carrying out its usual functions namely, vasodilation, anti-thrombotic effect, anti- proliferative effect for the cells of the vessel wall, control of the attachment of inflammatory cells, and homeostasis of extracellular protein production, leading to the development of AGA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENDOTHELIAL CELL REGULATION OF T CELL ACTIVATION Principal Investigator & Institution: Hughes, Christopher C.; Associate Professor; Molecular Biology and Biochem; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2002; Project Start 01-JUN-1996; Project End 30-APR-2006 Summary: (provided by applicant): Cultured human endothelial cells (EC) can present antigen to resting memory T cells and provide sufficient co-stimulation to induce IL-2 and IFN-gamma synthesis. In addition, EC signals induce CsA resistance in T cells, which suggests a mechanism to explain the chronic immune inflammation that often develops in the vessel walls of transplanted organs. In the previous funding period we showed that EC lie along a spectrum of antigen presenting ability between dendritic cells and activated B cells at one end, and smooth muscle cells at the other. EC provide co-stimulation early in T cell activation due to their ability to induce lipid raft aggregation in responding T cells, thus amplifying TCR signaling; they do not appear to target a single, specific co-stimulatory pathway. At later times, however, co-stimulation via specific pathways can alter the ensuing immune response. For example, we have

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shown that activated EC express the novel B7-like co-stimulatory molecules B7-H1 and GL-50, which have previously been shown to induce IL-10 synthesis. Also at later times in the presence of CsA, EC co-stimulatory signals allow build-up in the T cell nucleus of NFAT, a crucial regulator of IL-2 transcription. This appears to involve down regulation of GSK-3beta as a result of EC-derived wnt-5a signaling. We have identified other wnts in EC, and frizzled receptors in T cells, however, their function in regulating immune responses is not known. We propose to test the hypotheses that: 1) expression by EC of B7-H 1 and GL-50 allows EC to shape a local immune response by altering the balance of cytokines expressed by T cells; and, 2) that EC expression of wnt proteins, and activation of the wnt pathway in T cells, prolongs NFAT nuclear localization thus contributing to CsA-resistance in T cells. Our specific aims are: 1) To test the importance of B7-H 1 and GL-50 as EC co-stimulatory molecules; 2) to determine the role of the wnt pathway in modulating T cell responses to EC; and, 3) to test our hypotheses in vivo using the hu-PBL-SCID mouse grafted with synthetic microvessels. Completion of these aims will provide us with a better understanding of the role of EC in shaping immune responses, and may open avenues for design of therapies that reduce the severity of graft arteriosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENDOTHELIAL CYTOSKELETAL RESPONSES TO PLATELET PHOSPHOLIPIDS Principal Investigator & Institution: Garcia, Joe Gn.; Director; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 07-FEB-2003; Project End 31-JAN-2008 Summary: Alterations in vascular permeability are a defining feature of diverse processes including arteriosclerosis, inflammation, ischemia/reperfusion injury, angiogenesis, and the subject to intense investigation. In contrast, there is little known about processes that determine barrier protection or barrier restoration after edemagenic agents. Platelet-derived products are essential to maintaining the integrity of the endothelial cell barrier although this mechanism of barrier protection is undefined. In published data relevant to this Project, we demonstrated that sphingosine 1-phosphate (Sph 1-P), a phosphorylated lipid angiogenic factor released from activated platelets, ligates specific endothelial differentiation gene (Edg) receptors to stimulate chemotaxis and angiogenic responses. Sph 1-P produces rapid, sustained and dose-dependent increases in vascular barrier integrity in vitro and in vivo, and reverses barrier dysfunction elicited by thrombin. The mechanisms by which Sph 1-P enhances barrier function are unknown, however, our data strongly implicate endothelial cell cytoskeletal dynamics in this response. Sph 1-P-mediated barrier enhancement is depending upon cortical actin filament rearrangement and Rac-dependent recruitment of known cytoskeletal regulatory proteins. In this Project, we will examine the molecular basis of Sph 1-P-induced barrier enhancement and have targeted cortical cytoskeletal interactions with membrane adhesive proteins that promote vascular integrity. SA#1 will characterize the Sph 1-P-mediated rearrangement of the cortical cytoskeleton following shear stress and cyclic stretch and assess PAK, LIM kinase cofilin and PKCdelta involvement. SA#2 will investigate the role of Sph 1-P-induced tyrosine dephosphorylation in the alterations of zonula adherens (catenin complex) interaction with the actin cytoskeleton. SA#3 will define the involvement of the actin-binding protein, cortactin, in cortical actin rearrangement. SA#4 will define the involvement of the activated p125 focal adhesion kinase and Rho/Rac GTPase in Sph 1-p-medicated regulation of focal adhesion structure/function. Given the profound physiologic

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derangements that accompany vascular leak in multiple vascular pathobiologies, Sph 1P may provide a novel therapeutic intervention for treatment of these devastating disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXERCISE DOSE AND INSULIN SENSITIVITY IN OBESE CHILDREN Principal Investigator & Institution: Davis, Catherine L.; Pediatrics; Medical College of Georgia 1120 15Th St Augusta, Ga 30912 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 30-APR-2007 Summary: (provided by applicant): The long-term objective of this research program is to understand how behavioral factors such as physical activity can modify risk for cardiovascular disease, including diabetes. Type 2 diabetes has been increasing in children, suggesting that prevention efforts are needed during childhood. Insulin resistance (i.e., low insulin sensitivity), a central feature of type 2 diabetes, is associated with sedentary behavior, poor aerobic fitness, general and visceral adiposity, hypertension, inflammation, hemostatic dysfunction, dyslipidemia, African-American ethnicity, and arteriosclerosis risk. Increased physical activity results in reduced risk of diabetes and cardiovascular disease in adults. No experimental studies have examined dose-response relationships of exercise with insulin sensitivity and related health indicators in children. This application is a randomized, controlled dose-response trial to determine the effect of 4 mo of intensive physical training at two dose levels (40 min aerobic exercise, 5d/wk vs. 20 min, 5d/wk) on insulin sensitivity (via oral glucose tolerance test) in 240 overweight, sedentary African-American and white boys and girls in third grade. The specific aims of the study test the hypotheses that the high-dose group will improve more than the low-dose group, which is expected to improve relative to controls. Improvements in body composition (% body fat, visceral fat) and aerobic fitness will be tested to see whether they can account for improvements in insulin sensitivity. Additional aims of the study will explore the effects of exercise dose on factors associated with insulin resistance and cardiovascular risk (blood pressure, lipid/lipoprotein measures, C-reactive protein, fibrinogen), and whether the change in insulin sensitivity can account for any such improvements. Ethnic and sex differences in response to intervention will be assessed. It is possible that the stimulation of insulin sensitivity takes place within the first 20 min of exercise each day and greater amounts of exercise are unnecessary (a threshold effect). The youths assigned to the longerduration sessions may have difficulty maintaining the high-intensity exercise, with the result that they do not actually engage in a greater volume of exercise per session. By monitoring heart rate, we will be able to see if this occurs. Since so little is known in children about this important aspect of exercise dose, this project promises to contribute substantially to our understanding of how much exercise to recommend to obese youths in order to enhance their fitness, body composition and health comparison of effects of these different volumes of exercise would provide evidence for best practice guidelines and assist in designing large-scale health promotion programs for children. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FACTOR XLLL ACTIVATION AND SUBSTRATE SPECIFICITY Principal Investigator & Institution: Maurer, Muriel C.; Associate Professor; Chemistry; University of Louisville University of Louisville Louisville, Ky 40292 Timing: Fiscal Year 2002; Project Start 08-JUL-2002; Project End 31-MAY-2006

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Summary: In blood coagulation, the enzyme thrombin cleaves fibrinogen, sites for fibrin polymerization are revealed, and fibrin clot formation begins. Activated Factor XIII, a transglutaminase, is responsible for catalyzing the formation of covalent crosslinks between fibrin molecules and in fibrin-enzyme complexes. Thrombin activates Factor XIII by cleaving a peptide sequence that lies across the Factor XIII catalytic site. The thrust of this research project will be to examine in solution the structural features that govern the activation and substrate specificity of Factor XIII. The specific aims are designed to prove the following hypotheses: 1) There is no obvious consensus sequence for defining the substrate specificity of Factor XIII for glutamine donating groups. The glutamine containing substrates are hypothesized to interact with the Factor XIII enzyme surface using similar bound conformations with defined flexible and/or solvent exposed regions. Peptides based on natural and synthetic substrates will be examined. 2) The Factor XIII activation peptide segment has components that resemble the fibrinogen Aalpha chain, the thrombin receptor, and PPACK, all of which interact with thrombin. The Factor XIII activation peptide segment is hypothesized to adopt a bound conformation that allows for the most effective interactions with the thrombin surface. An understanding of how unique amino acid positions within this segment participate in binding may lead to the design of Factor XIII enzymes whose degree of activation and optimal target site can be controlled. A model system for these studies is Factor XIII V34L, a common polymorphism that has been correlated with protection against myocardial infarction and is more susceptible to thrombin cleavage than the native sequence. To address these specific aims, a combination of kinetic studies, hydrogen/deuterium exchange followed by MALDI-TOF mass spectrometry, 1D proton line broadening NMR, 2D TOCSY, 2D transferred NOESY, and molecular modeling will be used. Understanding the molecular details of how Factor XIII is activated and how its substrate specificity is regulated is critical considering the role this enzyme plays in increasing the risk of heart disease, stroke, and arteriosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RECEPTORS

FUNCTIONAL

HIERARCHY

OF

REMNANT

LIPOPROTEIN

Principal Investigator & Institution: Fazio, Sergio; Associate Professor; Medicine; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-JAN-1998; Project End 31-DEC-2002 Summary: (Adapted from applicant's abstract): The focus of this grant is the elucidation of the mechanism by which remnant lipoprotein particles are cleared by hepatic receptors. The Principal Investigator and his colleague, Dr. M. Linton, have pioneered the use of bone marrow transplant to study apo E delivery into genetically altered mice via transplanted macrophages. The critical observation in the preliminary data, which serves as the basis for the grant proposal, is that BMT into apo E deficient mice is capable of fully restoring normal lipid levels, but the same transplantation does not normalize lipids in animals that are deficient in both apo E and the LDL receptor. Apo E deficient animals who are homozygous for the LDL-R have a good response to BMT, but lipid values are higher than in animals with two intact genes encoding the LDL-R. Importantly, the apo E levels in the double ko animals are even higher than those found in normal mice, and data presented in the grant indicates that this apo E is present in the space of Disse in the liver, where lipoprotein capture by hepatic lipoprotein receptors should occur. These findings indicate that the apo E provided by macrophages does not substitute fully for endogenous hepatic apo E in generating a pathway that can metabolize remnant particles. The PI lists three major specific aims, each of which is

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divided into three subaims. The first aim is designed to assess the roles of the LDL receptor and the LRP receptor in the clearance of remnant lipoproteins using bone marrow transplantation of apo E expressing macrophages to partially re-constitute apo E expression in mice genetically deficient in apo E and the LDL-R. Turnover studies of apo B-48 and apo B-100 remnants will be analyzed before and after transplantation and the fate of lipoprotein associated apo E after internalization by either the LRP or LDL-R will be studied. In Specific Aim 2, the investigators will test their hypothesis that secretion-capture of lipoproteins in the space of Disse is critical to remnant uptake and that this process requires local apo E production by the hepatocyte. This will be accomplished using an adenovirus to express E locally in E deficient animals, before and after BMT. The effect of apo E expression on LRP activity will be assessed by radiolabeled antibodies directed against LRP in vivo, complemented by in vitro studies of apo E enriched B-VLDL binding to fibroblasts deficient in either the LDL-R or the LRP. The third specific aim will focus on the role of apo E and LRP in macrophage foam cell formation and atherosclerosis. BMT into LDL-R /apo E double ko's will permit the assessment of macrophage-specific E expression on atherosclerosis development in animals with persistently elevated lipids. Fetal hepatocyte transplantation is proposed as a method for generating LRP deficient macrophages to determine what activities of wild type macrophages are attributable to LRP. Finally, in vitro studies will be conducted to assess the role of LRP in the binding and degradation of B-VLDL. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTIONAL PRENYLTRANSFERASES

STUDIES

OF

TWO

RELATED

Principal Investigator & Institution: Erickson, Hans K.; Chemistry; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-MAR-2002 Summary: Two enzymes involved in isoprenoid metabolism of the sagebrush Artemisia tridentata spiciformis, chrysanthemyl diphosphate synthase (CDS) and farnesyl diphosphate synthase (FDS) have recently been cloned and over-expressed in Escherichia coli. Each enzyme represents a class of enzymes that promote the condensation of five carbon isoprenes. The proposed mechanism and products produced by the two enzymes are distinct; however, the amino acid sequences are 69% identical. The high sequence homology of these two enzymes provides a unique opportunity to investigate the structural basis for the different mechanisms catalyzed by each enzyme. A strategy of domain swapping will be employed to map the regions of the enzymes responsible for the unique chemistry catalyzed by CDS and FDS. The high sequence homology of these two enzymes provides a unique opportunity to investigate the structural basis for the different mechanisms catalyzed by each enzyme. A strategy of domain swapping will be employed to map the regions of the enzymes responsible for the unique chemistry catalyzed by CDS and FDS. Understanding the determinants that differentiate these two fundamental mechanisms in isoprenoid metabolism that are believed to use similar mechanisms. An example of squalene synthase (SQS), an enzyme linked to arteriosclerosis. SQS forms the intermediate presqualene diphosphate by a mechanism that is identical to that proposed for CDS to form chrysanthemyl diphosphate. By catalyzing the first committed step of the de novo biosynthesis of cholesterol, SQS, is a main target for drugs aimed at lowering serum cholesterol. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC CONTROL OF VASCULAR REMODELING Principal Investigator & Institution: Dumont, Daniel J.; Associate Professor; Sunnybrook & Women's Coll Hlth Scis Ctr Health Sciences Centre Toronto, Timing: Fiscal Year 2002; Project Start 14-AUG-2001; Project End 31-JUL-2005 Summary: Angiogenesis, the growth of blood vessels from pre- existing vessels, which is known to play a pivotal role in the progression of several different diseases, including diabetic retinopathy, arteriosclerosis and cancer. To-date, virtually all genes that have been shown to play a role in early vascular development of the embryo, are also expressed in the endothelium of these diseased tissues. Thus, implies that the disregulation of gene expression in the endothelium in these diseased tissues recapitulates the genes expressed in the activated endothelium of the developing embryo. The genetic control of this vessel growth is currently poorly understood, however several studies using gene-targeting in mice have revealed that numerous diverse signaling pathways produce overlapping defects in vascular remodeling. The working hypothesis for this proposal is that the defects observed in these different mouse mutants are the consequence of misregulation of a common subset of genes whose expression control vascular remodeling. This research will use gene expression profiling by gene chip and SAGE analysis to examine the genes expressed in four different mouse mutants that affect very different signaling pathways and result in overlapping vascular remodeling defects. The differential expression of genes in the heart and yolk sacs of the Tek/Tie2, Endoglin, VEGFR3, and Notch1 mouse mutants will be compared. This work will provide considerable insight into the role of these disparate signaling modalities in the angiogenic response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC MOUSE MODELS FOR CHRONIC INFLAMMATORY DISEASE Principal Investigator & Institution: Bullard, Daniel C.; Assistant Professor; Genetics; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: Systemic lupus erythematosus, Wegener's granulomatosis, and polyarteritis nodosa are chronic inflammatory diseases that have vasculitis as a major component. The pathogenesis of vasculitis in these and other disorders involves a complex interaction among inflammatory, genetic, and environmental factors. Evidence from both patient studies and in vitro models supports a central role for leukocyte/endothelial cell adhesion molecules, such as ICAM-1 and its beta2 integrin counterreceptors, in the development of vasculitis. However, the specific mechanisms by which ICAM-1 mediates vasculititic lesion formation are not clear. This project will use a straightforward genetic approach using the MRL/MpJ-Faslpr mouse model to define the ICAM-1-dependent pathways responsible for mediating vasculitis. MRL/MpJ-Faslpr mice containing mutations in ICAM-1, LFA-l, Mac-1 and P150/95 have now been generated and will be used to investigate the roles of leukocyte/endothelial interactions in lesion formation in vivo. The specific aims are to: (i) define, by comprehensive qualitative and quantitative analysis, the effects of ICAM-1 deficiency on development and progression, organ distribution, and inflammatory characteristics of lesions of vasculitis in MRL/MpJ-Faslpr mice; (ii) define the relative contributions of ICAM-1 in mediating neutrophil, lymphocyte, and monocyte adhesion to MRL/MpJ-Faslpr endothelial cells; (iii) determine the roles of ICAM-1 in neutrophilmediated damage to MRL/MpJ-Faslpr endothelial cells; and (iv) determine whether

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MRL/MpJ-Faslpr mice with null mutations in the ICAM-1 ligands CD11a (LFA-1), CD11b (Mac-1), or CD11c (p150/95) will alter development and progression, organ distribution, or inflammatory characteristics of lesions of vasculitis. Upon successful completion of these aims, detailed mechanistic information regarding the roles of ICAM-1 in mediating leukocyte/endothelial adhesion and damage during the development of vasculitis will be obtained. In addition, new insights will be gained towards the general understanding of the pathogenesis of vasculitis as well as other leukocyte-mediated vascular injuries such as transplantation arteriosclerosis, and other reperfusion injuries. There have been many requests for these mutant mice or materials derived from these models; therefore, these models are contributing significantly to ongoing research that is relevant to several NIH institutes, including NIAMS, NHLBI, and NIAID. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC TREATMENT FOR ATHEROSCLEROSIS Principal Investigator & Institution: Teng, Ba-Bie; Associate Professor; Human Genetics Center; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2002; Project Start 01-DEC-1994; Project End 30-JUN-2004 Summary: The objective of this proposed research is to define target gene(s) underlying predisposition to atherosclerosis and to develop human gene therapy for the treatment of hyperlipidemia. Studies will be carried out to define genetic factor(s) that contributes to atherosclerosis by developing dyslipidemia murine model. We will use these models to elucidate the molecular mechanisms of the disease and to evaluate novel therapeutics. The proposal seeks out to establish the effectiveness of using adeno-associated virus vector for gene delivery of ribozyme in diseased animals. Studies will also investigate the efficacy of using ribozyme as a potential therapeutic agent by generating transgenic mouse expressing ribozyme. Studies will also address new approaches for gene delivery of multiple genes together by using helper-dependent adenovirus vector in vivo to evaluate the synergistic effect of this strategy on the treatment for hyperlipidemia. Taken together, these studies will provide understanding of target(s) underlying predisposition to atherogenesis. The study will shed new insights to the understanding of the structure/function of the apoB mRNA hammerhead ribozyme, and the possible application of using this ribozyme as a therapeutic agent for the treatment of atherosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GLOMERULAR HYPERHOMOCYSTEINEMIA

INJURY

ASSOCIATED

WITH

Principal Investigator & Institution: Li, Pin-Lan; Physiology; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532264801 Timing: Fiscal Year 2003; Project Start 01-JUN-1998; Project End 31-MAR-2007 Summary: (provided by applicant): There is a large body of clinical and epidemiological evidence that hyperhomocysteinemia may be a critical pathogenic factor in the progression of end-stage renal disease (ESRD) and in the development of cardiovascular complications related to ESRD. Despite extensive clinical studies demonstrating the association of hyperhomocysteinemia with ESRD, it remains unknown whether elevations of plasma homocysteine (Hcys) levels can lead directly to the development of glomerular injury in ESRD. In this proposal, we hypothesize that elevations of plasma Hcys produce glomerular dysfunction and consequent sclerosis. We propose that this

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occurs independently of arterial blood pressure and contributes to the great susceptibility to glomerulosclerosis in the Dahl S rat model of hypertension. We will first determine whether chronic elevations of plasma Hcys levels result in glomerular dysfunction and injury in the rats with experimental hyperhomocysteinemia and explore the mechanisms mediating the sclerotic effects of Hcys in the glomeruli. Since nitric oxide (NO) and superoxide have been reported to importantly contribute to hyperhomocysteinemia-induced abnormality of extracellular matrix metabolism and arteriosclerosis, we will examine the effects of chronic hyperhomocysteinemia on NO and superoxide levels or related enzyme activity in the glomeruli by fluorescence microscopic imaging analysis and fluorescence spectrometry. Then, we will determine whether hyperhomocysteinemia contributes to glomerular injury in Dahl S rats and whether decreases in plasma Hcys levels associated with a choline and vitamin B therapy regimen prevent the rapid progression of glomerular damages in these rats. We will also explore the renal mechanisms increasing plasma Hcys levels by characterizing the biochemical pathways responsible for the abnormal metabolism of Hcys in the kidney of Dahl S rats using the kinetic analysis of enzyme activities with HPLC techniques and by expression analysis of related genes. The results of these studies will clarify the role of hyperhomocysteinemia as a risk factor or pathogenic factor in glomerular dysfunction and injury in ESRD and provide new insights into the mechanism contributing to the susceptibility and progression of glomerular injury associated with hypertension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEPARIN COFACTOR II ACTIVATION MECHANISM Principal Investigator & Institution: Foshay, Miriam C.; Biochem and Molecular Biology; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2006 Summary: (provided by applicant): Heparin cofactor II (HCII) is a thrombin inhibitor found in relatively high concentration in plasma and in most tissues of the body. A member of the serpin superfamily, it is important to the prevention of thrombosis and arteriosclerosis. Heparin and dermatan sulfate accelerate its rate of inhibition 10[3] to 10[4]-fold through an allosteric mechanism that is only partly understood. This unique mechanism appears to involve binding of the N-terminus of HCII to exosite I of thrombin following the binding of glycosaminoglycans (GAG). Although some of the residues involved in this mechanism have been identified through site-directed mutagenesis, the structural changes that occur have not been identified. Another unusual feature of HCII is its active site sequence, which makes the serpin more sensitive to activation by particular GAG and therefore confers greater site specificity. This proposal seeks to use a combination of heteronuclear single quantum correlation (HSQC) NMR and fluorescence spectroscopy to elucidate in solution the sequence of events leading to HCII activation. A proposed model will be tested through the following specific aims 1) to determine the relative mobility of the N-terminus and its binding site(s), including the binding site of the hirudin-like acidic region, 2) to establish the activation mechanism by monitoring changes following the binding of heparin and dermatan sulfate, and 3) to determine whether the reactive center loop is partially inserted in beta-sheet A, and whether that insertion is affected by the binding of GAG. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Arteriosclerosis

Project Title: HIGH BLOOD PRESSURE RESEARCH Principal Investigator & Institution: Ayers, Carlos R.; Professor; Internal Medicine; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 01-JUL-1994; Project End 30-JUN-2004 Summary: This is an interdisciplinary post-doctoral training grant application for 6 positions per year. The area of training is in hypertension, arteriosclerosis and vascular biology. The research training period is for two more years. The trainees are trained for positions in academic medicine. Additional clinical training for board qualification is supported by hospital sources. The departments include Internal Medicine Cardiology, Endocrinology and Nephrology), Pediatrics (Nephrology Cardiology), Anesthesiology, Biochemistry, Physiology Pharmacology and Biomedical Engineering. This is the only NIH institutional training grant supporting M.D. cardiovascular research training in the clinical departments of this institution. Almost all of the trainees have a basic scientist as a mentor; some have more than one mentor. The main research training projects have been in molecular or cell biology, however, and projects in whole animals and human subjects are done. There are three strong research areas that support the major part of research training: vascular smooth muscle program project group, the group working on the renin-angiotensin-aldosterone system and the vascular biology/arteriosclerosis program group. The greatest strength of this training program is the recruitment of highly qualified MD trainees to this program. We are now averaging 6 MD trainees/year. These trainees elect basic training that my include both a basic and clinical science mentors. Basic statistics, data management and research ethics are the only required courses but those training in vascular biology are required to take Vascular Cell Biology and Cellular and Molecular Biology are strongly recommended. The trainees are expected to attend lab meetings, selected seminars in Physiology, Vascular Smooth Muscle, Vascular Biology, Pharmacology, Biochemistry and Internal Medicine. Monthly journal clubs and research seminars in Cardiology are attended. MD trainees may earn the PhD degree. The research environment is superior and research grant support of the faculty is excellent. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HOMOCYSTEINE-INDUCED ENDOTHELIAL CELL GROWTH INHIBITION Principal Investigator & Institution: Wang, Hong; Medicine; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2009 Summary: (provided by applicant): Hyperhomocysteinemia is an independent risk factor for myocardial infarction and stroke, yet the mechanisms by which homocysteine (Hcy) promotes arteriosclerosis are not clear. Most of the reported biological effects of Hcy in vascular cells have been attributed to oxidative mechanisms, which were observed at Hcy concentrations higher than 1 mM or higher, and can be mimicked by cysteine, another nonpathogenic biothiol. Thus, a biochemical mechanism unique to Hcy remains to be identified. We have proposed hypomethylation as a specific mechanism by which Hcy induces vascular injury and leads to cardiovascular disease. The basic hypothesis of the ongoing and this proposed projects is that Hcy, at clinically relevant concentrations, selectively inhibits EC growth through a hypomethylation-related mechanism. The ongoing research is designed to investigate the role of Ras demethylation in Hcy-EC growth, to dissect the mechanism in Hcy signaling using cellular and animal models. Because damage to EC is a key feature of arteriosclerosis,

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the growth inhibition of EC may represent an important mechanism to explain Hcyinduced arteriosclerosis. In the proposed study, we hypothesize that hypomethylation of other molecules may also play an important role in Hcy-related EC growth inhibition. We added two new aims to characterize methylation status of genomic DNA and protein, to examine the activities of histone methyltransferase in Hcy-treated EC (Aim 4), and to identify new functional target genes using retrovirus-mediated genetic screening and radiolabelled methylation sensitive two-dimensional electrophoresis proteomics (Aim 5). These two new aims are expansion of the funded project and would explore key functional molecular mechanisms by which Hcy inhibit EC growth. The broad, long-term objective of this proposal is to elucidate Hcy signaling in EC growth inhibition, and to evaluate its importance in the role of atherogenesis in Hcy pathology. If we can identify the key events in Hcy-induced arteriosclerosis, genetic or biochemical approaches to block these steps could lead to therapeutic advantage. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HOST-VIRAL ARTERIOSCLEROSIS

IMMUNE

RESPONSES--TRANSPLANT

Principal Investigator & Institution: Valantine, Hannah A.; Assistant Professor of Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002 Summary: (provided by applicant): Previous studies indicate that HCMV infection is a risk factor for TA. Viral-specific CD4 and CD8 T cell responses appear to be critical for maintenance of HCMV latency. HCMV genomes or gene products have been detected in the cells of the coronary vasculature in patients with TA. We hypothesize that such local infection could enhance alloreactivity via direct effects of the virus on cell function as well as by recruiting recipient inflammatory cells. The studies of Specific Aim 1, longitudinal assays will follow viral load and HCMV-specific effector cells (circulating CD4 and CD8 T lymphocytes) during primary infection (donor +/ recipient -), latency with reactivation or reinfection (recipient +/donor - or recipient +/donor +), and latency without reactivation (non-transplant HCMV + healthy individuals). An inverse correlation is expected between the risk of progression to TA and the frequency of HCMV-specific T cells capable of producing cytokines (IL-2 and IFN-gamma), and TNF family ligands (TNF-cc, CD40-ligand, fas-ligand). The risk of progression to TA may directly correlate with an increased frequency of T cells producing Th2-type cytokines, IL-4, IL-10, and IL-13, which are expected to be ineffective in limiting viral replication. The studies of specific aim 2 will follow the frequency and function of CD4 and CD8 T cells recognizing pp65 epitopes, a widely recognized indicator viral antigen, and determine whether the HCMV-specific memory/effector response is reduced in heart transplant patients who progress to TA compared to these cells in healthy adults. Patients who are infected with HCMV and are HLA-A.2 positive will be evaluated for the presence of CD8 T cells that bind the HCMV pp65 495.503- class I tetramer and cell activation function, based on CD69 expression and IFN-gamma production and basal perforin expression. Similar studies will be performed for CD4 T cell responses with HLA-DR/pp65 peptide tetramers, if these become available. We anticipate that transplant patients will have a decreased frequency of memory/effector CD4 and CD8 T cells with specificity for pp65-derived peptides, and that a greater proportion of cells with this antigenic specificity will have reduced function, based on cytokine secretion, compared to healthy control HCMV seropositive individuals. We expect that the risk of TA would be lower in patients with more rapid control of systemic or local HCMV infection due to robust HCMV-specific adaptive immune responses. It is also plausible

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Arteriosclerosis

that in cases of direct HCMV infection of the graft vasculature, these delayed adaptive immune responses might ultimately contribute to the later development of TA. Together, these studies should provide insight into human CD4 and CD8 memory/effector T cell responses following primary and recurrent HCMV infection in cardiac transplant recipients and their relationship with the evolution of TA. They should also provide insight into the relationship between HCMV infection and allograft rejection in other transplant contexts. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTEGRINS

HYPERTENSION

AND

ARTERIAL

INJURY--A

ROLE

FOR

Principal Investigator & Institution: Meininger, Gerald A.; Regents Professor and Associate Head; Medical Physiology; Texas A&M University Health Science Ctr College Station, Tx 778433578 Timing: Fiscal Year 2002; Project Start 15-AUG-1999; Project End 31-JUL-2004 Summary: The overall goal of this project is to test the prevailing hypothesis that hypertension and arteriosclerosis may be linked through a mechanism that involves oxidative stress. Our working hypothesis is that oxidative stress in hypertension and atherosclerosis acts to induce similar alterations in the expression of specific integrins and extracellular matrix (ECM) proteins that are responsible for changes in vasomotor function and vascular smooth muscle (VSM) phenotype. Our recent studies have established a novel link between VSM and endothelial integrins and the control of vascular tone. In addition, preliminary data indicates that oxidative stress can alter the expression of at least one of the VSM integrins linked to vasomotor activity and an ECM protein that is a ligand for this receptor. These altered integrin/matrix interactions may predispose the arterial wall to development of vascular pathology. This project incorporates a model of renal hypertension and atherogenesis that will be studied at various stages of disease development in large, intermediate and microvascular sized arterial vessels. Assessments will be made of the redox status, integrin and ECM profiles and vascular reactivity to soluble and insoluble integrin-binding ligands. These ligands will include synthetic Arginine-Glycine-Aspartic Acid (RGD) containing peptides and type I collagen and osteopontin, which are up-regulated following vascular injury. Our strategy is combining studies of intact vessels, cellular, biochemical and molecular approaches will provide a powerful approach for testing our hypothesis and systematically integrating our results, The specific aims are: Aim 1: Characterize the vasomotor response for large intermediate and small arterial vessels to known integrinbinding peptides, type I collagen and osteopontin at varius stages of development for a rat model of renal hypertension and/or imposed oxidative stress (allylamine treated). Vasoactivity will be correlated with measurements of redox status and integrin/ECM profiles. Aim 2: Characterize the vascular redox status and mechanisms leading to the development of oxidative stress in models of renal hypertension and atherogenesis and evaluate the role of NFkappaB as a common signal transduction pathway. Aim 3. Characterize and evaluate changes in vascular ECM/integrin expression at the gene and protein levels that are associated with renal hypertension or oxidative stress and to define the influence of oxidative stress on extracellular matrix and integrin gene expression. These studies will provide new information that will advance our understanding vascular function in hypertension and atherosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IFN GAMMA IN HUMAN GA Principal Investigator & Institution: Tellides, George; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2003 Summary: IFN-gamma in Human Graft Arteriosclerosis is the major limitation of cardiac transplantation and is characterized by pathological remodeling and dysfunction of coronary arteries, termed graft arteriosclerosis (GA). The pathogenesis of GA is poorly understood, but is likely immune- mediated and may result from chronic delayed type hypersensitivity (DTH) responses by recipient T cells to donor vascular antigens. Activated T cells induced DTH through secretion of cytokines, such as interferon-gamma (IFN-gamma). Paradoxically, IFN-gamma is generally thought to have an anti-proliferative effect on vascular smooth muscle cells (VSMCs) and considered to function as a pro-arteriosclerotic agent solely because of its immunomodulatory effects on vascular cells and infiltrating leukocytes. However, we have recently reported that IFN- gamma elicits arteriosclerosis in the absence of leukocytes. Our observations have led us to hypothesize that IFN-gamma acts directly on VSMCs to potential platelet-derived growth factor (PDGF)-BB induced mitogenesis through interactions involving growth factor receptors and STAT proteins. To test our hypothesis with the experiments planned in this project, we have formed productive collaborations with other investigators of the program application and together we have developed novel models of GA by establishing methods to transplant human and pig coronary arteries to immunodeficient mouse hosts and by defining conditions for the long-term organ culture of human and pig coronary arteries. We will use these approaches to elucidate the effects of IFN- gamma on vascular tissues in vivo and in vitro. The aims of our application are: (1) to test the hypothesis that IFN-gamma growth stimulatory signals to VSMCs are mediated by STAT3 and are enhanced by PDGF-BB; (2) to test the hypothesis that IFN-gamma growth inhibitory signals to VSMCs are mediated by STAT1 and are diminished by PDGF-BB; (3) to test the hypothesis that IFNgamma induced proliferation of VSMCs is independent of IFN-gamma effects on endothelial cells; and (4) to validate our model by confirming that the expression of certain IFN gamma-dependent gene products correlates with the presence and degree of GA in human cardiac allografts the outcomes of these studies will provider considerable new information about the role of IFN-gamma in GA. Our experimental work performed in conjunction with Cores B and C will provide a mechanistic extension to the studiers of Project 1. The reagents we characterize in conjunction with Cores D and E will be applied in imaging studies by Project 3. The comparisons between experimental and clinical specimens in conjunction with Project 3, Cores D and E will validate our models. Our findings may ultimately have diagnostic, prognostic, and therapeutic clinical utility. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMAGING DTH, IFN GAMMA RESPONSES & GA IN HUMAN ARTERIES Principal Investigator & Institution: Bender, Jeffrey R.; Professor and Associate Chief; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2003 Summary: Imaging DTH, IFN-gamma Responses and GA in Human Arteries. Graft arteriosclerosis (GA) is the major cause of late graft failure in cardiac transplantation. Reliable non-invasive tools for the detection of GA, specifically in its early form, do not

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Arteriosclerosis

currently exist. Coronary angiography and myocardial perfusion imaging are routinely performed but have limited detection accuracy for early disease. However, the detected neointima is not predictive of the clinical course. The overall goal of this project is to develop non-invasive, nuclear imaging-based modalities for early GA detection, based upon the immunopathogenesis. Our approaches will be closely linked to the Project 1 and 2 hypotheses, that TH1 cells are potent stimulators of the GA response through the elaboration of IFN-gamma which in turn, induces chemokine production, growth factor receptor expression and smooth muscle cell (SMC) activation/proliferation. We have recently established small animal imaging models which target modulated membrane markers in pathologic states, including an arterial injury model in mice. Specific proposals now include: (1) to define expression levels of known, carefully chosen candidates target molecules, including CXCR3 and CCR5 (T cells), PDGFbeta-R, alphavbeta3 and VCAM-1 (endothelial cells and SMC), IP- 10 and Mig (secreted), on CD4+ TH1 cells, IFN-gamma activated SMC and EC, in (a) cell culture, (b) organ culture, (c) human-to-mouse vascular transplant segments in a SCID mouse model, and (d) human specimens of chronic vascular rejection; (2) to select novel potential imaging ligands using a peptide phage display library and biopanning, in vitro, ex vivo, and in vivo, directing the phage biopanning at the same spectrum of immune-activated cells/tissues; (3) to radiolabel chosen ligands (antibodies, peptides and other small molecules) and determine their pharmacologic properties both in vitro and in vivo, using radioimmunoassays and autoradiography; and (4) to perform gamma camerabased in vivo imaging in the human arterial transplant to SCID mouse model, using a limited number of radiotracers selected in 1-3, above. Defined targeted imaging approaches will be the foundation for patient-based studies in the future. Ultimately, the ability to detect early pathogenetic features of GA may provide prognostic data and generate a new paradigm for treatment of transplant patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INFECTIOUS TOLERANCE IN TRANSPLANT RECIPIENTS Principal Investigator & Institution: Kupiec-Weglinsky, Jerzy W.; Professor; Surgery; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-JUL-1998; Project End 30-JUN-2003 Summary: The mechanism behind allograft (Tx) acceptance may include a process termed "infectious tolerance"(IT). IT propagates itself into new sets of recipients by transferred mononuclear cells (MNC). Lew rats sensitized with BN skin Tx reject donorspecific cardiac Tx in 200 days after treatment with CD4 mAb (RIB-5/2). This effect is accompanied by features characteristic for the IT pathway. The PI will use this rat Tx model to define key mechanisms contributing to IT. He hypothesizes that acquisition of IT to MHC-incompatible organ Tx results from host mechanisms controlled by regulatory CD4+ T cells. Once established, the Th2-type response becomes dominant and instrumental to the maintenance of well-functioning Tx in tolerant recipients. The PI plans to address the following questions: (1) What are the identity and functional characteristics of regulatory T cells mediating IT? He will fractionate MNC from RIB-5/2 mAb-treated cardiac Tx recipients into phenotypically distinct subsets and evaluate their efficacy to confer tolerance into new cohorts of test cardiac Tx recipients. These tolerance-conferring cells will be also studied for their ability to overcome allorecognition properties in "mixing" experiments, following re-transplant of "parked hearts" into new sets of test recipients, and in thymectomized hosts. The recirculatory routes of transferred cells will be identified. He will also analyze the functional profile of

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tolerant cells in vitro (MLR, CTL, cytokine elaboration). (2) What is the role of intra-Tx cytokine network in IT? First, the PI will test whether infusion of anti-IL-4 mAb of rIFNg/rIL-2 may prevent tolerance induction, and recreate cardiac Tx rejection in test recipients. He also proposes to use in vivo gene transfers utilizing IL-4 and IFN-g encoding replication-deficient adenoviral vectors. He will determine whether intra-Tx overexpression of IL-4 may boost the Th2-type milieu, and amplify the IT pathway. He will assess how cytokine gene transfer affects intra-Tx cellular infiltrate/activation and Th1/Th2 cytokine expression profile. This approach will be then employed in an attempt to counteract the IL-4-mediated effects by intra-Tx overexpression of the IFN-g gene. (3) How does local expression of cytokine-controlled allo-Abs and "protective" molecules affect Tx injury in tolerant hosts? Th2-mediated depression of certain IgG isotypes in parallel with upregulation of protective molecules (Bcl-2, Ccl-xL, A-20, HO) may contribute to the avoidance of chronic Tx rejection in tolerant hosts. The PI will test whether manipulations within the Th1/Th2 cytokine network, as proposed in Aim 2, will modify intra-Tx deposition of IgG isotypes and expression of protective proteins, with resultant avoidance of Tx arteriosclerosis and chronic rejection in the IT pathway. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INHIBITION OF MACROPHAGE ACTIVATION BY SMAD3 Principal Investigator & Institution: Feinberg, Mark W.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 04-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): Transplant-associated arteriosclerosis (TAA) is the major cause of death in recipients who survive more than one year after cardiac transplantation. TAA is characterized by infiltration of inflammatory cells followed by the formation of a diffuse, concentric neointima in which smooth muscle cells and lipidladen macrophages accumulate. Cells of the immune system-particularly the macrophage-play a key role in TAA. Through uptake of oxidized lipids, elaboration of inflammatory cytokines, and release of proteolytic enzymes, activated macrophages are critical to TAA. The long-term objectives are to identify mechanisms regulating these processes. The pleiotropic growth factor, TGF-01, is an important regulator of cellular growth, differentiation, and immune modulation. Efforts to elucidate mechanisms by which TGF-beta1 mediates its functions have identified a number of effector proteins termed Smads. Although nine Smads have been identified, their role in macrophage biology has not been assessed. We found that a single member of the Smad family. Smad3-is critical for inhibiting markers of macrophage activation. This proposal aims to investigate the role of Smad3 in regulating activated macrophages and its role in the pathogenesis of TAA. Our data suggest that a novel mechanism is regulating Smad3's inhibitory function likely involving binding to an essential co-factor in macrophages. Thus, we propose to identify and characterize interaction partners for Smad3 in macrophages and assess how such factor(s) may affect Smad3's regulation on macrophage activation. To assess the effect of Smad3 on a broad range of macrophage effector functions, we will employ adenoviral strategies to overexpress both Smad3 and a dominant negative Smad3 in macrophages. Finally, to evaluate the in vivo role of Smad3, we will determine the contribution of Smad3 in the development of transplant arteriopathy using a mouse model of cardiac allograft transplantation in Smad3-/recipient mice. Insight into the mechanism governing SmadYs role in inflammation may provide potential, therapeutic targets applicable to a number of inflammatory diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Arteriosclerosis

Project Title: INOS VASCULOPATHY

GENE

THERAPY

TO

PREVENT

ALLOGRAFT

Principal Investigator & Institution: Simmons, Richard L.; Distinguished Service Professor; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002 Summary: Based on current data from the United Network for Organ Sharing (UNOS), cardiac allograft vasculopathy (CAV) is the leading cause of death after the first year of transplantation and accounts for 25% of all deaths annually after the third year. Initial studies from our laboratory have demonstrated that the expression of inducible nitric oxide synthase (iNOS; NOS2) can suppress the development of neointimal hyperplasia and prevent the development of CAV. The proposal described herein will test the hypothesis that viral vectors capable of transferring the human iNOS gene can suppress the development of CAV without causing undue toxicity to cardiac myocytes. Furthermore, this proposal will serve as the pre-clinical basis for near-term clinical trials for the future prevention of CAV in humans. In order to serve these ends, we will carry out the following Specific Aims: 1) to determine the efficacy of several viral vectors (adenoviral, adeno-associated virus, and lentivirus) containing the human iNOS gene (Ad-iNOS, AAV-iNOS, Lt-iNOS) and their respective control vectors for suppression of cardiac transplant arteriosclerosis in the rat model; 2) to determine toxicity of Ad-iNOS, AAV-iNOS, and Lt- iNOS and their respective control vectors in rat models; 3) to determine efficacy and toxicity of the ideal viral vector (Ad-iNOS, AAV-iNOS, or LtiNOS) and its respective control vector as determined in Specific Aim #2, in a porcine model of chronic rejection and 4) to determine the toxicity in human hearts that are being supported with ventricular assist devices. In this proposal we plan to address several key questions including 1) what effect will chronic iNOS expression have on myocardial contractility; 2) will chronic iNOS expression induce cardiac myocyte apoptosis; 3) will iNOS expression induce acute cellular rejection; 4) what effect will iNOS expression during an episode of acute cellular rejection have on global cardiac function and 5) can iNOS be delivered in a safe and efficacious manner such that CAV can be prevented in a large animal model of chronic rejection? We plan to address these questions using both in vitro and in vivo models. Upon completion of the specific alms outlined whin this proposal our goal will be utilize the data obtained from these experiment to serve as a guideline by which to proceed with a safe and efficacious iNOS-based gene therapy trial for the therapeutic prevention of CAV. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: KALLIKREINS-KININS COMPLICATIONS

AND

DIABETIC

VASCULAR

Principal Investigator & Institution: Jaffa, Ayad A.; Professor; Medicine; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2003 Summary: (provided by applicant): The risk factors that contribute to the development of vascular disease in diabetes are not fully defined. Our objective in this application is to define the unique role of the kallikrein-kinin system (KKS) in the pathogenesis of vascular complications and to elucidate the underlying mechanisms involved in this process. Our hypothesis which is based on preliminary data generated from the DCCT/EDIC-cohort of type 1 diabetic patients, demonstrate, for the first time, an association between plasma prekallikrein levels and surrogate markers of

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macrovascular disease (internal and common carotid intima-medial wall thickness). IN addition, our data also demonstrates an association between KKS components and established vascular disease risk factors such as, hypertension, elevated lipids, microalbuminuria, fibrinogen and PAI1. Further, our data also demonstrates that KKS components positively correlate with the circulating levels of the prosclerotic factor connective tissue growth factor (cTGF). We have also discovered that there is a strong correlation between the circulating levels of cTGF and the excretion rate of albumin. Finally, our recent data at a cellular level indicates that kinins participate in the development of diabetic vascular injury by acting through their receptors to stimulate several key-signaling pathways that promote proliferation and/or sclerosis of vascular cells. In this regard, bradykinin (BK) stimulates the levels of collagen 1, cTGF and transforming growth factor-beta (TGF-beta) in vascular smooth muscle cells (VSMC). This increase in collagen 1 by BK was mediated via autocrine activation of TGF-beta. Moreover, the induction of TGF-beta by BK in VSMC was mediated via activation of the MAPK pathways. Therefore, we hypothesize that activation of the KKS components by the diabetic state plays a pivotal role in the initiation and progression of diabetic vascular disease. To test our hypothesis, we propose the following specific aims.1. Determine whether diabetic patients who develop vascular disease have markers of altered KKS activity, compared with patients who do not develop vascular disease. For these studies we will define the relationships of biomarkers of KKS components (plasma prekallikrein, kininogen, Factor XII) to indices of macrovascular disease in type 1 and type 2 diabetic patients. We will also identify novel polymorphisms to markers of vascular and renal dysfunction in diabetic patients.2. Determine the role and contribution of the KKS to modulate production of biomarkers of vascular and renal injury. For these studies, we will measure the circulating levels of TGF-beta and cTGF in type 1 and type 2 diabetic patients. We will define interrelationships between KKS and TGF-beta and cTGF, and determine whether TGF-beta and cTGF will predict the development of diabetic vascular complications. The effect of peroxisome proliferatoractivated receptor-gamma (PPAR-gamma) activators on BK signaling to promote VSMC sclerosis will be examined. 3. Investigate if hyperglycemia will modulate the assembly and activation of KKS on endothelial cell surfaces. These studies will provide a comprehensive and critical assessment of the contribution of the KKS to diabetic vascular disease and will enhance our understanding of the multi-factorial mechanisms underlying vascular disease in diabetics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LDL ARTERIOSCLEROSIS

BINDING

PROTEINS

OF

ARTERIAL

WALL:

Principal Investigator & Institution: Lees, Robert S.; Massachusetts Institute of Technology Cambridge, Ma 02139 Timing: Fiscal Year 2002 Summary: This project involves the isolation and characterization of novel LDL-binding proteins of the arterial wall. We have isolated 3 such and are studying the molecular conformation with multiple techniques, including NMR. The project is still in its early phase and no reportable results are available yet. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIPID MAPS Principal Investigator & Institution: Dennis, Edward A.; Chemistry and Biochemistry; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 920930934

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Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 30-SEP-2003 Summary: (provided by applicant): Lipids are central to the control of cellular function and disease. The scope of the actions of lipids has only recently become widely recognized, going beyond an appreciation for their well-established roles in energy metabolism and membrane structure. Changes in the levels of one lipid class not only affect the other members of that class, but can also strongly affect other classes as well. While investigators have been able to monitor concurrent changes in a few members of one lipid class, no comprehensive strategy has emerged for characterizing the global changes in lipid metabolites ("lipidomics"), in contrast to the global level analyses routinely carried out for nucleic acids (genomics) and proteins (proteomics). We outline a new strategy that would lead to the integration of lipids into the general focus of 21st Century biology; namely, into a fully quantitative systems-level biology. Our collaboratory, the National Alliance for the Comprehensive Characterization of Lipid Function, will develop an integrated Lipid Metabolomics and Proteomics System, termed LIPID MAPS. The specific aim of LIPID MAPS for this grant period is to develop the requisite technology and conduct an interconnected research program that will yield lipidomics as a fully established research strategy. Through using a common set of biological, biochemical and analytical technologies, and a rich information infrastructure, we will be able to connect and integrate the results from individual research units, and then share our findings with the entire research community to enable a much broader effort. Numerous physiological processes involve changes in tissue levels of lipids, which also relate to lipid involvement in disease. Thus, lipids play a central role in many diseases, from inflammatory processes to arteriosclerosis, Alzheimer's disease, cancer and stroke. Yes, in contrast to other macromolecules, lipids have remained such a challenge that no coordinated national program for their study exists. We believe that the experimental technologies are now in hand for a functional characterization of LIPID MAPS. This functional characterization, coupled with our knowledge of other macromolecules and cell processes, will enable the community as a whole to establish predictive models for homeostasis and drug responses in disease states. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIVER/INTESTINAL METABOLISM OF BILE ACIDS/CHOLESTEROL Principal Investigator & Institution: Hylemon, Phillip B.; Professor; Biochemistry; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2002; Project Start 01-DEC-1986; Project End 31-AUG-2007 Summary: (provided by applicant): Background: Cholesterol and bile acids have been implicated in playing important roles in several major diseases of "Western Society" including: arteriosclerosis, cholesterol gallstone disease, cholestatic liver diseases, and colon cancer. The overall goal of this renewal application is aimed at a more detailed understanding of how the body regulates bile acid and cholesterol homeostasis, liver/intestinal physiology and determining if secondary bile acids are involved in the risk of cholesterol gallstone disease. The overall goal will be accomplished through the following specific aims: a) determine which cell signaling pathways are activated by bile acids in primary hepatocytes and which are important in regulating genes involved in cholesterol metabolism and phospholipid transport; b) determine if JNK-1 and JNK2 null mice are defective in cholesterol homeostatic mechanisms and if bile acid activated cell signaling pathways "cross-talk" with bile acid activated nuclear receptors e.g., FXR (Dent, Hylemon); c) characterize in detail the FTF/HNF-4 site in the sterol 12alphahydroxylase (CYP8bl) promoter and elucidate the molecular mechanism by which

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FTF/SHP specifically regulates CYP8b1 transcription; d) characterize the molecular mechanism involved in the SREBP-2 mediated suppression of the CYP8B1 promoter; e) characterize the significance and physiological role SREB-2-mediated suppression of CYP8b1 (Gil); f) determine the role of steroidogenic acute regulatory (StAR) protein and other intracellular cholesterol transport proteins (SCP-2, MLN64) play in the regulation of bile acid synthesis in the liver; g) determine if StAR is expressed in the liver (Pandak,Gil); h) determine the 3 dimensional (3D) structure and catalytic mechanism of bile acid 7alpha and 7beta-dehydratase from Clostridium scindens; i) express, purify, and characterize a novel 3-oxo-delta4steroid oxidoreductase from C. scindens; j) clone, sequence, and analyze the bai operon from Clostridium hylemonae TN271; k) isolate, characterize, and identify cholic acid 7alpha-dehydroxylating bacteria from cholesterol gallstone patients with high (>30%) deoxycholic acid and controls; and I) determine if gallstone patients are colonized by unique species of 7alpha-dehydroxylating bacteria. (Hylemon, Heuman). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LOW DENSITY LIPOPROTEIN Principal Investigator & Institution: Smith, Lou c; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002 Summary: Low density lipoproteins (LDL) are the major cholesterol transporters in the blood circulation. LDL are the end stage particles resulting from the metabolism of very low density lipoproteins (VLDL) and they stay in the blood circulation for 2-3 days until being taken up by liver. LDL contain apolipoprotein apoB-100 which is one of the largest proteins known (4536 amino acids). Very little is known about the threedimensional structure of LDL. According to existing hypotheses, LDL are simply microemulsions with a non-polar core and an outside shell which provides the water solubility for the particle. The shell is formed by the amphipathic apolipoprotein and phospholipids. Elevated levels of VLDL, LDL and apo B-100 are associated with a significantly increased risk of coronary arteriosclerosis and heart attack. We used electron cryomicroscopy of ice-embedded LDL and computer image processing to study their three-dimensional structure We proposed, based on three-dimensional reconstruction, that LDL are not structureless, easily deformable lipid sacks as was commonly believed. Rather, they have an oval shape and a consistent internal structure. The particle s core has a stable structure consisting of several compartments. Its outer shell most probably consists of apolipoprotein B-100 and phospholipids and the core compartmentalization might correspond to either ordered lipids, or protein intrusions. To distinguish between the two hypotheses further study is needed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF ACCELERATED GRAFT ARTERIOSCLEROSIS Principal Investigator & Institution: Baldwin, William M.; Associate Professor; Pathology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-MAY-1997; Project End 30-APR-2003 Summary: The overall objective of this multidisciplinary research program is to identify the mechanisms of accelerated graft arteriosclerosis (AGA) in heart transplant recipients in order to better identify and treat this disorder. The working hypothesis is that various causes of vascular injury during and after transplantation trigger multiple host and donor dependent responses resulting in AGA. Five projects and three core support units

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will address the objectives and hypotheses of this program. Project 1 will examine how the response of vascular endothelial cells to injury leads to AGA. The focus of this project will be to examine the role of the heterotrimeric G-protein signaling pathway and of cytotoxic lymphocyte- mediated apoptosis triggered by fas overexpression on endothelial cells. Project 2 will examine how cytomegalovirus (CMV) contributes to AGA. In particular, the role of non-permissive CMV infection and the interaction of CMV gene products with the p53 tumor suppressor gene product, platelet- derived growth factor (PDGF), and transforming growth factor beta (TGF beta) will be examined. Project 3 will examine the role of molecular mediators in the inflammatory and proliferative responses characteristic of AGA. The focus of this project will be on the growth-stimulating compounds TGF-beta and PDGF, and the anti-proliferative and vasodilating compound nitric oxide. Project 4 will examine the role of complement (C) and antibody in AGA, focusing on responses to ischemic, alloimmune, autoimmune and viral (CMV) injury. In particular, early and late C components will be examined separately, as will antibody responses to specific major histocompatibility complex (MHC) and heat shock protein (HSP) epitopes. Project 5 will examine the role of cellmediated immunity to autologous (HSP, host-MHC), to allogeneic (donor MHC), and to exogenous (CMV) antigens in the development of AGA. In particular, the repertoire, function, and specificity of cyclosporine A-induced autoreactive T-cells in mediating AGA will be examined. The Administrative Core (Core A) will provide administrative and statistical support. The Pathology/Clinical Core (Core B) will process and bank human and animal tissues for study, and provide a central resource for quantifying pathologic changes. The animal core (Core C) will provide uniform animal heart transplants for in vivo studies. Each pathway examined in this Program will be studied using banked human tissues, dissected out with in vitro and in vivo animal models, and defined at the molecular and cellular levels. The molecular and cellular mechanisms identified in turn will form the basis for developing novel diagnostic and therapeutic strategies which can be translated back to patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MEDIATORS OF ACCELERATED GRAFT ARTERIOSCLEROSIS Principal Investigator & Institution: Lowenstein, c; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002 Summary: Arteriosclerosis of graft vessels is the most common long-term cause of death of a patient with a transplanted heart. Graft arteriosclerosis is a diffuse, circumferential disease, characterized by an infiltrate of inflammatory cells, and a neointima formed by smooth muscle cells. A wide variety of soluble mediators affect the migration and proliferation of these cells into graft vessels, and we propose that two mediators, nitric oxide and transforming growth factor-beta, are crucial to the development of graft arteriosclerosis. Our preliminary data show that immediately after cardiac transplantation, humans produce a burst of nitric oxide and other radicals. Furthermore, our data show that in the months after transplantation, nitric oxide synthase is expressed in mononuclear inflammatory cells migrating into arteries of cardiac allografts in rats and humans. Nitric oxide can have both beneficial and harmful effects to the host, but the role of nitric oxide in the vessel wall is unknown. Our first specific aim is to determine the pattern of expression of inducible nitric oxide synthase. and determine the effect of nitric oxide on the vessel wall. If synthesized in cardiac allografts, transforming growth factor-beta could in theory damage endothelial cells, and also cause smooth muscle cell proliferation by inducing the release of platelet derived

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growth factor. Our preliminary data show that the effects of these growth factors can be abrogated by the over-expression of dominant negative mutant receptors in vitro. Our second specific aim is to determine the role of transforming growth factor-beta and platelet derived growth factor in the development of graft arteriosclerosis, using a unique method to study isolated, modified endothelial cells in vivo. We then plan in our third specific aim to examine how transforming growth factor-beta affects the production of nitric oxide in endothelial cells. These aims are directly related to other projects within this program project. Transforming growth factor-beta induces endothelial cell apoptosis, which is studied in Project 1. Regulation of nitric oxide production in dysfunctional endothelial cells is also explored in Project 1. CMV, studied in Project 2, can induce nitric oxide synthase in infected cells. Fixation of complement, studied in Project 4, can also induce production of nitric oxide. Both nitric oxide and transforming growth factor-beta are released by activated macrophages, which are involved in antigen presentation during cell-mediated immunity studied in Project 5. Thus, many pathways could lead to the release of the mediators we are studying, which in turn lead to the development of graft arteriosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NUTRITION ACADEMIC AWARD Principal Investigator & Institution: Knopp, Robert H.; Professor of Medicine; Medicine; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 30-SEP-1998; Project End 31-AUG-2003 Summary: Cardiovascular disease accounts for about 50 percent of all mortality nationwide in both men and women. While many cardiovascular disease risk factors bear on the occurrence of cardiovascular disease, poor nutritional status is estimated to account in its own right for at least a two-fold increase in cardiovascular disease. These effects are mediated through multiple dietary factors, including the classical fat sources, saturated fat and cholesterol, but other less well recognized nutrients including omega-3 fatty acids, antioxidant vitamins, vitamins bearing on homocysteine levels, other antioxidants such as isoflavones and carotenoids, plant estrogens, soya, salt, trace minerals and alcohol. Physicians have an impression that diet is ineffective in preventing arteriosclerosis, in part because nutrition education is fragmented and inconsistent in medical schools despite nationwide recommendations. In light of these facts, a strong case can be made for embarking on a nutrition education program that is focused around one preventable disease state, arteriosclerosis, and directed at the education of medical students at several levels, postgraduate physicians and paraprofessionals. Plans are presented for the development of an educational program for 2nd, 3rd and 4th-year medical students, residents, research fellows, practicing physicians and allied health care professionals. The proposed members of the Nutrition Academic Award team are gifted teachers and all are conducting nutrition related research of national and international significance. This educational effort is strongly supported by the University of Washington School of Medicine and is already partially underway. Education evaluation components are proposed that are both well established or innovative and will build on evaluation elements from previous preventive cardiology research conducted at this institution. The past track record of teaching substantive and well received courses in cardiovascular disease prevention at the medical school and post-graduate levels assures that an authoritative and continually updated curriculum can be developed, put into practice at the University of Washington and distributed to other medical schools and health-training facilities. It is

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time to begin aggressive, substantive nutrition educational programs in cardiovascular disease prevention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOGENESIS ARTERIOSCLEROSIS

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Principal Investigator & Institution: Libby, Peter; Chief, Cardiovascular Medicine; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-SEP-1990; Project End 30-SEP-2003 Summary: Transplantation-associated arteriosclerosis (TxAA) is an intimal fibroproliferative lesion composed predominantly of vascular smooth muscle cells and associated matrix proteins, admixed with mononuclear inflammatory cells. TxAA causes progressive, insidious vascular occlusion and results in allograft ischemia; it represents the major long-term limitation to solid organ transplantation. Although TxAA is largely ascribed to an immune- mediated allogeneic response, it occurs even in the setting of immunosuppression adequate to block acute parenchymal rejection, and does not correlate strictly with episodes or severity of allograft rejection. Thus, cytokine-induced endothelial dysfunction, recruitment and activation of antigen-non-specific cells, or antibody-mediated processes may modulate the development of TxAA. We have proposed that TxAA is due to a chronic delayed-type hypersensitivity response of host T cells to donor vascular wall cells, distinct from the cytolytic response characteristic of acute rejection. This chronic response persists in part because of incomplete elimination of relevant foreign antigens. Moreover, the initial immune-specific response triggers the release of antigen non-specific effectors such as macrophages and cytokine networks less susceptible to immune modulation. We propose here to continue our long-term objectives of unraveling the mechanisms by which specific effector cell subsets and cytokines initiate and promote TxAA. Using a murine heterotopic cardiac transplant model, Specific Aims of this proposal are: 1) Test the hypothesis that acute rejection and TxAA are mediated via distinct T cell subsets and cytokines. Mice genetically-deficient in particular cytokines or their receptors ("knock-outs"), as well as adoptive transfer methodology, will be used to evaluate the contribution of specific cell subsets (e.g., Thelper 1-type cells, B cells) and cytokines in either promoting or ameliorating acute rejection and TxAA. 2) Identify the mechanisms underlying our seminal observations that acute parenchymal rejection and allograft failure are accelerated in inteferon (GKO) recipients, while TxAA is completely abrogated in long-term allografts in GKO recipients. The observations point to distinct mechanisms mediating acute vs. chronic allograft pathologies, and suggest that different therapeutic interventions will be uniquely applicable to each. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: POSTDOCTORAL TRAINING IN ARTERIOSCLEROSIS RESEARCH Principal Investigator & Institution: Ginsberg, Henry N.; Professor; Medicine; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 01-JUL-1978; Project End 30-JUN-2008 Summary: (provided by applicant): This application requests continued funding, at a level of eight training positions, for a postdoctoral training program in arteriosclerosis which began in 1978 and was last renewed on July 1, 1998. The goal of this program is to train basic and clinical investigators with broadly based knowledge in the major fields related to arteriosclerosis research. Atherosclerotic cardiovascular disease has a major

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impact on the health of the American population, making this training program very relevant. This training program functions within a broad framework of research dealing with various aspects of atherosclerotic cardiovascular disease: A strength of the program is the many collaborative interactions that exist between faculty, and collaborative research programs for trainees has always been stressed. A group of senior scientists will act as mentors both to postdoctoral trainees working in their laboratories as well as to other trainees in the laboratories of more junior faculty members. On the whole, the senior faculty have worked together at Columbia for more than 10 years. They interact through research efforts such as the SCOR in Molecular Medicine and Vascular Biology, and educational programs such as the Institute of Human Nutrition. Dr. Henry Ginsberg, PI and Director of the training program has been actively engaged as a mentor of young basic and clinical scientists for many years. The proposed training plan focuses on a strong didactic program that enhances the outstanding laboratory experience the trainees will receive. Mentoring is also a focus of the program. New faculty have been added to bring new strengths to the program in molecular biology and genetics. All of the faculty utilize molecular biologic and cell biologic methods, including the development and study of transgenic and targeted knockout mice, to address basic and clinical questions. The program will continue to recruit a mix of Ph.D. and M.D. trainees. Regardless of the research focus, all trainees will enroll in didactic programs to strengthen their knowledge in biostatistics and clinical trials; those conducting basic research will take coursework in molecular pharmacology. Trainees will work in laboratories with a mix of M.D. and Ph.D. faculty, other M.D. and Ph.D. postdoctoral scientists, and graduate students. A pro-active program to enhance recruitment of scientists from underrepresented ethnic groups is proposed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF WEIBEL-PALADE BODY SECRETION IN AGA Principal Investigator & Institution: Lowenstein, Charles J.; Assistant Professor; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: Accelerated graft arteriosclerosis (AGA) is the most common long-term cause of death in patients with cardiac allografts. AGA is characterized by a neointima of smooth muscle cells and macrophages in the arteries of transplanted organs. Although the pathogenesis of AGA is not completely understood, a variety of inducers-including complement, granzyme B, antibodies, and viral infections--may play a role in the process of inflammation and proliferation that ultimately leads to AGA. We and others have previously shown that nitric oxide (NO) inhibits AGA. In particular, NO derived from the inducible NO synthase (iNOS, or NOS2) appears to limit the vasculopathy that is a hallmark of AGA. For example, adenoviral delivery of NOS2 decreases AGA. In contrast, inhibitors of NOS increase AGA. Furthermore, genetic deletion of NOS2 exacerbates AGA: cardiac allografts develop more severe AGA when transplanted into NOS2 knockout mice, compared to hearts transplanted into wild-type mice. Thus NO derived from NOS2 protects cardiac allografts from AGA. The molecular mechanisms by which NO inhibits AGA are unknown. However, we recently discovered that NOS2 decreases inflammation in cardiac allografts. In particular, we found that NOS2 inhibits the release ot Weibel-Palade bodies from endothelial cells in donor hearts. Since Weibel-Palade bodies contain inflammatory and thrombotic mediators, inhibition of Weibel-Palade body release may explain part of the antiinflammatory effects of NO in AGA and other vascular diseases. We now propose to explore the molecular mechanism by which NO inhibits Weibel-Palade body release.

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Preliminary Data shows that NO blocks Weibel-Palade body release from cultured endothelial cells. We will begin by determining whether or not NO can inhibit the triggering of Weibel-Palade body release by various inducers of AGA. Then we will define the mechanisms by which Weibel-Palade bodies are normally released. We will next determine the molecular targets of NO. Finally, we will examine the physiological relevance of these mechanisms in a murine model of AGA. These studies will characterize novel molecular mechanisms by which radicals regulate vascular inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF APEG-1 IN VASCULAR SMOOTH MUSCLE BIOLOGY Principal Investigator & Institution: Perrella, Mark A.; Assistant Professor; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 28-FEB-2006 Summary: (Verbatim from the application): Proliferation of vascular smooth muscle cells (VSMC) is a hallmark of arteriosclerosis. Because no genes have been identified that specifically inhibit VSMC proliferation, it has been difficult to develop an effective therapy for excessive VSMC growth. We have isolated the cDNA encoding APEG-l, a novel protein preferentially expressed in differentiated VSMC. During dedifferentiation of VSMC in vitro and in vivo, APEG-l mRNA underwent a rapid downregulation. Infecting VSMC with a recombinant adenovirus of constitutively active cGMPresponsive protein kinase (PKG) reversed this downregulation. Microinjection of an APEG-l expression plasmid into VSMC inhibited DNA synthesis, implicating APEG-l as a growth inhibitor. Thus, we hypothesize that APEG-l is a VSMC-specific growth inhibitor that functions downstream of the cGMP/PKG-signaling pathway. A 2.7-kb fragment of mouse APEG-l 5-flanking DNA directed a high level of VSMC-specific promoter activity, which could be repressed by a 0.8-kb APEG-l DNA fragment located 5' to the 2.7-kb fragment. The goals of our proposed work are to investigate the molecular mechanisms mediating APEG-l's VSMC-specific promoter activity, to test whether APEG-l is a VSMC-specific growth inhibitor, and to determine the molecular mechanisms by which APEG-l regulates VSMC growth and differentiation. To achieve these goals, we propose four specific aims. AIM 1. Identify specific DNA sequences (cisacting elements) and their cognate DNA-binding proteins (trans-acting proteins) important for APEG-l 's restricted expression in VSMC in vitro. In addition, we will identify the cGMP-responsive element(s) and their binding proteins in the APEG-l promoter. AIM 2. Test the specificity and potency of the APEG-l VSMC-specific cisacting elements identified in AIM 1 by using recombinant adenoviruses or transgenes containing reporters driven by these elements in mice. AIM 3. Study the effect of APEG-l on growth and differentiation in VSMC. AIM 4. Isolate APEG- l's interaction partners to elucidate the molecular mechanisms by which APEG- 1 regulates VSMC growth and differentiation. information obtained from these proposed experiments should provide fundamental knowledge about the biology of APEG-l and the differentiation of VSMC, and also critical insight into the treatment of atherosclerosis and restenosis after coronary artery bypass or angioplasty/stent placement. Furthermore, the identification of VSMC-specific promoters will be crucial for future use of gene therapy to direct foreign gene expression in the blood vessel wall. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF CKLE IN VASCULAR SMOOTH MUSCLE CELLS Principal Investigator & Institution: Gray, Susan J.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 01-JAN-2002 Summary: The vascular smooth muscle cell (VSMC) is a critical participant in the development of obstructive vascular disease (arteriosclerosis, restenosis after balloon angioplasty, and transplant vasculopathy). In response to vascular injury, the SMC undergoes a change in phenotype-from that of a quiescent/differentiated cell to one that dedifferentiates, proliferates, and elaborates extracellular matrix (ECM). Members of the Kruppel- like family of zinc finger transcription factors are critical regulators of cellular growth and differentiation. We have identified a novel member of this family expressed in both the heart and vasculature termed CKLF (Cardiovascular Kruppel-like Factor). Our preliminary data support a role for CKLF in VSMC differentiation, proliferation, and ECM production. Aim 1 is to identify the CKLF repression domain and generate a dominant negative (CKLFdn) using reporter gene studies. Aim2 is to assess the effect of retroviral overexpression of CKLF and CKLFdn on growth, differentiation, TGFbI levels, and ECM production in smooth muscle cells. Aim3 is to determine the function of CKLF in vivo by generating null mice through homologous recombination. These studies may allow for novel strategies in the treatment of occlusive vascular disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF CYSTEINE-RICH PROTEIN 2 IN VASCULAR DISEASE Principal Investigator & Institution: Yet, Shaw-Fang; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-APR-1997; Project End 30-JUN-2006 Summary: (provided by applicant): Vascular smooth muscle cells (VSMC) in the blood vessel wall normally exhibit a differentiated, contractile phenotype. However, in response to arterial injury or hypercholesterolemia, VSMC dedifferentiate and proliferate leading to neointima formation-one of the hallmarks of arteriosclerosis. The molecular mechanisms regulating this phenotypic modulation are still not well defined. Understanding the transcriptional control of genes expressed in VSMC will provide insights into the complex regulatory mechanisms of VSMC differentiation, dedifferentiation and proliferation. Cysteine-rich protein (CRP) 2, also known as smooth muscle LIM protein (SmLIM), is a member of the LIM-only CAP family. CRP2 is expressed in arterial, but not venous smooth muscle cells (SMC). CRP2 expression is down regulated in response to arterial wall injury. Thus, we hypothesize that CRP2 may play an important role in the blood vessel wall remodeling under pathological conditions. Understanding the transcriptional regulation and function of CRP2 may provide insight into the phenotypic modulation of arterial SMC. Our goals are to investigate the transcriptional regulation of CRP2 gene expression in arterial SMC and to determine the biological function of CRP2 in vascular remodeling. We propose the following: AIM 1. Investigate the molecular mechanisms regulating CRP2 expression in arterial SMC. In vivo footprinting experiments and transgenic mouse studies will be performed to identity arterial SMC-specific elements. AIM 2. Determine whether an absence of CRP2 protein alters vascular remodeling under pathological conditions. We have generated CRP2 null mice and will subject these mice to models of arteriosclerosis. AIM 3. Determine whether CRP1 acts in conjunction with CAP2 to modulate the phenotype of arterial SMC. We hypothesize that CAP 1, a closely related protein that is expressed in SMC, may also contribute to the vascular remodeling. We will generate

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CRP1 and CRP2 double null mice and subject the mice to vascular disease models. The proposed experiments will allow us to determine the role of CRP2 in the phenotypic modulation of VSMC in arteriosclerosis. Information obtained from these experiments should provide not only fundamentally important knowledge about the dedifferentiation and proliferation of VSMC but also critical insight into the treatment of arteriosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF CYTOMEGALOVIRUS IN AGA OF THE CORONARY ARTERY Principal Investigator & Institution: Hayward, Gary S.; Professor; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002 Summary: Epidemiological evidence suggests that cytomegalovirus (HCMV) infection is a major contributing risk factor to the development of accelerated graft arteriosclerosis (AGA) in heart transplant recipients. We have obtained evidence for non-lytic chronic or latent infection by in situ hybridization in up to 70% of coronary artery sections in CMV positive recipients exhibiting AGA. HCMV IE1 and IE2 RNA, but not the 2.7kb IR4 delayed-early RNA were found to be expressed in large numbers of infiltrating mononuclear lymphocytes or monocytes (MNC) and in many endothelial cells (EC) as well as in some clustered smooth muscle cells (SMC) in the intima. Patterns of HCMV IE1 and IE2 protein expression correlated with the RNA results but differed in each cell type with SMC predominantly expressing the IE1 protein; EC the IE2 protein and MNC synthesizing neither protein. No late proteins were detectable except in occasional mature macrophages in the myocardium with inclusion bodies. We hypothesize that the expression of a limited subset of viral transcriptional regulatory genes in these nonpermissively infected cells may alter cellular gene expression and functional activity or the proliferation state of one or more of these cell types in ways that may trigger or exacerbate the changes involved in coronary arteriosclerosis. The specific aims of this project are thus to 1) Definitively characterize the in situ status of viral regulatory gene expression in different cell types in vessel walls with and without disease. 2) Examine the effects of HCMV infection and IE1 or IE2 expression from adenovirus vectors on cellular levels of p53, TGF-beta and PDGF, in quiescent and non-permissive BC and SMC culture systems with a view towards understanding the mechanisms involved in relevant cellular changes. We will also focus on the mechanisms of CMV.induced overexpression of p53 and determine whether the absence of p53 genes affects AGA in the presence or absence of CMV in a transgenic knock-out mouse model. 3) Examine otherwise inaccessible early events (especially in proliferating SMC in the intima) in a latently infected donor rat model that produces AGA within 20 days after cardiac transplantation and utilize genetically marked rat CMV to follow reactivation events. Parts of the work will be carried out in collaboration with other groups in the project. Our anticipation is that detailed knowledge of the role of CMV and its close relatives HHV6 and HHV.7 in AGA will lead to a better understanding of how to manage and monitor the disease, as well as to the development of potentially useful therapeutic or preventative strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF NFY IN IRRADIATION INDUCED GENE ACTIVATION Principal Investigator & Institution: Jahroudi, Nadia; Assistant Professor; Medicine; Yeshiva University 500 W 185Th St New York, Ny 10033

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Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-AUG-2004 Summary: A major component of all organs is a vascular system that provides a network of capillary vessels for nutrient exchange. The use of irradiation therapy in treatment of many types of cancer results in both immediate and delayed vascular damage that is a consequence of injury to endothelial cells. Damage to the vascular endothelial cells is thus a major cause of complications including, thrombus formation, premature coronary arteriosclerosis, and myocardial infarction, or fibrosis, that occur as a consequence of irradiation therapy. Irradiation results in a decreased expression of anti-coagulant and an increased expression of pro-coagulant factors, such as von Willebrand factor (VWF) in endothelial cells. The circulating VWF molecules in the blood are proposed to be mainly responsible for initial steps of platelet adhesion. Increased VWF expression in response to irradiation results in elevated levels of platelet deposition, which may be a major cause of thrombus formation after irradiation therapy. The formation of platelet thrombi provides a defense mechanism by preserving the vascular integrity after injury, however it can precipitate diseases such as atherosclerosis. A number of irradiation responsive transcription factors have been identified that activate some of the downstream irradiation inducible genes in endothelial cells, however the mechanism of irradiation induction of many other genes including that of VWF is not known. In addition to its major role in development of irradiation induced vascular disease, VWF is a molecule with a highly restricted endothelial specific expression pattern that provides an opportunity to investigate the mechanism of endothelial specific gene regulation in response to irradiation. In our studies, we have found that ionizing radiation results in transcriptional upregulation of VWF. We have now identified the sequence CCAAT in the VWF promoter as the irradiation responsive cis- acting element. We have also demonstrated that NFY transcription factor interacts with the CCAAT element and mediates the irradiation induced VWF promoter activation. We hypothesize that irradiation results in posttranslational modification of NFY thus increasing its transactivation function. We now propose in specific aim l) to determine the nature of posttranslational modification of NFY in response to irradiation; and in specific aim 2) to determine the molecular mechanism that leads to NFY modification in response to irradiation of endothelial cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF THE GRANZYME B PATHWAY IN AGA Principal Investigator & Institution: Rosen, Antony; Professor; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: The long-term objectives of this project are to define the role of the granzyme B pathway in accelerated graft atherosclerosis, and its predominant mechanisms of pathogenesis in this setting. Recent data has underscored the fact that the granzyme B pathway plays a central role in transplant rejection, acting through induction of death and dysfunction of target cells through cleavage of highly specific intracellular and extracellular substrates. In preliminary studies, we have demonstrated that differentiated vascular smooth muscle cells (vSMCs) are preferentially and highly susceptible to granzyme B-induced proteolysis, and have observed that fibrillin-1 (a component of microfibrils in extracellular matrix which is prominent in blood vessels) is efficiently cleaved by granzyme B. We hypothesize that the granzyme B pathway plays a critical role in initiating and driving the specific vascular phenotype in AGA, through induction of ongoing damage of differentiated vSMCs, and cleavage of a critical extracellular matrix signal which leads to dysregulation of smooth muscle cell and

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endothelial cell function. We will address this hypothesis through the following specific aims: (1) Define the activity, targets and mechanisms of the granzyme B-induced dysfunction in vivo in human cardiac transplantation using unique probes of granzyme B-induced cleavage of intracellular and extracellular substrates; (2) Define the functional consequences of the granzyme B pathway on vessel structure and function, including intact vessels and isolated smooth muscle cells in vitro; (3) Address the role of granzyme B in development of AGA lesions in vivo by examining the effects of deficiency of GrB either in the whole animal or in distinct microenvironments, using granzyme B-deficient mice or mice expressing intracellular or secreted forms of a potent GrB inhibitor in vascular smooth muscle cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SMLIM, A VASCULAR SMOOTH MUSCLE LIM PROTEIN Principal Investigator & Institution: Jain, Mukesh K.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-JUL-1998; Project End 30-JUN-2003 Summary: (Adapted from applicant's abstract) Arteriosclerosis remains the principal cause of myocardial infarction, stroke, and peripheral vascular disease in developed societies. Although the proliferation and de-differentiation of vascular smooth muscle cells (VSMC) is critical for the development of the arteriosclerotic lesion, the molecular mechanisms regulating these events are poorly understood. The long-term objectives are to define the molecular mechanisms regulating the growth and differentiation of vascular smooth muscle cells. Previously, they have identified and characterized a novel zinc-finger transcription factor named SmLIM that is highly and preferentially expressed in VSMC. Other members of this group of proteins have been shown to play essential roles in the development, growth, and differentiation of specific cell types. Thus, they hypothesize that SmLIM plays a similar role in VSMC. This proposal aims to investigate the role of SmLIM in regulating the state of VSMC differentiation and to define the molecular mechanisms regulating its preferential pattern of expression in VSMC. To assess the role of SmLIM in regulating the VSMC phenotype, they will establish stable clones overexpressing SmLIM in the sense and antisense orientations. They will then assess clonal characteristics such as growth, contractility, and expression of various markers of differentiation to determine SmLIM function in VSMC. SmLIM is highly and preferentially expressed in VSMC. Gene transcription is regulated by the interaction of specific DNA sequences (cis-acting elements) and their cognate binding proteins (trans-acting factors). Thus, they plan to identify and characterize the cis-acting elements and trans-acting factors important in regulating SmLIM expression. The proposed work will allow them to understand the importance of SmLIM in regulating VSMC growth and differentiation. Furthermore, identification of VAMC-specific cisand trans-acting factors will be crucial to the future success of efforts to restrict the expression of foreign genes to the blood vessel wall for gene therapy of vascular disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SMOOTH MUSCLE CELL GROWTH CONTROL BY CCN PROTEINS Principal Investigator & Institution: Castellot, John J.; Anatomy and Cellular Biology; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2003; Project Start 15-DEC-1993; Project End 30-JUN-2007 Summary: (provided by applicant): The long-term goal of this project is to elucidate the cellular, molecular, and biochemical mechanisms regulating the proliferation and

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motility of vascular smooth muscle cells (VSMC). VSMC hyperproliferation is a key early event in the pathogenesis of arteriosclerosis, and is the major cause of the high failure rate (restenosis) of many vascular surgical procedures. A hallmark of restenosis is intimal SMC hyperplasia during the first few weeks following surgery. Clearly, a detailed understanding of the mechanisms and molecules that regulate VSMC mitogenesis and migration will provide a therapeutic rationale for controlling VSMC hyperplasia following vascular surgery, and may provide important insights into the pathophysiologic basis for atherogenesis. Our laboratory has provided strong evidence that CCN5, a heparin-induced growth arrest-specific gene, inhibits proliferation and motility in cultured VSMC. Based on this evidence the following hypothesis will be tested: CCN5 is an autocrine regulator of VSMC proliferation and motility in culture and in vivo, and exerts it anti-proliferative and anti-motility effects, at least in part, through regulation of extracellular matrix synthesis and composition. To test this hypothesis, we will: 1) Continue our functional analysis of CCN5 on proliferation, motility, and extracellular matrix in SMC cultured from normal and injured arteries, using adenovirus vectors, recombinant CCN5, small inhibitory RNAs and anti-sense mRNA approaches, 2) Examine the physiologic and developmental functions of CCN5 in knock-out and transgenic mice, with particular attention to cardiovascular defects. In situ hybridization and immunohistochemistry will be employed to determine the spatial and temporal expression pattern of CCN5 mRNA and protein in developing embryos of wild-type, CCN5 heterozygotes and homozygotes. Functional analysis of VSMC cultured from the arteries of genetically altered mice that over- or under-express CCN5 will be carried out; and 3) Characterize the role of CCN5 in both mouse and rat models for vascular injury. We will determine if CCN5 gene or protein therapy might be a useful approach for suppressing restenosis in both the mouse wire-injury and rat balloon angioplasty model systems. The experiments proposed in this application should provide novel insights into VSMC pathophysiology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURAL BASIS OF SMOOTH MUSCLE CONTRACTION Principal Investigator & Institution: Craig, Roger W.; Professor; Cell Biology; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: Smooth muscle is essential to the normal operation of the body, playing crucial roles in vascular, respiratory, digestive, and other functions. Malfunction of smooth muscle is implicated in major diseases such as hypertension, asthma and arteriosclerosis. Smooth muscle contraction is ultimately a result of the sliding of actin filaments past myosin filaments. The long term objective of this project is to elucidate the structural basis of smooth muscle contraction and its regulation at the molecular level. Exciting new insights into smooth muscle function have recently become possible by solution of the crystal structures of several contractile and regulatory proteins and by recent advances in electron microscopy and image processing. We will take advantage of these advances to carry out the following Specific Aims: (1) To define the threedimensional molecular architecture and composition of native smooth muscle myosin filaments; (2) To determine the molecular basis of the side-polar structure of smooth muscle myosin filaments and the structural significance of SM1 and SM2 myosin isoforms; (3) To determine the three- dimensional molecular structure of the actin filaments in smooth muscle; and (4) To elucidate the three-dimensional organization of the actin and myosin filaments in smooth muscle cells, and the structural basis of their interaction. Electron microscopy will be used to determine the molecular structure of the

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actin and myosin filaments, and the structural changes that accompany contraction. Muscle filaments will be preserved in close-to their native states using state-of-the-art techniques, and their three- dimensional structures will be computed by helical or tomographic reconstruction. A near-atomic understanding of filament structure and its relation to function will be gained by fitting the atomic structures of actin and the myosin head to the filament structures determined by electron microscopy. Novel structural insights into molecular assembly, organization and function will be obtained using complementary molecular biological and immunological approaches. Both vascular and gastrointestinal smooth muscle model systems will be studied. The results of this project should provide fundamental insights into the molecular mechanism of smooth muscle contraction and regulation, and into structural changes that may occur in diseased states. Preliminary data are presented showing the feasibility of our goals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURAL CELL BIOLOGY IN CARDIOVASCULAR DISEASE Principal Investigator & Institution: Atkinson, David N.; Professor; Physiology and Biophysics; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2002; Project Start 30-SEP-1985; Project End 31-DEC-2005 Summary: The objective of this program is to understand the Structural Biology of the macromolecular complexes involved in the transport of lipids into and out of cells. The aims of the project are: to define the 3-dimensional structures of cellular receptors and their ligands bound to LDL (Project 1): to study the formation of primordial nascent triglyceride-rich particles in the endoplasmic reticulum and understand how the secondary and tertiary structures of the N-terminal 41% apo-B regulates this process (Project 2); to understand the structure and conformation of apo-B, the 3- dimensional structure of LDL, the organization of apo-B on LDL, and to define the formation and 3dimensional structure of exchangeable apolipoproteins on nascent ans plasma HDL (Project 3); to understand the binding of fatty acids to albumin, the transfer of fatty acids from albumin and movement across membranes into cells, structural and dynamic features of intracellular fatty acid binding proteins, and the effect of fatty acids on intracellular Ph (Project 4). State-of-the-art techniques of structural biology are used to study isolated or reconstituted macromolecular complexes. Low resolution structures of individual particles (and/or 2 dimensional arrays) often decorated with site specific labels are obtained by electron microscopy, in particular cryo-EM, combined with image analysis and reconstruction. Detailed structures of individual proteins or protein-lipid complexes are determined by x-ray crystallography. The solution structure of peptides that model regions of proteins or small proteins such as the intracellular fatty acid binding proteins are determined by multi-dimensional NMR. High resolution molecular arrangements can be superimposed onto the low resolution structure of macromolecular assemblies obtained by electron microscopy to generate a "higher resolution" macromolecular structure. These studies can provide the biological structures involved in the processes by which lipids are moved into, within, and out of cells. Such information will allow the development of new molecular based strategies to control hyper beta lipoproteinemia, fatty acid-induced cellular damage in ischemia, and arteriosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: THE FNK KINASE AND VASCULAR CELL GROWTH CONTROL Principal Investigator & Institution: Winkles, Jeffrey A.; Senior Scientist; American National Red Cross Rockville, Md 20855

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Timing: Fiscal Year 2002; Project Start 01-MAY-2001; Project End 30-APR-2005 Summary: (Applicant's abstract): The long-term goal of the research in our laboratory is to understand the molecular mechanisms that regulate growth factor-stimulated cell cycle progression. Most cells in adult, higher organisms are generally in a quiescent nonproliferative state, referred to as the GO phase of the cell cycle. If activated by an appropriate extracellular mitogen, these cells can exit from the resting state and reinitiate cell proliferation. In the context of vascular biology, the onset of endothelial cell (EC) proliferation is associated with the pathogenesis of numerous "angiogenic diseases" (e.g., cancer, diabetic retinopathy) while smooth muscle cell (SMC) accumulation occurs during the development of atherosclerosis, transplant-associated arteriosclerosis and restenosis after vessel wall injury. It is likely that fibroblast growth factor (FGF)- 1 and FGF-2 play an important role in vascular cell growth control. These factors act by binding and thereby activating specific transmembrane receptor tyrosine kinases. This triggers downstream intracellular events, including the stimulation of protein phosphorylation cascades and the transcriptional activation of specific genes. We have used a differential display approach to identify FGF-inducible genes in NIH 3T3 cells and vascular cells. One of these genes, named Fnk, is an immediate-early response gene encoding a member of the polo family of structurally-related serine/threonine kinases. We hypothesize that Fnk expression and enzymatic activity is critical for growth factor-stimulated cell cycle progression. The specific aims of this proposal are: 1) To determine whether the addition of FGF-2 to quiescent murine NIH 3T3 cells promotes changes in Fnk synthesis, phosphoamino acid content, enzymatic activity and subcellular localization, 2) To identify candidate Fnk regulatory proteins and substrates by screening for Fnkbinding proteins, 3) To determine whether Fnk overexpression or underexpression alters NIH 3T3 cell, human microvascular EC, or human aortic SMC proliferation in vitro, and 4) To determine the phenotypic consequences of Fnk deficiency in vivo. It is anticipated that these studies will provide important information on the biological functions of the Fnk protein and its potential role in vascular cell growth control in vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISM

TRANSPLANT

ARTERIOSCLEROSIS:

VIRAL

AND

HOST

Principal Investigator & Institution: Mocarski, Edward S.; Professor; Microbiology and Immunology; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 10-SEP-2001; Project End 30-JUN-2006 Summary: (provided by applicant): The fundamental objective of this Program in Immunopathogenesis of Chronic Graft Rejection is to address "TA: Viral and Host Mechanisms" by understanding pathogenic processes underlying this common manifestation of chronic rejection in heart transplant recipients. The Program Project focuses on the contribution of human cytomegalovirus (HCMV) in conjunction with immunopathogenic and inflammatory modulation that develops in patients who progress to TA. The study involves a large, organized multi-level evaluation of 160 heart transplant recipients. Peripheral blood and endomyocardial biopsy specimens will be collected eight times over the first year and three times in successive years to follow immune, virologic and inflammatory indicators that will be correlated with TA. The first project in this program will focus on the contribution of the HCMV-specific CD4 and CD8 T cell memory/effector function during the reactivation from latent or the initiation of primary infection and the progression to TA. This project will also investigate the activation state of cells. An inverse correlation is expected between the risk of

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progression to TA and the frequency of functional HCMV-specific T cells. The second project of this program will focus on levels of HCMV DNA and the induction of viral gene expression in patients at risk of TA. Sensitive solution and in situ DNA amplification and hybridization approaches will be used to follow viral DNA and mRNA levels in the follow-up period. This project will investigate the role of virus encoded or -induced chemokine (UL146/vCXC-l) and chemokine receptor (US28) expression in progression of TA. The proinflammatory capacity of viral strains and the highly variable UL146 chemokine gene, from patients progressing to TA will be investigated. An increase in virological indicators is expected during progression to TA. The third project will determine the impact of the Nitric Oxide Synthase(NOS) pathway by focusing on two major changes that can be measured in patients: (i) increases in vascular superoxide anion (O2-), and (ii) increases in ADMA. This project will investigate how HCMV infection augments these abnormalities via cytokine induced alterations in oxidative stress and ADMA accumulation. An impact of HCMV on endothelial and inflammatory NOS pathways is expected during progression to TA. Importantly, all three projects will work in parallel in peripheral blood cells/plasma/serum as well as directly in endomyocardial biopsies at all sampling times. Such an intense longitudinal study should provide the best possible setting to uncover associations and identify the contribution of HCMV to TA. The mechanisms, prognostic value and points of therapeutic intervention-directed at HCMV, the immune response to HCMV, immune activation and immunopathogenic events and the role of NOS pathways will all potentially emerge as a result of these collaborative efforts. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TREATMENT OF HCMV IN TRANSPLANT VASCULAR SCELROSIS Principal Investigator & Institution: Hicks, James B.; Virogenomics, Inc. 9020 Sw Washington Square Rd, Ste 140 Tigard, or 972234433 Timing: Fiscal Year 2002; Project Start 20-SEP-2002; Project End 19-MAR-2003 Summary: (provided by applicant): Transplant Vascular Sclerosis (TVS) is an accelerated form of arteriosclerosis that is responsible for significant number of cases of chronic rejection in solid organ transplantation procedures. The incidence of TVS is approximately 15% of patients per year, leading to a prevalence of up to 60% of patients surviving at least 5 years. Among the risk factors identified for chronic rejection through TVS is infection by human cytomegalovirus (H)(CMV), an endemic herpesvirus carried by more than 60% of the U.S. population. (H)CMV infection does not cause noticeable acute disease in healthy individuals, but is implicated in several forms of chronic vascular disease. Recent work by Virogenomics' founding scientists has shown the CMV infection of arterial, but not venous, smooth muscle cells (SMC) results in significant cellular migration in vitro. Migration is dependent of expression of a specific one of the four chemokine receptors encoded by either rodent or human CMV. Virogenomics is testing the hypothesis that blocking the expression or function of US28, the human (HCMV) form of the gene can reduce or eliminate TVS in HCMV infected transplant patients. In this Phase I application we propose to test the effect of antisense molecules on the expression of r33, the rat CMV version of the receptor, and furthermore, to test whether antisense treatment can block SMC migration in vitro. The Phase II goals will extend this antisense strategy into animal models for TVS and eventually to initiate a drug discovery program to identify small molecule blocking human US28 function, with the ultimate goal of developing human therapeutics for the viral component of TVS. PROPOSED COMMERCIAL APPLICATIONS: Successful completion of this Phase I project will lead directly into Phase II animal model studies to determine whether

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antisense interention at the cell surface receptor level can reduce the negative effects of CMV on transplant vascular sclerosis in vivo. The commercial application will either be an antisense drug candidate or a validated assay system that will make it possible to screen for small molecule drug candidates or antibodies that work through this mechanism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRIAL OF RISK MANGEMENT ACCELERATED ATHEROSCLEROSIS IN SLE

FOR

PREVENTION

OF

Principal Investigator & Institution: Liang, Matthew H.; Professor; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002 Summary: For over 20 years it has been known that people with systemic lupus erythematosis are at much higher risk of succumbing to atherosclerotic vascular disease. The precise etiology is not known but the available data suggests that the usual mechanics of & risk factors for arteriosclerosis are operative. These are probably enhanced by other factors such as corticosteroid use and the disease itself. The means of preventing ASVD complication (primary prevention) or their recurrence (secondary prevention) have not been studied. Their proposal for a placebo controlled clinical trials of 3 strategies; to establish proof of concept using a surrogate endpoint a risk model based on the Framingham study. Each arm of the study represents a clinically relevant strategy and incorporates in a styled approach with increasingly proven medications, all are delivered by a novel telephonic risk factor management system. This pilot study will develop important data necessary for a large definitive RCT using clinically endpoints. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VASCULAR TOXICITY OF ALDEHYDES Principal Investigator & Institution: Bhatnagar, Aruni; Professor; Medicine; University of Louisville University of Louisville Louisville, Ky 40292 Timing: Fiscal Year 2003; Project Start 03-APR-2003; Project End 31-DEC-2007 Summary: (provided by applicant): Extensive epidemiological data suggest that exposure to aldehydes or aldehyde-generating pollutants increases the risk of cardiovascular disease. However, the mechanisms by which aldehydes affect cardiovascular health are not known. We propose that exposure to environmental aldehydes such as acrolein or trans-2-hexenal exacerbates arteriosclerosis. Based on our preliminary results, we suggest that aldehyde exposure leads to lipoprotein modification, which induces vascular inflammation, and dysregulates cell growth, thereby resulting in the formation of more extensive, unstable, and cellular lesions. To test this hypothesis in Specific Aim 1 we will examine how exposure to inhaled acrolein or dietary hexenal or acrolein affects the progression of atherogenesis in wild type, apoE and low-density lipoprotein receptor- null mice. We will also determine whether the atherogenecity of aldehydes is modulated by the extent of hypercholestremia. The second aim of the project is to elucidate aldehyde-induced changes in lipoproteins. For this, we will examine the severity and the extent of lipoprotein changes in aldehydeexposed mice and test whether aldehyde exposure causes modification, cross-linking or aggregation of lipoproteins and elicits the development of autoantibodies against protein-aldehyde adducts. Our final aim is to delineate the atherogenic consequences of aldehyde-induced lipoprotein modification. We will establish whether modifications due to aldehyde exposure increase the atherogenicity of lipoproteins, and whether

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aldehydes disrupt cholesterol metabolism by preventing the maturation of the HDL (high-density lipoprotein) particle. Finally, we will examine whether the aldehydeinduced dyslipidemia is due to the inhibition of lecithin: cholesterol acyl transferase (LCAT) and if the dyslipidemic changes are diminished in LCAT-deficient mice. Together the results of this project will provide new information about the effects of the most toxic and abundant pollutants in the environment on arteriosclerosis, and reveal mechanisms by which they contribute to the risk of heart disease - which is the leading cause of death in the industrialized world. Successful completion of these studies will form the basis of future assessment of human risk and susceptibility. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VIRAL CHEMOKINE RECEPTORS: TRANSPLANT VASCULAR SCLEROSIS Principal Investigator & Institution: Orloff, Susan L.; Surgery; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 01-FEB-2001; Project End 31-JAN-2004 Summary: The long term goal of this project is to identify mechanisms involved with human cytomegalovirus (HCMV) acceleration of transplant vascular sclerosis. The primary cause of graft loss of all vascularized organ transplants is due to a vascular lesion associated with chronic rejection. This form of vasculopathy referred to as TVS is characterized by concentric neointimal smooth muscle cell proliferation that results in vessel occlusion and ultimately graft failure. To date the only therapy available to treat severe TVS is retransplantation. Clinical studies in transplant recipients have demonstrated a direct link between HCMV and the acceleration of TVS. Based on these findings, we have developed a rat model of heart and small bowel transplantation in which CMV infection accelerates the time and severity of TVS. While the exact mechanism through which CMV mediates this process is unknown, recent work from our group suggests that CMV may contribute to TVS through induction of smooth muscle cell (SMC) migration towards sites of chemokine production through expression of a virally encoded chemokine receptor (US28). We have also observed that Rat and Murine CMV also induce SMC migration through their respective viral chemokine receptors R33 and M33, which are functional homologues of HCMV US28. We hypothesize that the mechanism of CMV-accelerated TVS involves the expression of virally encoded chemokine receptors leading to intimal SMC migration, which results in the characteristic vascular lesions of TVS. Therefore, we will utilize our in vitro and in vivo models to extend our observations and determine the role of virally encoded chemokine receptors in the development of TVS in three specific aims. First, using a rat cardiac transplant model of chronic rejection, we will determine the effects of virus on the kinetics of disease progression of TVS and the extent of viral expression in tissues as well as the cell types involved in the process. We will also determine the host factors such as chemokines and cytokines, and the contribution of R33 involved at various stages of the development of RCMV-induced TVS. Secondly, we will characterize the R33 domains involved in signaling which induce SMC migration and the ligands, which serve as agonists or antagonists to induced cellular movement. In the last specific, we will generate recombinant RCMV which contain mutations in domains involved in signaling to understand their contribution to TVS in the rat cardiac transplant model. Lastly, antagonists of R33 induced SMC migration in vitro will be tested for their ability to block TVS in the in vivo rat model. These studies will provide a valuable animal model to understand the role of CMV in the acceleration of TVS. In addition completion

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of these studies will form the basis for novel and rational design of therapeutic strategies to enhance long-term graft survival in HCMV infected transplant recipients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VITAMIN E AND ATHEROSCLEROSIS IN LDLR-/-MICE Principal Investigator & Institution: Meydani, Mohsen; Professor of Nutrition; None; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2006 Summary: (provided by applicant): Recent human trials report that for patients with established atherosclerotic lesions, vitamin E (E) treatment does not reverse this process, thus concluding that E supplementation does not reduce mortality from coronary heart disease (CHD). Yet, much convincing epidemiological and experimental evidence indicates the potential preventive rather than therapeutic effect of E supplementation on reducing the risk of arteriosclerosis and CHD. To date, no controlled studies have been conducted to demonstrate the preventive role of E supplementation started at an early age on arteriosclerosis. We hypothesize that "supplementation with vitamin E from an early age prevents or retards the development of atherosclerosis and the risk of CHD in individuals with either Western dietary habits (high fat/cholesterol) or a reduced intake of fat and cholesterol." Since long-life E supplementation studies on humans is not practical, we propose testing this hypothesis on a LDL-receptor deficient (LDLR-/-) mouse by feeding mice: a) moderate or b) high fat/cholesterol diet from the age of 5 wks and supplementing both groups' diets with E starting from ages 5 weeks, 6 and 12 mo, to the age of 18 mo. The extent of aortic lesions will be examined by en face microscopic examination, immunohistochemistry, and molecular techniques. The presence and extent of oxidized LDL, macrophages, T cells, and smooth muscle cell populations, as well as endothelial cells expression of adhesion molecules, ICAM-1, VCAM-1, and PCAM-1, will be measured by immunohistochemistry, while aortic expression of mRNA for adhesion molecules as well as inflammatory cytokines and chemokines will be measured by using RT-PCR analysis. In addition, gene chip microarray techniques will be used to determine responsive genes to dietary interventions. The study's results will provide valuable information on the potential preventive role of E supplementation started early in life compared to middle and later ages in reducing the risk of atherosclerosis, the leading cause of morbidity and mortality from CHD in the US. 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 “arteriosclerosis” (or synonyms) into the search box. This search gives you access 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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to full-text articles. The following is a sample of items found for arteriosclerosis in the PubMed Central database: •

Immunologic Basis of Transplant-Associated Arteriosclerosis. by Shi C, Lee W, He Q, Zhang D, Fletcher DL, Newell JB, Haber E.; 1996 Apr 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39485

•

Role of Infectious and Immune Factors in Coronary and Cerebrovascular Arteriosclerosis. by Stollberger C, Finsterer J.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=119967

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

A novel serotonin blocker, sarpogrelate, increases circulating adiponectin levels in diabetic patients with arteriosclerosis obliterans. Author(s): Yamakawa J, Takahashi T, Itoh T, Kusaka K, Kawaura K, Wang XQ, Kanda T. Source: Diabetes Care. 2003 August; 26(8): 2477-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12882890&dopt=Abstract

•

Determinants of graft arteriosclerosis after heart transplantation. Author(s): Scott CD, Colquhoun IW, Gould K, Au J, Dark JH. Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 1992; 5 Suppl 1: S238-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14621789&dopt=Abstract

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

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•

Effects of lipid abnormalities on arteriosclerosis and hemostatic markers in patients under hemodialysis. Author(s): Kushiya F, Wada H, Sakakura M, Mori Y, Gabazza EC, Nishikawa M, Nobori T, Noguchi M, Izumi K, Nakasaki T, Takagi M, Shiku H. Source: Clinical and Applied Thrombosis/Hemostasis : Official Journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2003 July; 9(3): 203-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14507108&dopt=Abstract

•

Effects of low-density lipoprotein apheresis on plasma matrix metalloproteinase-9 and serum tissue inhibitor of metalloproteinase-1 levels in diabetic hemodialysis patients with arteriosclerosis obliterans. Author(s): Nakamura T, Matsuda T, Suzuki Y, Ueda Y, Koide H. Source: Asaio Journal (American Society for Artificial Internal Organs : 1992). 2003 JulyAugust; 49(4): 430-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12918586&dopt=Abstract

•

Estimating the stenosis probabilities in arteriosclerosis obliterans using generalized estimating equations. Author(s): Nakashima E, Tsuji S, Fukuoka H, Ohtaki M, Ito K. Source: Statistics in Medicine. 2003 July 15; 22(13): 2149-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12820280&dopt=Abstract

•

Homocysteine, Marfan syndrome and arteriosclerosis. Author(s): McCully KS. Source: European Heart Journal. 2003 November; 24(22): 1995-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14613733&dopt=Abstract

•

Peripheral macrohemodynamics in patients with lower limb arteriosclerosis obliterans and type II diabetes mellitus. Author(s): Savel'ev VS, Koshkin VM, Nosenko EM, Dadova LV, Gracheva OA, Koshkina IV, Agafonov VF. Source: Angiol Sosud Khir. 2003; 9(1): 9-20. English, Russian. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12811388&dopt=Abstract

•

Vascular pathology in Alzheimer disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. Author(s): Thal DR, Ghebremedhin E, Orantes M, Wiestler OD. Source: Journal of Neuropathology and Experimental Neurology. 2003 December; 62(12): 1287-301. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14692704&dopt=Abstract

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CHAPTER 2. NUTRITION AND ARTERIOSCLEROSIS Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and arteriosclerosis.

Finding Nutrition Studies on Arteriosclerosis 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 “arteriosclerosis” (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 is a typical result when searching for recently indexed consumer information on arteriosclerosis: •

Combined vitamin C and E supplementation retards early progression of arteriosclerosis in heart transplant patients. Author(s): Vascular Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA. Source: Liu, L Meydani, M Nutr-Revolume 2002 November; 60(11): 368-71 0029-6643

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

A role of oxidative stress-generated eicosanoid in the progression of arteriosclerosis in type 2 diabetes mellitus model rats. Author(s): Second Department of Internal Medicine, Kagawa Medical University, Kagawa, Japan. Source: Shinomiya, K Fukunaga, M Kiyomoto, H Mizushige, K Tsuji, T Noma, T Ohmori, K Kohno, M Senda, S Hypertens-Res. 2002 January; 25(1): 91-8 0916-9636

•

Coronary arteriosclerosis in salmon: growing old or growing fast? Author(s): Department of Biological Sciences, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada. [email protected] Source: Farrell, A P Comp-Biochem-Physiol-A-Mol-Integr-Physiol. 2002 August; 132(4): 723-35 1095-6433

•

Treatment of arteriosclerosis. Author(s): Abteilung fur Kardiologie, Universitatsklinikum Essen, Germany. [email protected] Source: Schmermund, A Erbel, R Dtsch-Med-Wochenschr. 2003 January 3; 128(1-2): 41-7 0012-0472

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

•

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

•

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

•

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

•

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/

•

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

Nutrition

61

•

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

•

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

•

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

•

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

•

Healthnotes: http://www.healthnotes.com/

•

Open Directory Project: http://dmoz.org/Health/Nutrition/

•

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

•

WebMD®Health: http://my.webmd.com/nutrition

•

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

The following is a specific Web list relating to arteriosclerosis; 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: •

Vitamins Vitamin D Alternative names: Calciferol, Calcitrol, Cholecalciferol, Erocalciferol Source: Integrative Medicine Communications; www.drkoop.com

•

Minerals Magnesium Source: Integrative Medicine Communications; www.drkoop.com

•

Food and Diet High Cholesterol Source: Healthnotes, Inc.; www.healthnotes.com

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CHAPTER 3. ALTERNATIVE ARTERIOSCLEROSIS

MEDICINE

AND

Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to arteriosclerosis. 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 arteriosclerosis 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 “arteriosclerosis” (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 arteriosclerosis: •

A preliminary investigation of Tanakan in the treatment of hypertensive arteriosclerosis and stroke in rats. Author(s): Fang Y, Huang R, Zhang Y, Lin J, Li J. Source: Chinese Medical Journal. 2000 May; 113(5): 425-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11776097&dopt=Abstract

•

Combined vitamin C and E supplementation retards early progression of arteriosclerosis in heart transplant patients. Author(s): Liu L, Meydani M. Source: Nutrition Reviews. 2002 November; 60(11): 368-71. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12462519&dopt=Abstract

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•

Molecular biology of transplant arteriosclerosis and sites of therapeutic intervention. Author(s): Hayry P, Aavik E, Palgi M, Petrov L, Savolainen H, Luoto NM, Loubtchenkov M, Frosen J. Source: Transplantation Proceedings. 2001 February-March; 33(1-2): 293-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11266824&dopt=Abstract

•

Recipient cells form the intimal proliferative lesion in the rat aortic model of allograft arteriosclerosis. Author(s): Johnson P, Carpenter M, Hirsch G, Lee T. Source: American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2002 March; 2(3): 207-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12096782&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/

•

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

•

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

•

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

•

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

Alternative Medicine 65

The following is a specific Web list relating to arteriosclerosis; 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 Arteriosclerosis Source: Integrative Medicine Communications; www.drkoop.com Atherosclerosis and Heart Disease Prevention Source: Prima Communications, Inc.www.personalhealthzone.com Heart Attack Source: Healthnotes, Inc.; www.healthnotes.com High Triglycerides Source: Healthnotes, Inc.; www.healthnotes.com Parkinson's Disease Source: Integrative Medicine Communications; www.drkoop.com

•

Alternative Therapy Chelation Therapy Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,679,00.html

•

Herbs and Supplements Aesculus Alternative names: Horse Chestnut; Aesculus hippocastanum L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Aortic Glycosaminoglycans Source: Prima Communications, Inc.www.personalhealthzone.com Calciferol Source: Integrative Medicine Communications; www.drkoop.com Calcitrol Source: Integrative Medicine Communications; www.drkoop.com Cherry Fruit Extract Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10015,00.html Cholecalciferol Source: Integrative Medicine Communications; www.drkoop.com

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EDTA Source: Integrative Medicine Communications; www.drkoop.com Erocalciferol Source: Integrative Medicine Communications; www.drkoop.com Ethylenediaminetetraacetic Acid (EDTA) Source: Integrative Medicine Communications; www.drkoop.com Flaxseed Alternative names: Linum usitatissimum, Linseed Source: Integrative Medicine Communications; www.drkoop.com Linden Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca Linseed Source: Integrative Medicine Communications; www.drkoop.com Linum Usitatissimum 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 ARTERIOSCLEROSIS Overview In this chapter, we will give you a bibliography on recent dissertations relating to arteriosclerosis. 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 “arteriosclerosis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on arteriosclerosis, we have not necessarily excluded non-medical dissertations in this bibliography.

Dissertations on Arteriosclerosis 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 arteriosclerosis. 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 Noninvasive Viscoelastic Pressure-flow Measurement of Human Carotid Artery to Follow the Progression of Arteriosclerosis by Horvath, Istvan, PhD from Rutgers the State U. of N.J. - New Brunswick and U.M.D.N.J., 2003, 156 pages http://wwwlib.umi.com/dissertations/fullcit/3093015

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 ARTERIOSCLEROSIS Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning arteriosclerosis.

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

Cardio Vascu-Grow for treatment of coronary heart disease Condition(s): Coronary Disease; Coronary Heart Disease; Myocardial Ischemia; Coronary Arteriosclerosis Study Status: This study is currently recruiting patients. Sponsor(s): Cardio Vascular Genetic Engineering; Cardiovascular Clinical Research Purpose - Excerpt: Treatment for no-options heart patients with coronary artery disease. Procedure involves the injection into the heart of a protein growth factor that stimulates the growth of new blood vessels around blocked coronary arteries. Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00032318

•

Clopidogrel for High Atherothrombotic Management and Avoidance (CHARISMA)

Risk

Condition(s): Arteriosclerosis Study Status: This study is currently recruiting patients. Sponsor(s): Sanofi-Synthelabo 8

These are listed at www.ClinicalTrials.gov.

and

Ischemic

Stabilization,

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Arteriosclerosis

Purpose - Excerpt: RATIONALE: * Atherothrombosis is a progressive and generalized vascular disease resulting in events leading to myocardial infarction (heart attack), stroke, and vascular death. * In patients at risk for this disease, it is characterized by an unpredictable, sudden disruption of atherosclerotic plaques, which may lead to total occlusion of artery due to formation of a clot. The use of aspirin (blood thinner agent) for reducing those major ischemic events is either indicated, or recommended by international guidelines. However, aspirin fails to prevent a high percentage of such lifethreatening events. Therefore, more effective blood thinning therapy may provide additional clinical benefit to such patients. * The results of the CURE trial in patients with unstable angina demonstrate the additional benefit of long-term treatment (up to one year) with clopidogrel, (a blood thinner agent), when administered in combination with standard therapy including aspirin. The purpose of CHARISMA is to investigate whether a similar clinical benefit of clopidogrel may apply to a broad population of high-risk patients receiving low-dose aspirin therapy. Such population includes patients with previous cardiovascular, neurovascular or peripheral arterial manifestations of atherothrombosis and patients with combinations of recognized risk factors for atherosclerosis. Objectives: * To assess the efficacy of clopidogrel 75 mg once-daily by comparison with a placebo, in preventing cardiovascular morbidity/mortality. The study will compare the efficacy of the two regimens in preventing the occurrence of major cardiovascular complications (stroke, heart attack, cardiovascular death) in highrisk patients who are otherwise receiving low-dose aspirin therapy (75-162 mg daily). * To evaluate the safety of clopidogrel in this population, and more specifically the incidence of fatal or severe bleeding (as per GUSTO definition), in order to estimate the global benefit of clopidogrel in this patient population. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00050817 •

Dietary Nitrate and Nitrite to Increase Nitric Oxide in Patients with Coronary Artery Disease Condition(s): Coronary Arteriosclerosis Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: This study will determine whether dietary nitrates and nitrites can produce nitric oxide in the body and dilate blood vessels in patients with coronary artery disease. Nitric oxide is normally made by endothelial cells that line blood vessels. It plays an important role in maintaining the normal function of arteries by keeping them open and preventing damage from substances such as cholesterol in the blood stream. Coronary artery disease is caused by atherosclerosis (hardening of the arteries or build-up of cholesterol and scar tissue within the walls of the arteries). Once arteries become clogged, the ability of the endothelium to produce nitric oxide diminishes considerably and may speed up the disease process, leading to shortness of breath, chest pain, and an increased risk of heart attack or stroke. Patients 21 years of age and older with coronary artery disease may be eligible for this study. Participants will have a medical history and physical examination, electrocardiogram (recording of the electrical activity of the heart), echocardiogram (ultrasound test of the heart), treadmill exercise stress test (see below), and will meet with a dietitian. They will be hospitalized at the NIH Clinical Center on two occasions. For 1 week before each admission, they will

Clinical Trials 71

follow a diet prescribed by an NIH nutritionist. The diet before one admission will be high in nitrates and nitrites, and the diet before the other admission will be low in nitrates and nitrites. Each admission will last 4 days, during which participants will undergo the following tests: - Forearm blood flow study: Small tubes are placed in the artery and vein at the inside of the elbow of the dominant arm (right- or left-handed) and a small tube is placed in a vein of the other arm. The tubes are used for infusing saline (salt water) and for drawing blood samples. A pressure cuff is placed around the upper part of the dominant arm, and a rubber band device called a strain gauge is also placed around the arm to measure blood flow. When the cuff is inflated, blood flows into the arm, stretching the strain gauge at a rate proportional to the flow. Maximum grip-strength of the dominant arm is measured with a dynamometer. Forearm blood flow is measured and blood samples are drawn at the following times: 20 minutes after the tubes are placed; during a hand-grip exercise; and 4 minutes after the exercise is completed. - Brachial artery reactivity study: This test measures how well the patient's arteries widen. For the procedure, the patient rests on a bed for 30 minutes. An ultrasound measuring instrument is then placed over the artery just above the elbow. The artery size and the flow of blood through it are measured before and after a pressure cuff around the forearm is inflated. Fifteen minutes later, the same measurements are taken before and 3 minutes after a nitroglycerin tablet is placed under the patient's tongue. Treadmill exercise testing: Patients exercise on a treadmill until they experience chest pain, shortness of breath, or tiredness. The patient's heart rhythm is monitored continuously and blood pressure is measured every 3 minutes. A nurse and doctor are in attendance throughout the study. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00069654 •

The Effect of Exercise on Stem Cell Mobilization and Heart Function in Patients Undergoing Cardiac Rehabilitation Condition(s): Coronary Arteriosclerosis Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: This study will look at the effect of a cardiac rehabilitation exercise program on release of stem cells from the bone marrow and on heart function. Stem cells are primitive cells produced and released by the bone marrow, circulate in the bloodstream and develop into white blood cells, red blood cells and platelets. Some stem cells may also develop into other kinds of cells, including those that make up heart muscle, especially if the heart has been damaged or is not getting sufficient blood. Stem cells called endothelial progenitor cells (EPCs) are thought to form new blood vessels that can carry blood to areas of the heart muscle that are oxygen-deprived because of clogged arteries. Previous experiments have shown that some EPCs can be forced out of the bone marrow by exercise. This study will examine whether repeated exercise and lifestyle changes increase the number of EPCs released into the bloodstream and if these cells improve heart and blood vessel function. Patients 21 years of age and older with coronary artery disease may be eligible for this study. Candidates will be screened with a medical history and physical examination, including a cardiovascular evaluation, and blood tests. The participants will be enrolled in a 2- to 3-month cardiac rehabilitation program that includes 24 to 36 60-minute sessions of exercise, plus instruction on

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lifestyle changes related to diet, stress management, and relaxation techniques. In addition, participants will undergo the following tests and procedures: - Brachial reactivity study: This test measures how well the arteries widen. The patients rest for 30 minutes, and then an ultrasound device is placed over the artery just above the elbow. The device measures the size of the artery and blood flow through it before and after the patient is given a spray of nitroglycerin under the tongue. - Blood tests for EPC levels and genetic testing: These measure EPCs and determine whether certain genes that may regulate EPC function are turned on or off. Genes are made up of DNA, the molecules that lead to the production of proteins by cells. Some of these proteins may be important in releasing EPCs from the bone marrow to travel in the bloodstream to the heart and repair blood vessels and muscle cells. - Treadmill exercise testing: Patients exercise on a treadmill with continuous monitoring of the heartbeat and frequent measurements of oxygen saturation, using a finger clip device. The patient continues to exercise until moderate chest pain, shortness of breath, or fatigue develops. - Questionnaire: Patients fill out a 15-minute questionnaire about their general physical and mental health status at the first and last visits to the clinic. - Magnetic resonance imaging (MRI) of the heart: Patients who are eligible to undergo MRI have this test twice during the study, once before beginning the rehabilitation program and again after completing the program. The MRI shows heart function and blood flow in the heart. For this test, the patient lies on a stretcher inside a long narrow cylinder (the scanner). During the scan, the drug dipyridamole, which increases blood flow to the heart, is infused into a vein of the hand or arm. Another drug, gadolinium, is also infused to brighten the images produced. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00053456 •

Androgens and Subclinical Atherosclerosis in Young Women - Ancillary to CARDIA Condition(s): Cardiovascular Diseases; Coronary Arteriosclerosis; Heart Diseases; Polycystic Ovary Syndrome Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To examine whether serum androgens, measured earlier in life, and variation in genes related to androgen synthesis, metabolism, and signaling are associated with early-onset subclinical coronary atherosclerosis in young adult women from the community. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00037245

•

Aortic Calcium: Epidemiology and Progression -- Ancillary to MESA Condition(s): Cardiovascular Diseases; Heart Diseases; Atherosclerosis; Coronary Arteriosclerosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To study the epidemiology of aortic calcium. Study Type: Observational

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Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00059124 •

Arterial Endothelial Function--An Epidemiologic Study Condition(s): Cardiovascular Diseases; Heart Diseases; Coronary Arteriosclerosis; Carotid Artery Diseases Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine if risk factors measured in childhood can predict the development of atherosclerotic coronary and carotid artery disease in adulthood. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005545

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Epidemiology of Carotid IMT Progression in MESA - Ancillary Study Condition(s): Atherosclerosis; Cardiovascular Diseases; Heart Diseases; Carotid Artery Diseases; Coronary Arteriosclerosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine the factors associated with progression of sub-clinical atherosclerosis and to evaluate the associations between the progression of sub-clinical atherosclerosis and the development of clinically manifest atherosclerosis. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00063440

•

Epidemiology of Coronary Artery Calcification Condition(s): Cardiovascular Diseases; Atherosclerosis; Coronary Arteriosclerosis; Heart Diseases; Coronary Disease Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Using subjects from the Rochester Family Heart Study (RFHS), to characterize predictors of coronary artery calcification (CAC), a potent marker of atherosclerosis, among individuals from the general population. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005349

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Epidemiology of Coronary Calcification in the Elderly Condition(s): Cardiovascular Diseases; Heart Diseases; Coronary Arteriosclerosis; Coronary Disease; Hypertension Study Status: This study is no longer recruiting patients.

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Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To investigate the prevalence and prognostic value of subclinical atherosclerosis in the Pittsburgh SHEP cohort and a cohort of normal controls. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005756 •

Epidemiology: Oxidative Stress and Early Atherosclerosis Condition(s): Cardiovascular Diseases; Heart Diseases; Atherosclerosis; Coronary Arteriosclerosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To measure serum concentrations of alpha tocopherol, selenium and all major carotenoids (alpha- and beta- carotene, lutein, (beta-cryptoxanthin and lycopene) in Black and white, male and female, high and low education individuals aged 18-30 in 1985-86. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005393

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Family Blood Pressure Program - GENOA Condition(s): Cardiovascular Diseases; Heart Diseases; Hypertension; Coronary Arteriosclerosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To localize, identify, and evaluate common polymorphic variation in genes involved in determining interindividual differences in blood pressure (BP) levels and essential hypertension status in three racial groups: African-Americans, MexicanAmericans, and Non-Hispanic Whites. The study consists of a six grant network, which in turn is part of an NHLBI initiative, the Family Blood Pressure Program consisting of four networks. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005269

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Family Heart Study - Subclinical Atherosclerosis Network (FHS-SCAN) Condition(s): Cardiovascular Diseases; Heart Diseases; Atherosclerosis; Coronary Arteriosclerosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine familial and non-familial causes for susceptibility to atherosclerosis and the inflammatory response.

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Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00024596 •

Gene-by-Smoking Interactions and Risk of Atherosclerosis - Ancillary to ARIC Condition(s): Atherosclerosis; Cardiovascular Diseases; Heart Diseases; Coronary Disease; Carotid Artery Diseases; Peripheral Vascular Diseases; Cerebral Arteriosclerosis; Cerebrovascular Accident Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To evaluate common genetic variations, that in combination with exposure to tobacco smoke, may modify the risk of atherosclerosis. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00064545

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Genetics of Coronary Artery Disease in Alaskan Natives Condition(s): Heart Diseases; Cardiovascular Diseases; Atherosclerosis; Hypertension; Diabetes Mellitus; Coronary Arteriosclerosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To document cardiovascular disease and cardiovascular disease risk factors among 1,200 Native Alaskans who are members of approximately 40 families. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006192

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High Density Lipoprotein Subspecies and Coronary Disease Condition(s): Cardiovascular Diseases; Coronary Disease; Coronary Arteriosclerosis; Heart Diseases Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To investigate the relative contributions of high density lipoprotein-C (HDL-C) subspecies to risk for coronary heart disease (CHD) in two distinct existing populations (samples from the VA-HIT study and the Framingham Offspring Study [FOS]) as well as the response of these subfractions to gemfibrozil treatment. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005676

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Arteriosclerosis

Inflammation Genomics and Atherosclerosis - Ancillary to CARDIA Condition(s): Cardiovascular Diseases; Atherosclerosis; Coronary Arteriosclerosis; Inflammation; Heart Diseases; Thrombosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To examine the associations of common variation in inflammation/thrombosis genes with intermediate quantitative phenotypes and subclinical coronary atherosclerosis in the Coronary Artery Risk Factor Development in Young Adults (CARDIA) Study, a large, bi-racial cohort study. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00046605

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Multi-Ethnic Study of Atherosclerosis (MESA) Condition(s): Atherosclerosis; Cardiovascular Diseases; Heart Diseases; Coronary Arteriosclerosis; Coronary Disease; Cerebrovascular Accident; Myocardial Infarction; Heart Failure, Congestive; Heart Failure; Diabetes Mellitus, non-insulin dependent; Hypertension; Diabetes Mellitus Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To conduct a prospective observational study of the characteristics of subclinical cardiovascular disease (disease detected non-invasively before it has produced signs and symptoms) that predict progression to clinically overt cardiovascular disease in a diverse and representative population-based sample of men and women aged 35-84. Specifically the study shall: determine characteristics related to progression of subclinical to clinical cardiovascular disease; identify factors related to newer measures of subclinical disease and examine relationship of new to established measures; and develop population-based methods, suitable for application in future screening and intervention studies, for identifying asymptomatic persons at highest risk of clinical events. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005487

•

Multi-Ethnic Study of Atherosclerosis (MESA) - Ancillary Eye Study Condition(s): Atherosclerosis; Cardiovascular Diseases; Coronary Arteriosclerosis; Coronary Disease; Cerebrovascular Disorders; Heart Failure, Congestive; Myocardial Infarction; Heart Diseases; Diabetes Mellitus, non-insulin dependent; Hypertension; Diabetic Retinopathy; Macular Degeneration; Diabetes Mellitus Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To evaluate the relation of retinal microvascular characteristics to subclinical cardiovascular disease, clinical disease, and their risk factors in the MultiEthnic Study of Atherosclerosis (MESA) cohort.

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Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00041444 •

Myocardial Perfusion, Risk Factors, and Coronary Calcium Condition(s): Cardiovascular Diseases; Coronary Arteriosclerosis; Coronary Disease; Heart Diseases Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine whether an impairment of myocardial perfusion reserve is an early indicator of coronary artery disease. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006502

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Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Condition(s): Cardiovascular Diseases; Atherosclerosis; Heart Diseases; Coronary Disease; Coronary Arteriosclerosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To conduct a multicenter prevalence survey for characterizing pathologically the extent of atherosclerosis in the aortas and coronary arteries of young persons dying from accidental causes, suicide, or homicide. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005679

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Prevalence & Progression of Subclinical Atherosclerosis Condition(s): Atherosclerosis; Cardiovascular Diseases; Coronary Arteriosclerosis; Carotid Artery Diseases; Menopause Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To evaluate subclinical atherosclerotic disease in menopausal women. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006503

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Serum Sex Hormone Levels and Subclinical Atherosclerosis - Ancillary to MESA Condition(s): Cardiovascular Diseases; Atherosclerosis; Coronary Arteriosclerosis; Coronary Disease; Heart Diseases

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Arteriosclerosis

Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To assess the associations of serum sex hormones with the presence and progression of subclinical atherosclerosis. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00064532 •

Sex Steroid Hormones and Risk of CHD in Women Condition(s): Cardiovascular Diseases; Postmenopause; Coronary Arteriosclerosis

Heart

Diseases;

Coronary

Disease;

Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To investigate the relationship between endogenous estrogen and androgen levels and risk of coronary heart disease among postmenopausal women in the Women's Health Initiative-Observational Study (WHI-OS). Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006407 •

South Bay Heart Watch (SBHW) Progression of Coronary Calcium Study Condition(s): Cardiovascular Diseases; Coronary Arteriosclerosis; Coronary Disease; Heart Diseases Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To assess changes in coronary calcium measured by electron beam computed tomography (EBCT) as a predictor of coronary heart disease (CHD) events. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006497

•

Ventricular Size and Value Calcification Measures by Computed Tomography Ancillary to MESA Condition(s): Cardiovascular Diseases; Heart Diseases; Atherosclerosis; Coronary Arteriosclerosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To rescan 6,700 subjects in the MESA study to obtain computed tomography measures of calcification. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00065780

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•

Women's Antioxidant and Cardiovascular Study (WACS) Condition(s): Cardiovascular Diseases; Coronary Arteriosclerosis; Coronary Disease; Heart Diseases; Myocardial Infarction; Myocardial Ischemia Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine if supplements of vitamin C, vitamin E, and betacarotene reduce all major cardiovascular events in high risk women with a prior history of atherosclerotic cardiovascular disease. The trial is piggybacked on the Women's Health Study (WHS), a primary prevention trial of vitamin Eand aspirin in a low risk population of women. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000541

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Antioxidants and Prevention of Early Atherosclerosis Condition(s): Cardiovascular Diseases; Carotid Artery Diseases; Cerebral Arteriosclerosis; Cerebrovascular Disorders; Heart Diseases; Vascular Diseases; Atherosclerosis Study Status: This study is suspended. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To evaluate the effects of vitamin E supplementation in retarding the progression of common carotid artery intima-media thickening in African Americans. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000600

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Apolipoprotein A-I Gene Polymorphism and Atherosclerosis Condition(s): Coronary Arteriosclerosis; Cardiovascular Diseases; Heart Diseases; Atherosclerosis Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To further define the linkage of the Apo A-I gene polymorphism to genetic high density lipoprotein (HDL) deficiency and premature coronary artery disease. Also, to utilize this gene marker to define the prevalence of genetic HDL deficiency in patients with premature coronary disease and to determine the relative risk of premature coronary disease associated with the Apo A-I gene polymorphism. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005183

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Apolipoprotein Polymorphisms and Risk of Coronary Heart Disease Condition(s): Cardiovascular Diseases; Heart Diseases; Coronary Arteriosclerosis; Coronary Disease Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine the relative risk in a defined population of angiographically demonstrated coronary artery disease due to genetic polymorphisms at the four apolipoprotein genomic regions. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005225

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Asymptomatic Carotid Artery Plaque Study (ACAPS) Condition(s): Cardiovascular Diseases; Carotid Stenosis; Cerebral Arteriosclerosis; Cerebrovascular Disorders; Heart Diseases; Vascular Diseases Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine whether warfarin or lovastatin alone or in combination retarded the progression of atherosclerotic plaques in the carotid arteries of high risk individuals with asymptomatic carotid stenosis. Also, to determine if a full scale trial was feasible. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000469

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Atherosclerosis and Omega-3 Fatty Acids in Alaskan Natives Condition(s): Cardiovascular Diseases; Heart Diseases; Atherosclerosis; Coronary Arteriosclerosis Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine whether there were differences in the prevalence and extent of atherosclerotic lesions in the coronaries and aortas between Alaskan natives and non-natives, and whether the extent of the lesions was related to omega-3 fatty acids in blood and tissues. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005236

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Central Obesity and Disease Risk in Japanese Americans Condition(s): Cardiovascular Diseases; Heart Diseases; Atherosclerosis; Hypertension; Obesity; Diabetes Mellitus, non-insulin dependent; Hyperinsulinism; Insulin Resistance; Coronary Arteriosclerosis; Diabetes Mellitus; Metabolic Syndrome X Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To conduct a longitudinal study of central obesity and related risk factors found to be associated with hypertension and atherosclerotic cardiovascular disease (ASCVD) in a previously-examined cross-sectional cohort of second-generation Japanese Americans and in a newly-recruited cohort of third generation Japanese Americans. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005365

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Childhood Passive Smoking: Cohort Study of Cardiac Risk Condition(s): Cardiovascular Diseases; Heart Diseases; Lung Diseases; Coronary Arteriosclerosis Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine the effects of long-term exposure to passive smoking on the cardiovascular and oxygen transport systems in pre-adolescent twins. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005242

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Cholesterol-Lowering Atherosclerosis Study (CLAS) Condition(s): Arterial Occlusive Diseases; Cardiovascular Diseases; Carotid Artery Diseases; Cerebral Arteriosclerosis; Cerebrovascular Disorders; Coronary Arteriosclerosis; Coronary Disease; Heart Diseases; Myocardial Ischemia; Atherosclerosis Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine whether combined therapy with the lipid lowering agents colestipol hydrochloride plus niacin would produce significant change in coronary, carotid, and femoral artery atherosclerosis and coronary bypass graft lesions as determined by angiography. Also, to determine possible correlations between lesion changes and plasma lipid and lipoprotein cholesterol levels and to explore interrelationships of atherosclerosis change in femoral, coronary, and carotid arteries. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000599

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Correlates of Angiographic Changes and Coronary Events Condition(s): Cardiovascular Diseases; Coronary Disease; Coronary Arteriosclerosis; Heart Diseases Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To examine the appropriateness of angiographic and ultrasound endpoints as predictors of subsequent clinical coronary events. Follow-up data from the Cholesterol Lowering in Atherosclerosis Study (CLAS) were used. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005433

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Endothelial Progenitor Cells and Risk Factors for Coronary Artery Disease Condition(s): Coronary Arteriosclerosis Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: This study will measure and compare the levels of endothelial progenitor cells (EPCs) in the blood of people with and without risk factors for atherosclerosis (hardening of the arteries) to see if there is a relationship between these cells and cardiovascular risk factors such as smoking, high cholesterol level and high blood pressure. Healthy male volunteers between the ages of 21 and 55 years with and without heart disease risk factors may be eligible for this study. Candidates must have no evidence of coronary or peripheral vascular disease, proliferative retinopathy, or other chronic disease and no history of cancer, migraine-type headache, cluster headache, raised intraocular pressure, raised intracranial pressure, hyperthyroidism. Participants will undergo the following procedures at the NIH Clinical Center: - Medical history and physical examination - Blood tests to measure EPC level and various risk and growth factors - Brachial reactivity study - This ultrasound study tests how well the subject's arteries widen. The subject rests on a bed for 30 minutes. An ultrasound measuring device is placed over the artery just above the elbow. The size of the artery and blood flow through it are measured before and after inflating a pressure cuff around the forearm. The pressure cuff stops the flow of blood to the arm for a few minutes. After a 15-minute rest, the drug nitroglycerin is sprayed under the subject's tongue. Before the nitroglycerin spray and 3 minutes after it, the size of the artery and blood flow through it are measured again. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00013975

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Epidemiology of Atherosclerosis Condition(s): Atherosclerosis; Cardiovascular Diseases; Heart Diseases; Coronary Arteriosclerosis Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI)

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Purpose - Excerpt: To determine the role of genetic factors in predicting resistance and susceptibility to coronary artery disease. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005147 •

Epidemiology of Coronary Heart Disease in Men Aged 40 and Over Condition(s): Atherosclerosis; Coronary Arteriosclerosis; Coronary Disease; Heart Diseases; Cardiovascular Diseases Study Status: This study is not yet open for patient recruitment. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To examine whether the prevalence of subclinical coronary and aortic atherosclerotic disease is different among Japanese in Japan, Japanese in Hawaii, and black and white Americans. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00069797

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Estrogen and Graft Atherosclerosis Research Trial (EAGER) Condition(s): Cardiovascular Diseases; Coronary Arteriosclerosis; Coronary Disease; Heart Diseases; Myocardial Ischemia; Postmenopause Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine if postmenopausal hormone replacement therapy in women following coronary bypass surgery will reduce the occurrence of graft occlusion and delay the development of graft atherosclerosis. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000605

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Estrogen Replacement and Atherosclerosis (ERA) in Older Women Condition(s): Cardiovascular Diseases; Coronary Arteriosclerosis; Coronary Disease; Heart Diseases; Myocardial Ischemia; Postmenopause Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine if estrogen replacement therapy, with or without low dose progesterone, slows progression or induces regression of coronary atherosclerosis in postmenopausal women. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below

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Web Site: http://clinicaltrials.gov/ct/show/NCT00000549 •

Familial Atherosclerosis Treatment Study (FATS) Condition(s): Cardiovascular Diseases; Coronary Arteriosclerosis; Coronary Disease; Heart Diseases; Myocardial Ischemia Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To compare the effects of two intensive lipid-lowering regimens with conventional therapy on coronary atherosclerosis as assessed by arteriography. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000512

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Lifestyle Heart Trial Condition(s): Cardiovascular Diseases; Coronary Arteriosclerosis; Coronary Disease; Heart Diseases; Hypercholesterolemia; Hypertension; Myocardial Ischemia Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To assess long-term effects of a strict lifestyle change program on lipids, blood pressure, myocardial perfusion, and coronary atherosclerosis. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000471

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Magnetic Resonance Imaging of Narrowed Arteries Condition(s): Arteriosclerosis Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: This study will compare four methods of imaging arteries: angiography (x-ray picture) - intravascular ultrasound (ultrasound from inside the artery) - magnetic resonance imaging (MRI) from outside the body - MRI using an antenna to take pictures inside the arteries of the pelvis Standard angiography shows blockages inside the artery, but does not provide any information about the arterial wall itself. New ways of looking at the artery walls with MRI and ultrasound may provide insight into how arteries cause disease. Patients 21 years of age and older who require catheterization and angiography of the heart, kidney, or leg arteries because of atherosclerosis (narrowing of the arteries), may be eligible for this study. Participants will undergo MRI and intravascular ultrasound of the arteries immediately after their catheterization and angiography. The additional imaging will add from 1 to 2 hours to the angiogram procedure. - Angiography: Using the sheaths already in place in the groin artery, catheters (flexible plastic tubes) are placed inside the arteries in order to

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inject a contrast dye to take x-ray pictures. (Patients who had an angiogram of the leg artery as part of their medical care will not repeat this test.) - Intravascular ultrasound: An anti-clotting drug called heparin is given through a vein to prevent clot formation. Blood samples are taken during the test to see if more heparin is needed. Special wires are used to guide the catheters to the proper location inside the arteries. A special ultrasound catheter is advanced over one of these wires to the large artery that supplies blood to the legs. X-rays are used to help the physician place the ultrasound in the correct location to take ultrasound pictures of the artery wall. - Magnetic resonance imaging: A special MRI catheter is advanced through the catheter in the groin. With the catheter in place, the patient is carried to a stretcher and moved into a long metal cylinder (the MRI scanner) for imaging. During the scanning, a contrast drug called gadolinium is injected into an arm vein to brighten the images. The patient is able to speak through a microphone at all times to the person taking the pictures. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00029575 •

Pooling of Cohort Studies on Diet & Coronary Disease Condition(s): Coronary Arteriosclerosis; Cardiovascular Diseases; Heart Diseases Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To quantify the role of dietary factors in the etiology of coronary heart disease by pooling data from 12 major prospective studies on diet and coronary heart disease used a comprehensive assessment of diet. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006309

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Stanford Coronary Risk Intervention Project (SCRIP) Condition(s): Cardiovascular Diseases; Coronary Arteriosclerosis; Coronary Disease; Heart Diseases; Myocardial Ischemia Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine whether modification of risk factors altered the rate of progression of coronary artery disease in arteries with mild atherosclerosis and no mechanical intervention in patients who had coronary bypass surgery or percutaneous transluminal coronary angioplasty (PTCA). Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000508

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Women's Angiographic Vitamin and Estrogen Trial (WAVE) Condition(s): Cardiovascular Diseases; Coronary Arteriosclerosis; Coronary Disease; Heart Diseases; Myocardial Ischemia; Postmenopause Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To assess whether hormonal replacement therapy and/or antioxidant treatment would stabilize or inhibit progression, and induce regression of coronary plaques. The mechanisms by which these treatments modified atherosclerosis in women were also explored. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000555

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 “arteriosclerosis” (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: •

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 ARTERIOSCLEROSIS 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 “arteriosclerosis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on arteriosclerosis, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Arteriosclerosis By performing a patent search focusing on arteriosclerosis, 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 arteriosclerosis: •

Amino- and amido-diphenyl ethers Inventor(s): Bischoff; Hilmar (Wuppertal, DE), Faeste; Christiane (Haan, DE), Haning; Helmut (Wuppertal, DE), Kretschmer; Axel (Wuppertal, DE), Pernerstorfer; Josef (Wuppertal, DE), Schmidt; Gunter (Wuppertal, DE), Vohringer; Verena (Wuppertal, DE), Woltering; Michael (Wuppertal, DE) Assignee(s): Bayer Aktiengesellschaft (leverkusen, De) Patent Number: 6,555,580 Date filed: July 31, 2001 Abstract: The invention relates to novel amino- and amido-diphenyl ethers, processes for their preparation and their use in pharmaceuticals, in particular for the indications of arteriosclerosis and hypercholesterolaemia. Excerpt(s): European Application 580 550 A (Ciba Geigy; 1994) describes oxamic acid derivatives having cholesterol-lowering properties in mammals. This application describes an in vitro test based on the binding to thyroid hormone cell receptors (socalled T.sub.3 nuclear receptors). The pharmacological property which is stressed is the reduction in plasma cholesterol, in particular LDL cholesterol. Cholesterol-lowering effects are also described in the European Application EP-A-188 351 (SKF; 1986) for certain diphenyl ethers with thyroid hormone-like effects. and the respective salts and hydrates thereof show a pharmacological effect and can be used as pharmaceuticals or for producing pharmaceutical formulations. Web site: http://www.delphion.com/details?pn=US06555580__

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Bile salt conjugates Inventor(s): Gilat; Tuvia (Tel Aviv, IL) Assignee(s): Galmed International Limited (b'kara, Mt) Patent Number: 6,589,946 Date filed: February 21, 2002 Abstract: The present invention relates to bile acid or bile salt fatty acid conjugates (hereinafter called "BAFAC), to their use in dissolving cholesterol gallstones in bile, preventing their occurrence or recurrence, to their use in reducing or preventing arteriosclerosis and to methods for the treatment of said diseases. The conjugates are of the formula W--X--G in which G is a bile acid or bile salt radical, W stands for one or two saturated fatty acid radicals and X is either a direct bond or a bonding member between bile acid or bile salt and the fatty acid(s). The conjugation is advantageously performed at a position selected among the 3, 6, 7, 12 and 24 positions of the bile acid or bile salt nucleus. The fatty acids are preferably saturated fatty acids having 6-26 carbon atoms. Excerpt(s): The present invention relates to bile acid or bile salt fatty acid conjugates (hereinafter called "BAFAC"), to their use in dissolving cholesterol gallstones in bile, preventing their occurrence of recurrence, to their use in reducing or preventing arteriosclerosis and to methods for the treatment of said diseases. It should be noticed

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that the terms bile acids and bile salts are similar and are used interchangeably. Gallstones are found in about 15% of people in most industrialized countries. Most gallstones are cholesterol gallstones, i.e. cholesterol being their main component. Thus, cholesterol gallstones represent a major health problem. Bile is often supersaturated with cholesterol which tends to crystallize. The prevention of cholesterol crystallization in bile will prevent the formation of cholesterol gallstones or their recurrence after procedures such as lithotripsy, dissolution, or stone extraction. The residence time of newly secreted bile in the gallbladder is short--less than 12-24 hours. The prevention of cholesterol crystallization in bile during such a period could prevent gallstone formation. Web site: http://www.delphion.com/details?pn=US06589946__ •

Catechin multimers as therapeutic drug delivery agents Inventor(s): Larson; Drake (P.O. Box 355, Thermal, CA 92274) Assignee(s): None Reported Patent Number: 6,562,864 Date filed: May 3, 2002 Abstract: Described herein are catechin multimers, and particularly substituted catechin multimers, and their use as carrier moieties for the delivery of nucleophilic and cationic bioactive therapeutic agents to target sites in vivo. For example, substituted catechin multimers of the present invention may be administered alone, for the treatment of stenotic vascular diseases and disorders, such as atherosclerosis (also known as arteriosclerosis) and coronary heart disease (also known as coronary artery disease and ischemic heart disease). Alternatively, catechin multimers, substituted and otherwise, may be complexed with nucleophilic and/or cationic bioactive therapeutic agents, such as anti-thrombotic agents, cholesterol lowering agents, anti-plaque agents, anti-cancer agents, chemotherapeutic agents, anti-inflammatory agents, antibiotics, antimicrobials, wound healing agents, and the like, for the treatment of a variety of diseases and disorders, including but not limited to cardiac and vascular stenoses, cancer, inflammatory conditions, neurological conditions, infection, wounds, burns and the like. The catechin multimers, particularly the substituted catechin multimers, described herein have a strong affinity for polar proteins residing in the vascular endothelium as well as cell walls and membranes, and, accordingly, are able to provide targeted delivery of bioactive agents embedded therein and/or complexed therewith so as to potentiate their therapeutic effects. The therapeutic complexes may be pharmaceutically formulated "neat" (e.g., without additives) or with additives such as pharmaceutical carriers, diluents, buffers, adjuvants, excipients, surfactants, and stabilizers. Excerpt(s): The present invention is related to catechin multimers and their use as carrier moieties for the delivery of nucleophilic and/or cationic bioactive therapeutic agents to target sites in vivo. For example, substituted catechin multimers of the present invention may be administered alone, for the treatment of stenotic vascular diseases and disorders, such as atherosclerosis (also known as arteriosclerosis) and coronary heart disease (also known as coronary artery disease and ischemic heart disease). Alternatively, catechin multimers, substituted and otherwise, may be complexed with nucleophilic and/or cationic bioactive therapeutic agents, such as anti-thrombotic agents, cholesterol lowering agents, anti-plaque agents, anti-cancer agents, chemotherapeutic agents, anti-inflammatory agents, antibiotics, antimicrobials, wound healing agents, and the like, for the treatment of a variety of diseases and disorders,

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including but not limited to, vascular and cardiac stenoses, cancer, inflammatory conditions, neurological conditions, infections, burns, wounds, etc. Catechin multimers, particularly the substituted catechin multimers described herein, have a strong affinity for polar proteins residing in the vascular endothelium as well as the walls and membranes of other select cells and tissues, and, accordingly, are able to provide targeted delivery of bioactive agents embedded therein and/or complexed therewith so as to potentiate their therapeutic effects. Many diseases or disorders are characterized by localized pathology, i.e., affecting only select cells, tissues or organs. Examples of such diseases or disorders include but are not limited to cancers, stenotic vascular disorders such as atherosclerosis (or arteriosclerosis), inflammatory disorders, infections, wounds, burns, and certain neurological conditions. Treatment modalities for such diseases often rely on the ability to target bioactive agents to a diseased region or tissue in the body of a patient, while minimizing or preventing action of the bioactive agents on other regions or tissues in the body, such as undiseased regions or tissues. In other words, in treating such conditions, it is desirable to direct the appropriate drug to the affected area while at the same time avoiding unacceptable or toxic side effects to healthy tissue. Targeted drug delivery means are particularly important where the toxicity of the drug is an issue. Specific tissue targeting drug delivery methods potentially serve to minimize toxic side effects, lower the required dosage amounts, and decrease costs for the patient. Various methods for targeted delivery of bioactive agents are described in the literature. For example, one method involves the use of liposomes as delivery vehicles. Alternatively, structural features, such as receptor proteins and cell-specific antigens, have also been used in targeting delivery of a bioactive agent to a particular region or tissue. However, such structural features are associated with one or, at most a few, disease states. In addition, incomplete or irregular expression of such structural features may further limit their usefulness in targeted delivery of bioactive agents. Moreover, delivery of effective doses of bioactive agents to target cells is hampered by many factors, including but not limited to, low residence times in serum, ineffective targeting, loss of the therapeutic agent in solution before it may be taken up by the target cell, and degradation of the therapeutic in the endosomic/lysosomic pathway. Web site: http://www.delphion.com/details?pn=US06562864__ •

Cocoa powder rich in polyphenols, process for producing the same and modified cocoa containing the same Inventor(s): Tanaka; Masahiro (Saitama, JP), Terauchi; Masakazu (Saitama, JP) Assignee(s): Meiji Seika Kaisha, Ltd. (tokyo, Jp) Patent Number: 6,485,772 Date filed: December 15, 2000 Abstract: The invention provides a treating process of cacao beans, and more particularly cacao powder rich in polyphenols, a process for the preparation thereof and a prepared cacao composed of the cacao powder. According to the invention, the polyphenol contained in the cacao beans is allowed to remain as much as possible, by setting initial water content in the roasting treatment to 3-10% by weight. Although polyphenols have various favorable biological functions of anti-oxidating action, antidental cariesing action, action for preventing arteriosclerosis and so on, but those are unfavorable from the view point of taste because of astringency and bitterness. In a conventional process for preparing cacao powder, therefore, an operation for removing polyphenols has been carried out, but in the invention, the astringency and bitterness

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are inhibited by setting water content of the cacao nib to 3-10% by weight in the alkali treatment prior to the roasting treatment. Therefore, the invention provides a high functional cacao powder with good taste. Excerpt(s): The present invention relates to a process for treating cacao beans and more particularly, a cacao powder rich in polyphenols, process for the preparation thereof and prepared cacao comprising the same. A conventional cacao powder has been prepared through steps of crushing washed raw cacao beans to remove a shell and embryo and obtain a cacao nib, treating with an alkali the cacao nib, roasting the cacao nib, grinding the roasted cacao nib, expressing oil, and pulverizing the oil expressed substance. In general, the alkali and roasting treatments are started with such initial conditions that an amount of water is 10-25% by weight inclusive of moisture in the cacao nib and pH is 6.8-8.0. Web site: http://www.delphion.com/details?pn=US06485772__ •

Composition comprising soy protein, dietary fibres and a phytoestrogen compound and use thereof in the prevention and/or treatment of cardiovascular diseases Inventor(s): H.o slashed.ie; Lars Henrik (London, GB) Assignee(s): Nutri Pharma Asa (oslo, No) Patent Number: 6,630,178 Date filed: August 13, 2001 Abstract: A composition comprising (a) soy protein, (b) a phytoestrogen compound, and (c) dietary fibers. The soy protein (a) is present in an amount of at least 45 weight percent of the total protein content of the composition, said total protein content providing at least 15 percent of the total energy content of the composition. The phytoestrogen compound (b) is preferably a naturally occuring isoflavone and is present in an amount of more than 0.10 weight percent of the soy protein, and the dietary fibers (c) are preferably soybean fibers and are present in an amount of more than 4 weight percent of the total weight of the nutritional composition on a dry basis. The composition is useful in lowering serum cholesterol and LDL-cholesterol and serum triglyceride levels and for increasing the HDL/LDL-cholesterol ratio in serum of a subject suffering from arteriosclerosis and related cardiovascular diseases. Excerpt(s): The present invention relates to soy protein, phytoestrogens and dietary fibres and compositions thereof suitable for preventing, alleviating and/or treating cardiovascular diseases such as arteriosclerosis, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hypertension and related cardiovascular diseases. In particular a composition according to the present invention has improved effects in lowering levels of total serum cholesterol and LDL-cholesterol. A composition according to the present invention is also particularly useful in reducing the accumulation of cholesterol in the arterial wall of subjects at high risk for developing cardiovascular disease or already suffering from a cardiovascular disease such as atherosclerosis. A composition according to the present invention is also useful for lowering serum levels of total cholesterol and/or LDL-cholesterol and/or triglycerides and/or homocystein and/or for increasing serum levels of HDL-cholesterol and/or for improving the HDL/LDLratio in subjects at risk for developing cardiovascular diseases and in subjects already suffering from an arteriosclerotic condition such as e.g. atherosclerosis or a related cardiovascular disease. The present invention also relates to the use of these compositions in the manufacture of a medicament for treating a subject suffering from

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cardiovascular diseases, more particularly arteriosclerosis, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hypertension and/or related cardiovascular diseases. The present invention also concerns use of a composition according to the present invention in the prevention and/or treatment of said diseases and disorders and for lowering serum levels of total cholesterol and/or LDL-cholesterol and/or triglycerides and/or serum levels of homocystein in subjects. In addition, the present invention also provides methods for preventing and/or treating and/or prophylactically treating and/or alleviating by therapy said diseases and disorders. Lipid metabolism involves biosynthesis and degradation of e.g. fatty acids, triglycerides and cholesterol. Ingested triglycerides are hydrolysed in the small intestine and hydrolysis products are absorbed by the intestinal mucosa. Due to the relative insolubility of dietary lipids in water, lipid digestion and absorption is facilitated by the action of detergent substances such as bile acids secreted from the gallbladder. Bile acids are essential for lipid digestion and absorption through the intestinal mucosa. Triglycerides and cholesterol synthesized in the liver are transported in the bloodstream to peripheral tissues by transport proteins called lipoproteins. Lipoproteins are tiny vesicles coated by apoproteins, phospholipids and free cholesterol and with an interior consisting of the more hydrophobic lipids, cholesteryl esters and triglycerides. Apoproteins and lipoproteins are primarily synthesized in the liver. The lipoproteins are capable of performing an apoprotein mediated binding to a receptor on the surface of a cell into which the entire lipoprotein particle is taken up and further metabolised. Web site: http://www.delphion.com/details?pn=US06630178__ •

Contulakin-G, analogs thereof and uses thereof Inventor(s): Craig; A. Grey (Solana Beach, CA), Cruz; Lourdes J. (Manila, PH), Griffen; David (Greenville, NC), Hillyard; David R. (Salt Lake City, UT), Imperial; Julita (Salt Lake City, UT), Jones; Robert M. (Salt Lake City, UT), Layer; Richard T. (Sandy, UT), McCabe; R. Tyler (Salt Lake City, UT), Olivera; Baldomero M. (Salt Lake City, UT), Wagstaff; John D. (Salt Lake City, UT), Watkins; Maren (Salt Lake City, UT) Assignee(s): Cognetix, Inc. (salt Lake City, Ut) Patent Number: 6,489,298 Date filed: June 29, 2000 Abstract: The present invention is directed to contulakin-G (which is the native glycosylated peptide), a des-glycosylated contulakin-G (termed Thr.sub.10 -contulakinG), and derivatives thereof, to a cDNA clone encoding a precursor of this mature peptide and to a precursor peptide. The invention is further directed to the use of this peptide as a therapeutic for anti-seizure, anti-inflammatory, anti-shock, anti-thrombus, hypotensive, analgesia, anti-psychotic, Parkinson's disease, gastrointestinal disorders, depressive states, cognitive dysfunction, anxiety, tardive dyskinesia, drug dependency, panic attack, mania, irritable bowel syndrome, diarrhea, ulcer, GI tumors, Tourette's syndrome, Huntington's chorea, vascular leakage, anti-arteriosclerosis, vascular and vasodilation disorders, as well as neurological, neuropharmalogical and neuropsychopharmacological disorders. Excerpt(s): The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference, and for convenience are numerically referenced in the following text and respectively grouped in the appended bibliography. Mollusks of the genus Conus produce a venom that enables them to carry

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out their unique predatory lifestyle. Prey are immobilized by the venom that is injected by means of a highly specialized venom apparatus, a disposable hollow tooth that functions both in the manner of a harpoon and a hypodermic needle. Web site: http://www.delphion.com/details?pn=US06489298__ •

Cyclopeptide derivatives Inventor(s): Diefenbach; Beate (Darmstadt, DE), Goodman; Simon Lawrence (Darmstadt, DE), Jonczyk; Alfred (Darmstadt, DE), Kessler; Horst (Garching, DE), Sutter; Arne (Darmstadt, DE) Assignee(s): Merck Patent Gesellschaft (darmstadt, De) Patent Number: 6,566,491 Date filed: August 18, 1998 Abstract: The invention relates to compounds of the formula (I) R.sup.1 --Q.sup.1 --X-Q.sup.2 --R.sup.2, in which: Q.sup.1, Q.sup.2, each independent of one another, are missing or are --NH--(CH.sub.2).sub.n --CO--; R.sup.1, R.sup.2, each independent of one another, are missing or are cyclo-(Arg-Gly-Asp-Z), wherein Z is missing in side chain of Q.sup.1 or Q.sup.2 of if Q.sup.1 and/or Q.sup.2 missing, is bound to X, at least one of the groups R.sup.1 or R.sup.2 always having to be included; X is --CO--R.sup.18 --CO--, and if R.sup.1 --Q.sup.1 -- or R.sup.2 --Q.sup.2 -- are missing is R.sup.10, R.sup.13, HetCO or a flourescent pigment residue linked through a --CONH--, --COO--, NH-C(.dbd.S)--N--, --NH--C(.dbd.O)--NH--, --SO.sub.2 NH--or --NHCO-- bond; and Z, R.sup.10, R.sup.13, R.sup.16, R.sup.18, Het and n have the meaning given in claim 1. The invention also relates to the salts of said compounds. These compounds and their salts can be used as integrin inhibitors, in particular for the prevention and treatment of circulatory diseases, thrombosis, heart infarct, coronary heart diseases, arteriosclerosis, angiogenic diseases and in tumor therapy. Excerpt(s): where, provided that the residues are residues of optically active amino acids and amino acid derivatives, both the D and the L forms are included, and the salts thereof. Similar compounds of cyclic peptides are disclosed in DE 43 10 643. The invention was based on the object of discovering novel compounds possessing valuable properties, in particular those compounds which can be used for preparing pharmaceuticals. Web site: http://www.delphion.com/details?pn=US06566491__

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Cyclopeptide derivatives with integrin inhibitor properties Inventor(s): Finsinger; Dirk (Munchen, DE), Jonczyk; Alfred (Darmstadt, DE), Kantlehner; Martin (Freising, DE), Kessler; Horst (Schwalbach, DE), Meyer; Jorg (Egelsbach, DE), Nies; Berthold (Frankisch-Crumbach, DE) Assignee(s): Merck Patent Department (de) Patent Number: 6,610,826 Date filed: June 15, 2000 Abstract: Compounds of the formula IR--Q--X I,in which R, Q, and X are as defined herein, can be used as integrin inhibitors. In particular, compounds of formula I are suitable for the treatment of disorders caused by implants, defects, inflammations and of

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osteolytic disorders such as osteoporosis, thrombosis, cardiac infarct and arteriosclerosis. These compounds are also suitable for the acceleration and reinforcement of the integration process of implants and biocompatible surfaces into tissue. Excerpt(s): and their salts. Similar cyclic peptide compounds are disclosed in DE 43 10 643 and DE 195 38 741. The compound cyclo-(Art-Gly-Asp-Glu(.epsilon.-Ahx-CysNH.sub.2)-D-Val) is disclosed by D. Delforge et al. in Anal. Biochem. 242, 180-186 (1996). The invention is based on the object of finding novel compounds having valuable properties, in particular those which can be used for the production of medicaments. Web site: http://www.delphion.com/details?pn=US06610826__ •

Fat or oil composition Inventor(s): Katsuragi; Yoshihisa (Tokyo, JP), Masui; Kenji (Tokyo, JP), Toi; Tomoko (Tokyo, JP), Yasukawa; Takuji (Tokyo, JP) Assignee(s): Kao Corporation (tokyo, Jp) Patent Number: 6,495,536 Date filed: October 26, 1999 Abstract: Described is a fat or oil composition which comprises at least 35 wt. % of a diacylglycerol, the constituent fatty acids of said diacylglycerol satisfying the following equation: (an amount of a cis-form unsaturated fatty acid)/(an amount of a saturated fatty acid+an amount of a trans-form unsaturated fatty acid).gtoreq.6. Usual intake of the above-described composition as an edible oil makes it possible to reduce arteriosclerotic factors in blood, leading to the prevention of arteriosclerosis, furthermore, various degenerative diseases. Excerpt(s): The present invention relates to a fat or oil composition capable of reducing arteriosclerotic factors in blood when taken, similarly to a usual fat or oil, in the daily life. Arteriosclerosis is a risk factor of various circulatory diseases such as hypertension and thrombosis. Arteriosclerosis is caused by hypercholesterolemia, formation of thrombus or the like. The state of a high total cholesterol level is generally called hypercholesterolemia. The cholesterol in blood is classified into HDL, LDL, VLDL and the like by specific gravity. Among them, LDL is a principal risk factor of arteriosclerosis, while HDL is said to be useful for the prevention of arteriosclerosis. It is therefore important to increase the HDL cholesterol level in blood for the prevention of arteriosclerosis. On the other hand, local formation of thrombi in blood is also considered as one of the factors of arteriosclerosis. When the activity of plasminogen activator inhibitor type 1 (PAI-1) which serves to control the production of plasmin, that is, fibrinolysin in blood is exasperated, the production of plasmin is suppressed and formation of thrombi tends to occur. It is therefore essential to lower the activity of PAI1 for the prevention of arteriosclerosis. Web site: http://www.delphion.com/details?pn=US06495536__

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Indole and dihydroindole derivatives Inventor(s): Ackermann; Jean (Riehen, CH), Aebi; Johannes (Basel, CH), Dehmlow; Henrietta (Grenzach-Wyhlen, DE), Morand; Olivier (Hegenheim, FR), Panday; Narendra (Basel, CH), Weller; Thomas (Binningen, CH) Assignee(s): Hoffmann-la Roche Inc. (nutley, Nj) Patent Number: 6,503,907 Date filed: November 20, 2001 Abstract: The present invention relates to indole derivatives, dihydroindole derivatives and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof. The compounds are useful for the treatment and/or prophylaxis of diseases which are associated with 2,3-oxidosqualene-lanosterol cyclase such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, gallstones, tumors and/or hyperproliferative disorders, and treatment and/or prophylaxis of impaired glucose tolerance and diabetes. Excerpt(s): The present invention is concerned with novel indole and dihydroindole derivatives, their manufacture and their use as medicaments. 2,3-oxidosqualenelanosterol cyclase (EC 5.4.99.) is required for the biosynthesis of cholesterol, ergosterol and other sterols. Causal risk factors that directly promote the development of coronary and peripheral atherosclerosis include elevated low-density lipoprotein cholesterol (LDL-C), low high-density lipoprotein cholesterol (HDL-C), hypertension, cigarette smoking and diabetes mellitus. Other synergistic risk factors include elevated concentrations of triglyceride (TG)-rich lipoproteins, small, dense low-density lipoprotein particles, lipoprotein (a) (Lp(a)), and homocysteine. Predisposing risk factors modify the causal or conditional risk factors and thus affect atherogenesis indirectly. The predisposing risk factors are obesity, physical inactivity, family history of premature CVD, and male sex. The strong connection between coronary heart disease (CHD) and high LDL-C levels in plasma, and the therapeutic advantage of lowering elevated LDL-C levels are now well established (Gotto et al., Circulation 81, 1990, 17211733; Stein et al., Nutr. Metab. Cardiovasc. Dis. 2, 1992, 113-156; Illingworth, Med. Clin. North. Am. 84, 2000, 23-42). Cholesterol-rich, sometimes unstable, atherosclerotic plaques lead to the occlusion of blood vessels resulting in an ischemia or an infarct. Studies with respect to primary prophylaxis have shown that a lowering of plasma LDLC levels in plasma reduces the frequency of non-fatal incidences of CHD, while the overall morbidity remains unchanged. The lowering of plasma LDL-C levels in patients with pre-established CHD (secondary intervention) reduces CHD mortality and morbidity; meta-analysis of different studies shows that this decrease is proportional to the reduction of the LDL-C (Ross et al., Arch. Intern. Med. 159, 1999, 1793-1802). The clinical advantage of cholesterol lowering is greater for patients with pre-established CHD than for asymptomatic persons with hypercholesterolemia. According to current guidelines, cholesterol lowering treatment is recommended for patients who had survived a myocardial infarct or patients suffering from angina pectoris or another atherosclerotic disease, with a target LDL-C level of 100 mg/dl. Web site: http://www.delphion.com/details?pn=US06503907__

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Isolated nucleic acids encoding activated and suppressive forms of ATF6 Inventor(s): Haze; Kyosuke (Shizuoka, JP), Mori; Kazutoshi (Kyoto, JP), Yanagi; Hideki (Tekarazuka, JP), Yoshida; Hiderou (Shiga, JP), Yura; Takashi (Kyoto, JP) Assignee(s): Hsp Research Institute, Inc. (osaka, Jp) Patent Number: 6,635,751 Date filed: August 13, 2001 Abstract: A factor capable of efficiently regulating expression of an endoplasmic chaperone gene, a nucleic acid encoding it, a complementary strand nucleic acid thereof, a method for regulating expression of an endoplasmic reticulum chaperone gene, and a method for expressing a foreign gene is provided. The endoplasmic reticulum stress transcription factor is capable of regulating transcription-inducing activity, wherein the transcription-inducing activity is exhibited by an element having the nucleotide sequence shown in SEQ ID NO:1 or an element having a nucleotide sequence resulting from substitution of 1 to 3 bases with other bases in the nucleotide sequence as shown in SEQ ID NO:1. A method for controlling expression of an endoplasmic reticulum chaperone, comprising expressing the factor; a method for expressing a foreign protein, comprising positively regulating expression of an endoplasmic reticulum chaperone gene by the method for controlling expression; and a nucleic acid encoding activated form of ATF6, activated form of CREB-RP, suppressive form of ATF6, or suppressive form of CREB-RP, or the complementary strand thereto are also provided. It is expected to be applied to treatment or prophylaxis of cancers, arteriosclerosis, cystic fibrosis, ischemic diseases, wounds or ulcers. Excerpt(s): The present invention relates to a factor capable of efficiently regulating expression of an endoplasmic reticulum chaperone gene, a nucleic acid encoding it or a complementary strand nucleic acid thereof, a method for regulating expression of an endoplasmic reticulum chaperone gene, and a method for expressing a foreign gene. Mammalian cells, like other eukaryotic cells and prokaryotic cells, have developed a number of homeostatic mechanisms to cope with to various physiological and environmental conditions that threaten their survival. Among them, the tightly regulated synthesis of heat shock proteins (HSPs) is a well-known mechanism universally found in all organisms. In addition, the regulated synthesis of glucoseregulated proteins (GRPs), based on a mechanism differing from that of HSP described above, is specifically found in eukaryotic endoplasmic reticulum [Lee, A. S., Curr. Opin. Cell Biol. 4, 267-273 (1992); Morimoto, R. I. et al., The Biology of HEAT SHOCK PROTEINS and MOLECULAR CHAPERONES, Cold Spring Harbor Laboratory (1994)]. In mammals, eight kinds of GRPs, namely, GRP78/Bip, GRP94/ERp99, ORP150/GRP170, ERp72, GRP58/ERp60/ERp61, calreticulin, protein disulfide isomerase (PDI) and FKBP13, have been identified. These GRPs are a series of molecular chaperones or folding enzymes characteristic of the endoplasmic reticulum, each of which expression is induced by the accumulation of proteins that have failed to be folded or have undergone incorrect folding (hereinafter referred to as unfolded proteins) in the endoplasmic reticulum (endoplasmic reticulum stress) [Kozutsumi, Y. et al., Nature 332, 462-464 (1988); Lee, A. S., Trends Biochem. Sci. 12, 20-23 (1987)], and play a very important role in the folding of nascent secretory proteins and membrane proteins in the endoplasmic reticulum. Therefore, these GRPs are hereinafter generically referred to as "endoplasmic reticulum chaperones". Web site: http://www.delphion.com/details?pn=US06635751__

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Lecithin-cholesterol acyltransferase protein Inventor(s): Taniyama; Yoshio (Tsukuba, JP) Assignee(s): Takeda Chemical Industries, Ltd. (osaka, Jp) Patent Number: 6,498,019 Date filed: October 4, 1999 Abstract: This invention relates to a novel protein having a lecithin-cholesterol acyltransferase-like activity, etc. or its salt, a precursor protein of the protein or its salt, a partial peptide of the protein or its salt; a DNA coding for the protein; a recombinant vector; a transformant; a method for producing the protein, a pharmaceutical composition comprising the protein, the partial peptide or its salt; and an antibody to the protein or the partial peptide. The protein, the partial peptide or its salt, and the DNA are useful as an agent for treating or preventing arteriosclerosis, atherosclerosis, hyperlipidemia, hypercalorism, obesity or hypertriglyceridemia. The antibody can be used in assay of the protein, the partial peptide or its salt. The protein, the partial peptide or its salt is useful as a reagent for the screening for candidate medical compounds. Excerpt(s): The present invention relates to a novel protein having a lecithin-cholesterol acyltransferase-like activity etc. and a DNA coding for the protein. Cholesterol is an important lipid constituting the animal cell membrane and defining its character. Moreover, it is a precursor of steroid hormones, thus being a substance essential to animal life. However, due to the recent changes in dietary habit and ecology, arteriosclerosis and other adult diseases arising from pathological intracellular accumulation of cholesterol are now presenting a serious problem so that elucidation of the mechanisms of cholesterol metabolism in the body is being awaited. In the efflux of cholesterol from the peripheral cells, high density lipoprotein (hereinafter sometimes referred to briefly as HDL) is suspected to play a cardinal role and this assumption has been supported by the epidemiologic finding of an inverse correlation between risk for coronary artery disease and plasma HDL levels and the experimental finding that HDL in culture medium stimulates cholesterol efflux from cells and decreases the intracellular concentration of cholesterol (Journal of Lipid Research, 37, 2473, 1996). In the reverse cholesterol transport system, lecithin-cholesterol acyltransferase (hereinafter sometimes referred to briefly as LCAT) is involved to a significant extent. Web site: http://www.delphion.com/details?pn=US06498019__

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Ligands of nuclear receptor Inventor(s): Ando; Kunio (Kanagawa, JP), Magae; Junji (Ibaraki, JP), Tamura; Gakuzo (Tokyo, JP), Uchida; Takafumi (Kanagawa, JP) Assignee(s): Nuclear Receptor Research, Ltd. (kanagawa, Jp) Patent Number: 6,605,639 Date filed: June 14, 2001 Abstract: It has been newly found out that ascochlorin, which is a publicly known fatsoluble antibiotic, and its homologues serve as a ligand of retinoid X receptor and react in vivo with the amino group of serum protein to form Schiff bases without showing any side effect of retinoid. Ascochlorin and its homologues are usable in treating and/or preventing a disease or condition which can be relieved by the retinoid X receptor

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ligand-dependent gene transcriptional regulation (for example, diseases caused by the expression of insulin resistance, hypertension, cerebrovascular diseases, rheumatoid arthritis, autoimmune disease, Ca metabolic disorder, complication of diabetes, arteriosclerosis, etc.). Moreover, they can inhibit denaturation and/or necrosis of pancreatic Langerhans islet.beta.-cells and, therefore, are usable in making these cells to sustain the insulin productivity. Excerpt(s): This invention relates to ligands of retinoid X receptor and pharmaceutical compositions for treating and/or preventing diseases which can be alleviated by the retinoid X receptor ligand (RXRL)-dependent transcriptional regulation of certain genetic information. Diseases to be treated and/or prevented by use of the pharmaceutical compositions according to the present invention involve life-style related diseases. From the viewpoint of treating the life-style related diseases, there is an urgent need to develop drugs for use in the treatment of various vascular lesions causative of the onset of the life-style related diseases. Ischemic heart disease, which is prevalent when vascular lesions are present, is also referred to as coronary sclerosis. It is thought that around fifty percent of all deaths in the world are attributable this disease. Ischemic heart disease is the leading cause of death in most developed countries, and the second biggest cause of death in Japan. In addition it is estimated that the incidence of ischemic heart disease will rapidly increase in developing countries also. Major causes of ischemic heart disease, appear to include genetic factors, eating habits, stress, diabetes and hypertension. It is known that ischemic heart disease is closely related to life-style including diet. Hyperlipemia and hyperinsulinemia, which are induced by the excessive intake of high caloric diets, promote sedimentation of low density lipoproteins which are rich in cholesterol on the arterial wall. Degeneration of sedimented low density lipoproteins causes damage to the arterial wall; and leukocytes react to the damage in the arterial wall and infiltrate it to repair the lesion, resulting in chronic inflammation. Thus the mechanism of arteriosclerosis is understood to be as follows: In response to damage of arterial wall, leukocytes, which attempt to repair the damage, cause excessive inflammation which has the effect of thickening the arterial wall, resulting in a sclerosing lesion. Typical examples of known drugs for preventing ischemic heart disease are hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors. These HMG-CoA reductase inhibitors, which inhibit the biosynthesis of mevalonic acid as a rate-determining step in the biosynthesis of cholesterol, reduce the amount of cholesterol synthesized in the liver and thus lower the cholesterol content in the low density lipoprotein which is synthesized in the liver and released into the serum. That is to say, the main function of these drugs resides in inhibiting the biosynthesis of cholesterol and lowering the cholesterol content in the serum, thereby reducing the low density lipoprotein incorporated from the serum into the arterial wall depending on the concentration. Namely, these drugs exert a merely indirect and preventive effect. These HMG-CoA reductase inhibitors exhibit no effect on the sclerosing lesions associated with chronic inflammation which thickens the arterial wall in which macrophages and lymphocytes participate. Thus, it is impossible to achieve any direct therapeutic effect for healing chronic inflammation of an artery. An ideal remedy and/or preventive treatment for arteriosclerosis is a drug which shows an effect of lowering serum cholesterol level and, at the same time, a therapeutic and/or preventive effect on chronic inflammation induced by the sedimentation of cholesterol on the arterial wall. It is expected that such a drug, if any, would serve as an ideal remedy and/or preventive treatment for ischemic heart disease. Web site: http://www.delphion.com/details?pn=US06605639__

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Lipoproteins as nucleic acid vectors Inventor(s): Hoogeveen; Ron C. (Houston, TX), Moore; J. Paul (Stafford, TX) Assignee(s): Baylor College of Medicine (houston, Tx) Patent Number: 6,635,623 Date filed: May 14, 1998 Abstract: The present invention relates to materials and methods for the in vivo transport and deliver of nucleic acids. More particularly, it concerns the use of lipoproteins, including but not limited to, low density lipoproteins ("LDL"), and/or apolipoproteins for the binding and in vivo transport of nucleic acids. In addition, the present invention relates to the use of lipoproteins in the early detection of cancer and/or metastatic cancer and/or arteriosclerosis. Excerpt(s): The present invention relates to materials and methods for the in vivo transport and delivery of nucleic acids. More particularly, it concerns the use of lipoproteins, including but not limited to, low density lipoproteins ("LDL"), and/or apolipoproteins for the in vivo transport of nucleic acids. In addition, the present invention relates to the use of lipoproteins in the early detection of cancer and/or metastatic cancer and/or arteriosclerosis. The ultimate curative method for any genetic disorder, whether the disorder is inherited or results from a mutation, depends on an effective mode of replacing or augmenting non-functional gene(s). This process is now termed gene or genetic therapy. There are two important aspects to genetic therapy, the gene delivery system/vehicle and the gene control/expression program. Ideally, a replacement gene should become resident in the genome of the target cells/organism and be transferable to subsequent generations of cells and progeny, i.e., the change is incorporated into the germ cells or reproductive cells, the sperm and ovary. Although there have been several significant breakthroughs in this field, this area of biotechnology is still in its early development phase. The first step in any approach to gene replacement is the delivery of the specific gene (nucleic acid) to the cells. Many techniques have been and are being developed to deliver and express genes in cells and specific tissues in mammals in vivo. Several general, non-specific methods for delivering genes have been reported involving aerosol nucleic acid delivery to cells (Stribling et al., 1992); calcium phosphate precipitation, using a steep change in ionic strength (Wigler et al., 1979); DEAE-dextran (Sompayrac et al., 1981); electroporation, forcing the nucleic acid into the cell by using an electric field or current (Neumann et al., 1982); microinjection, physically injecting the nucleic acid into a cell (Benvensty et al., 1986; Wolff et al., 1990); and polycationic molecules such as polylysine polypeptides (Curiel et al., 1992) and cationic lipids (Lee et al., 1996). Web site: http://www.delphion.com/details?pn=US06635623__

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Method and apparatus for monitoring the cardiovascular condition, particularly the degree of arteriosclerosis in individuals Inventor(s): Keren; Hanan (Kfar Saba, IL) Assignee(s): Cheetah Medical Ltd. (kfar Saba, Il) Patent Number: 6,676,608 Date filed: May 23, 2000

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Abstract: A method and apparatus for monitoring the presence of arteriosclerosis in an individual includes detecting an ECG signal of the individual's heart, detecting a blood front wave in a peripheral artery of the individual, and measuring the time lag between a predetermined reference point of the detected blood front wave and a predetermined reference point in the ECG signal to provide an indication of the cardiovascular condition of the individual, particularly arteriosclerosis or arterial obstruction. Excerpt(s): The present invention relates to a non-invasive and simplified method and apparatus for monitoring the cardiovascular condition of an individual. The invention is particularly useful for monitoring the degree of arteriosclerosis and/or arterial obstruction in an individual, and is therefore described below with respect to this application. Arteriosclerosis is a condition in which arteries become thick and hard and loose their supple and elastic quality primarily as a result of aging and the deposit of fats, etc. on the vessel walls. It accounts for a large proportion of heart attacks and ischemic conditions produced by an inadequate blood supply to a region caused by a constriction or obstruction of a blood vessel in the arterial vascular system. It also accounts for many strokes, numerous instances of peripheral vascular disease, and most aneurysms of the aorta, which can rupture and cause fatal hemorrhage. The loss of elasticity of, and the deposit of fats on the artery walls are believed to be part of the normal aging process. However, arteriosclerosis is more likely to occur, or to increase in severity, in individuals who are overweight, smoke, have high blood pressure, suffer from diabetes, or have a family history of high cholesterol. Many techniques have been devised, both non-invasive and invasive, for monitoring the cardiovascular condition of an individual, and particularly for detecting the degree of arteriosclerosis or arterial obstruction that may be present. Web site: http://www.delphion.com/details?pn=US06676608__ •

Methods of using pomegranate extracts for causing regression in lesions due to arteriosclerosis in humans Inventor(s): Aviram; Michael (Kiriat-Haim, IL), Dornfeld; Leslie (Los Angeles, CA) Assignee(s): Stewart and Lynda Resnick Revocable Trust (los Angeles, Ca) Patent Number: 6,641,850 Date filed: November 19, 2001 Abstract: Methods of using pomegranate extracts of the present invention for treating patients with atherosclerosis, or increased intima-media thickness of an artery, are provided. The methods comprise the step of administering to the patient a composition comprising a therapeutically effective amount of an extract from pomegranate. The methods of the present invention may also be used to decrease the incidence of stroke or heart attack in a patient. Excerpt(s): The invention relates generally to pomegranate extracts and methods of using thereof, and specifically to methods of using pomegranate extracts for causing regression in lesions due to arteriosclerosis in humans. Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citation for these references may be found at the end of this application, preceding the claims. Oxidative stress, a major contributor to cardiovascular diseases (1), is associated with lipid peroxidation in arterial macrophages and in lipoproteins (1-3). Oxidized low-

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density lipoprotein (Ox-LDL) was shown to be atherogenic (2-4), thus, interventions to inhibit LDL oxidation by dietary antioxidants (4, 5) is of major importance to attenuate atherosclerosis. It was recently shown that vitamin E supplementation to patients with carotid artery stenosis inhibited LDL accumulation in arterial macrophages (6). Protection of lipids from oxidation can be also achieved by serum paraoxonase (PON1, an HDL-associated esterase that can hydrolyze and reduce specific lipid peroxides in arterial cells and lipoproteins in coronary and carotid lesions (7-10). Web site: http://www.delphion.com/details?pn=US06641850__ •

Pharmaceutical compositions and methods for the treatment of arteriosclerosis Inventor(s): Fujiwara; Toshihiko (Ebina, JP), Maeda; Naoyuki (Zushi, JP), Sada; Toshio (Tokyo, JP), Tsujita; Yoshio (Ichikawa, JP) Assignee(s): Sankyo Company, Limited (tokyo, Jp) Patent Number: 6,610,682 Date filed: August 21, 2001 Abstract: A pharmaceutical composition comprising as its active ingredients one or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, and one or more insulin resistance improving agents exhibits excellent arteriosclerotic progress inhibitory effects, and is useful as a drug, particularly as a drug for the prevention or treatment of arteriosclerosis. The invention also provides a method for the treatment or prophylaxis of arteriosclerosis by administering in combination (i) at least one of said angiotensin II receptor antagonists or angiotensin converting enzyme inhibitors and (ii) one or more insulin resistance improving agents to a mammal suffering from or susceptible to arteriosclerosis. The invention also provides kits containing at least a first container which comprises at least one angiotensin II receptor antagonists and/or angiotensin converting enzyme inhibitor and a second container which contains at least one insulin resistance improving agent. Excerpt(s): The present invention relates to a pharmaceutical composition comprising as its active ingredients one or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, and one or more insulin resistance improving agents (particularly a pharmaceutical composition for prevention or treatment of arteriosclerosis), a kit including a first container comprising one or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, and a second container comprising one or more insulin resistance improving agents for preparing a pharmaceutical composition (particularly a composition for prevention or treatment of arteriosclerosis), and a method which comprises administering in combination effective amounts of one or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, and one or more insulin resistance improving agents to warm-blooded animals for preventing or treating diseases (particularly arteriosclerosis). The occurrence of atherosclerosis is increasing with the adoption of Western-style diet and the growth of the aged population. This disease is the main cause of such disorders as myocardial infarction, cerebral infarction and cerebral apoplexy, and there is a need for its effective prevention and treatment. Examples of risk factors which cause atherosclerosis include hyperlipemia (particularly hypercholesterolemia), hypertension and saccharometabolism disorders based on insulin resistance. In addition, there are many

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cases in which these risk factors occur in the form of complications (Syndrome X), and are considered to be mutually interrelated Diabetes, 37, 1595-1607 (1988). Efforts have been made for the purpose of preventing and treating atherosclerosis by suppression of various risk factors such as hyperlipemia, hypertension and insulin resistance. Although HMG-CoA reductase inhibitors like pravastatin improve hyperlipemia, their inhibitory activity on arteriosclerosis in a case of administration alone is not enough, Biochim. Biophys. Acta, 960, 294-302 (1988). In addition, even insulin resistance improving agents like troglitazone do not exhibit sufficient atherosclerosis inhibitory activity in a case of administration alone (Japanese Patent Application (Kokai) No. Hei 7-41423). Web site: http://www.delphion.com/details?pn=US06610682__ •

RECOMBINANT DNA COMPRISING DNA CODING FOR MYOSIN HEAVY CHAIN SM1 ISO-FORM PROTEIN INSERTED INTO VECTOR DNA MICROORGANISM CARRYING THE RECOMBINANT DNA, AND AN AGENT FOR TREATMENT OF ARTERIOSCLEROSIS COMPRISING THE RECOMBINANT DNA Inventor(s): Arakawa; Emi (Tokyo, JP), Hasegawa; Kazuhide (Tokyo, JP), Ishiyama; Haruo (Kanagawa, JP), Matsuda; Yuzuru (Tokyo, JP), Oda; Shoji (Kanagawa, JP), Sugahara; Michihiro (Shizuoka, JP), Takahashi; Katsuhito (Osaka, JP) Assignee(s): Osaka Prefectual Government (osaka, Jp), Vessell Research Laboratory Co. Ltd. (tokyo, Jp) Patent Number: 6,593,304 Date filed: July 25, 1997 Abstract: The present invention relates to recombinant DNA comprising DNA coding for smooth-muscle-type myosin heavy chain SM1 isoform protein inserted into vector DNA, a microorganism carrying the recombinant DNA, and an agent for treatment of arteriosclerosis comprising the recombinant DNA. The recombinant DNA of the present invention can be used effectively as an agent for gene therapy of restenosis after PTCA treatment. Excerpt(s): The present invention relates to recombinant DNA comprising DNA coding for myosin heavy chain SM1 isoform protein inserted into vector DNA, a microorganism carrying the recombinant DNA and an agent for treatment of arteriosclerosis comprising the recombinant DNA which are used in gene therapy. Smooth muscle-type myosin heavy chain SM1 isoform protein is responsible for contraction and relaxation of smooth muscles, and is one of the myosin heavy chain isoform proteins expressed specifically in smooth muscle cells. As the DNA coding for the protein, the nucleotide sequence of cDNA coding for rabbit SM1 isoform is known (P. Babij et al.: Proc. Natl. Acad. Sci. USA, 88, 10676 (1991)), but there is not known any homology among nucleotide sequences for such DNAs. Further, there is not known any recombinant DNA comprising DNA coding for smooth muscle-type myosin heavy chain SM1 isoform protein inserted into vector DNA which recombinant DNA can be injected into animal cells. It has been reported that when cDNA coding for a protein called calponin which is a protein existing in smooth muscle cells is introduced and expressed in a vascular smooth muscle cell line derived from rat pulmonary arteries, the time required for doubling the cells is prolonged by about 4 hours (Takahashi et al.: Circulation, 88, I-174 (1993)) and that when cDNA for human calponin is injected into a rabbit topically at a site where the carotid artery has been abraded with a balloon, thickening of the intima is inhibited (Takahashi et al.: Circulation, 88, I-656 (1993)). It is

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not known that recombinant DNA comprising DNA coding for myosin heavy chain SM1 isoform protein inserted into vector DNA has pharmacological effect and is used for in gene therapy. Web site: http://www.delphion.com/details?pn=US06593304__ •

Substituted tetrahydronaphthaline and analogous compounds Inventor(s): Antons; Stefan (Leverkusen, DE), Bischoff; Hilmar (Wuppertal, DE), Brandes; Arndt (Wuppertal, DE), Bremm; Klaus-Dieter (Recklinghausen, DE), Logers; Michael (Wuppertal, DE), Muller; Stephan Nicholas (Wuppertal, DE), Naab; Paul (Wuppertal, DE), Paulsen; Holger (Wuppertal, DE), Schmeck; Carsten (Wuppertal, DE), Schmidt; Delf (Wuppertal, DE), Schmidt; Gunter (Wuppertal, DE), Stoltefuss; Jurgen (Haan, DE) Assignee(s): Bayer Aktiengellschaft (leverkusen, De) Patent Number: 6,586,613 Date filed: March 17, 2000 Abstract: Substituted tetrahydro-naphthalenes and analogous compounds are prepared by reducing or condensing appropriate functional substituents in substituted tetrahydro-naphthalenes and analogous compounds by customary methods and converting functional groups in this manner into the desired groups. The compounds according to the invention are suitable for use as active compounds in pharmaceuticals, in particular in pharmaceuticals for treating arteriosclerosis and also dyslipidaemias. Excerpt(s): The present invention relates to substituted tetrahydro-naphthalenes and analogous compounds, to processes for their preparation and to their use in pharmaceuticals. 7-(polysubstituted pyridyl)-6-heptenoates for the treatment of arteriosclerosis, lipoproteinaemia and hyperproteinaemia are known from the publication U.S. Pat. No. 5,169,857-A2. In addition, the preparation of 7-(4-aryl-3pyridyl)-3,5-dihydroxy-6-heptenoates is described in the publication EP-325 130-A2. and stereoisomers, stereoisomer mixtures and salts thereof. Web site: http://www.delphion.com/details?pn=US06586613__

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Utilization of osteocalcin promoter to deliver therapeutic genes to tumors Inventor(s): Cheon; Jun (Anam-Dong, KR), Chung; Leland W. K. (Lovingston, VA), Kao; Chinghai (Charlottesville, VA), Ko; Song-Chu (Charlottesville, VA), Sikes; Robert A. (Charlottesville, VA) Assignee(s): The University of Virginia Patent Foundation (charlottesville, Va) Patent Number: 6,596,534 Date filed: March 23, 2000 Abstract: A therapeutic agent based on a recombinant adenovirus which employs an osteocalcin promoter for the expression of thymidine kinase can be administered intravascularly to treat metastatic cancer, including osteosarcoma, breast cancer, prostate cancer, ocular melanoma or brain cancer. Systemic administration of this agent provides a preferred route over previous disclosure of local direct administration. The same therapeutic agent can be effectively employed in the treatment of benign conditions, including benign prostatic hypertrophy and arteriosclerosis.

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Excerpt(s): This invention pertains to the systemic administration of an active agent, a recombinant gene comprising an adenovirus (Ad) which contains an osteocalcin promoter (OC) which drives the expression of thymidine kinase (TK). The agent itself is fully disclosed in the parent application. This invention pertains to the discovery that Ad-OC-TK may be administered systemically, both to treat tumors, and to treat certain benign conditions such as benign prostatic hypertrophy and certain forms of arteriosclerosis. Toxic gene therapy for the treatment of cancer continues to gain prominence in basic research, but remains limited in clinical application because of an inability to deliver the toxic gene to the tumor cells with specificity. Many vectors (e.g. retroviruses, retroviral producing cells, adenoviruses, liposomes, and others) can deliver genes (therapeutic or toxic) to target cells. Localized delivery and restricted gene expression to the primary tumor have been accomplished via direct injection of therapeutic viruses in animal models.sup.1-4 and clinical trails.sup.5,6 This approach is not feasible for the treatment of metastatic disease because of the presence of multiple lesions that would each require separate injection and manipulation. Therefore, alternative approaches to the treatment of metastatic disease with gene therapy must be developed. Systemic delivery of therapeutic genes is attractive for targeting metastatic disease, pulmonary metastases in particular. Because the pulmonary vascular system would be the first encountered, the adenovirus would be trapped in the lung parenchyma, allowing for higher infectivity. Lesoon-Wood et al,.sup.7 reported the systemic delivery of wild type p53 complexed with liposomes, targeting the p53 mutated breast cancer cell line (MDA-MB435), inhibiting primary tumor growth by 60%, and decreasing pulmonary metastases in nude mice. Vile et al.sup.8 demonstrated inhibition of B-16 melanoma pulmonary metastases in syngeneic immunocompetent mice by a systemic delivery of retrovirus using a tyrosinase promoter to drive the expression of the toxic gene thymidine kinase (TK) gene. Web site: http://www.delphion.com/details?pn=US06596534__

Patent Applications on Arteriosclerosis 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 arteriosclerosis: •

4-Phenyltetrahydrochinoline utilized as an inhibitor of the cholesterol ester transfer protein Inventor(s): Bischoff, Hilmar; (Wuppertal, DE), Brandes, Arndt; (Wuppertal, DE), Bremm, Klaus-Dieter; (Recklinghausen, DE), Logers, Michael; (Wuppertal, DE), Schmeck, Carsten; (Wuppertal, DE), Schmidt, Delf; (Wuppertal, DE), Schmidt, Gunter; (Wuppertal, DE), Stoltefuss, Jurgen; (Haan, DE) Correspondence: Kurt Briscoe; Norris, Mclaughlin & Marcus, P.A.; 220 East 42nd Street, 30th Floor; New York; NY; 10017; US Patent Application Number: 20030232990 Date filed: March 31, 2003

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

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Abstract: The tetrahydroquinolines can be prepared by condensing appropriately substituted tetrahydroquinoline aldehydes with suitable substances and subsequently varying the substituents present by customary methods. The tetrahydroquinolines are suitable as active compounds in medicaments, in particular in medicaments for the treatment of arteriosclerosis and dyslipidaemias. Excerpt(s): The present invention relates to tetrahydroquinolines, to processes for their preparation and to their use in medicaments. The publication U.S. Pat. No. 5,169,857-A2 discloses 7-(polysubstituted pyridyl)-6-heptenoates for treating arteriosclerosis, lipoproteinaemia and hyperproteinaemia. Moreover, the preparation of 7-(4-aryl-3pyridyl)-3,5-dihydroxy-6-heptenoates is described in the publication EP-325 130-A2. Furthermore, the compound 5(6H)-quinolones,3-benzyl-7,8-dihydro-2,7,7-trimethyl-4phenyl, is known from the publication Khim. Geterotsikl. Soedin. (1967), (6), 1118-1120. and their salts and N-oxides. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Acetamide derivatives and the use thereof as inhibitors of coagulation factors xa and viia Inventor(s): Barnes, Christopher; (Bad Soden, DE), Dorsch, Dieter; (Ober-Ramstadt, DE), Gleitz, Johannes; (Darmstadt, DE), Juraszyk, Horst; (Seeheim-Jugenheim, DE), Mederski, Werner; (Erzhausen, DE), Tsaklakidis, Christos; (Weinheim, DE) Correspondence: Millen, White, Zelano & Branigan, P.C.; 2200 Clarendon BLVD.; Suite 1400; Arlington; VA; 22201; US Patent Application Number: 20030187037 Date filed: January 29, 2003 Abstract: Novel compounds of the formula I, in which R, R.sup.1 and R.sup.2 are as defined in patent claim 1, are inhibitors of coagulation factor Xa and VIIa and can be employed for the treatment of thromboses, myocardial infarction, arteriosclerosis, inflammation, apoplexis, angina pectoris, restenosis after angioplasty, claudicatio intermittens, tumours, tumour diseases and/or tumour metastases. Excerpt(s): and pharmaceutically tolerated salts, solvates and stereoisomers thereof. The invention also relates to the optically active forms, the racemates, the diastereomers and the hydrates and solvates, for example alcoholates, of these compounds. The invention had the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Agents for neutron capture therapy Inventor(s): Mody, Tarak D; (Sunnyvale, CA), Sessler, Jonathan L; (Austin, TX), Young, Stuart W; (Portola Valley, CA) Correspondence: Vinit G Kathardekar; Pharmacylics Inc; 995 E Arques Avenue; Sunnyvale; CA; 94085; US Patent Application Number: 20040023891 Date filed: February 25, 2003

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Abstract: Compounds, pharmaceutical formulations and methods for use in neutron capture therapy are provided, useful for treating diseases characterized by neoplastic tissue and arteriosclerosis. Excerpt(s): This application claims the benefit of priority from International Patent Application PCT/US01/26773, filed Aug. 28, 2001, which claims the benefit of priority from U.S. Provisional Application No. 60/229,366, filed Aug. 30, 2000, both of which are incorporated herein, by reference, in their entirety. The present invention relates to the use of metal complexes, in particular metallotexaphyrins, in neutron capture therapy. Neutron capture therapy is useful in the treatment of diseases characterized by neoplastic tissue, such as tumors, or plaque caused by atherosclerosis or other atheromatous diseases. The invention also relates to novel metallotexaphyrins, and pharmaceutical compositions containing such compounds. A much sought-after goal with respect to the treatment of cancer is the development of a therapy that selectively destroys diseased tissue, while not adversely impacting healthy tissues. Some progress has been made toward such a goal, and has led, for example, to the discovery and use of the class of agents known as sensitizers. Sensitizers are selectively taken up by a tumor or plaque, which is then treated with one or more forms of energy, such as light, radiation, or sonic energy, or alternatively with a chemotherapeutic drug, in order to destroy the tumor or plaque. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Amidocarboxylic acid compounds Inventor(s): Fujiwara, Toshihiko; (Ebina-shi, JP), Sakurai, Mitsuya; (Abiko-shi, JP), Takamura, Makoto; (Kawasaki-shi, JP), Yanagisawa, Hiroaki; (Tokyo, JP) Correspondence: Frishauf, Holtz, Goodman & Chick, P.C.; 767 Third Avenue - 25th Floor; New York; NY; 10017-2023; US Patent Application Number: 20040006141 Date filed: September 25, 2002 Abstract: Amidocarboxylic acid compounds of the formula: 1wherein R.sup.1 represents hydrogen or alkyl; R.sup.2 represents alkylene; R.sup.3 represents hydrogen, alkyl, alkoxy, alkylthio, halogen, nitro, dialkylamino, aryl, aralkyl, hydroxyl or acyl; R.sup.4 represents hydrogen or alkyl; X represents an aryl or hetero aryl; Y represents a single bond, oxygen, sulfur or N--R.sup.5, wherein R.sup.5 is hydrogen, alkyl, aliphatic acyl or aromatic acyl; Z represents alkylene; and W represents alkyl, hydroxyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkyloxy, aralkylthio, aryloxyalkyl, hetero aryl, hetero aryloxy, hetero alkylthio, heterocyclic, amino, alkylamino, N-alkyl-Narylamino, arylamino, aralkylamino or aralkyloxycarbonylamino. The compounds are used to treat diabetes mellitus, hyperlipemia, arteriosclerosis, obesity, impaired glucose tolerance, insulin-resistant non-IGT, fatty liver, diabetic complications, gestational diabetes mellitus, polycystic ovary syndrome, atherosclerosis, arthrosteitis, rheumatic arthritis, allergic diseases, asthma, cancer, autoimmune diseases, pancreatitis and cataracts. Excerpt(s): This application is a divisional application of application Ser. No. 09/540,765 filed Mar. 30, 2000, which is a continuation-in-part application of International Application PCT/JP98/04396, filed Sep. 30, 1998. The present invention relates to amidocarboxylic acid derivatives, or their pharmacologically acceptable salts or their pharmacologically acceptable esters. These compounds have some excellent effects of

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lowering blood glucose, reducing lipid, ameliorating insulin resistance, alleviating inflammatory diseases, immunoregulation, inhibiting aldose reductase, inhibiting 5lipoxygenase, suppressing generation of lipid peroxide, activating PPAR (peroxysome proliferator activated receptor) and alleviating osteoporosis. Furthermore, the present invention relates to a composition containing the above-mentioned amidocarboxylic acid derivatives, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof as an active ingredient useful in the treatment and prevention of the following diseases. They include diseases caused mainly by insulin resistance such as diabetes mellitus, hyperlipemia, obesity, impaired glucose tolerance (IGT), insulin resistant non-IGT (NGT), hypertension, fatty liver, diabetic complications (for example, retinopathy, nephropathy, neurosis, cataracts, coronary artery diseases, etc.), arteriosclerosis, gestational diabetes mellitus (GDM), polycystic ovary syndrome (PCOS) and cell injury caused by atherosclerosis (for example cerebral injury induced by apoplexy and the like); inflammatory diseases such as arthrosteitis, pain, pyrexia, rheumatic arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcers, cancer, cachexia, autoimmune diseases and pancreatitis; osteoporosis; cataracts; etc. The present invention relates to a use of these compounds, their salts and esters for producing a medicament for prevention or treatment of these diseases, or a method of treating or preventing these diseases by administration of pharmacologically effective amounts of such compounds to warm-blooded animals. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Aminoalkyl-substituted aromatic bicyclic compounds, methods for their preparation and their use as pharmaceuticals Inventor(s): Gossel, Matthias; (Hofheim, DE), Schwink, Lothar; (Stadtallendorf, DE), Stengelin, Siegfried; (Eppstein, DE) Correspondence: Heller Ehrman White & Mcauliffe Llp; 1666 K Street,nw; Suite 300; Washington; DC; 20006; US Patent Application Number: 20030212070 Date filed: August 14, 2002 Abstract: The present invention relates to aminoalkyl-substituted aromatic bicyclic compounds of formula I, 1which are valuable pharmaceutically active compounds that are suitable, for example, for the treatment of obesity, type II diabetes, arteriosclerosis, high blood pressure, paresthesia, depression, anxiety, anxiety neuroses, schizophrenia, disorders associated with the circadian rhythm, and drug abuse, as well as normalizing lipid metabolism. Excerpt(s): This application claims priority to German Patent Application 101 39416.0, filed Aug. 17, 2001, which is hereby incorporated by reference, in its entirety. All references cited below, including patents, patent applications and scientific journals and books also are herein incorporated by reference in their entirety. The invention relates to aminoalkyl-substituted aromatic bicyclic compounds and to the physiologically acceptable salts and physiologically functional derivatives thereof. Structurally similar nonaromatic bicyclic compounds with pharmacological action have already been described in the prior art (for example in WO 01/21577). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Aminobutyric acid derivatives and pharmaceutical composition containing the same as active ingredient Inventor(s): Sugiura, Tsuneyuki; (Mishima-gun, JP), Takahashi, Kanji; (Mishima-gun, JP) Correspondence: Stevens Davis Miller & Mosher, Llp; 1615 L Street, NW; Suite 850; Washington; DC; 20036; US Patent Application Number: 20040002480 Date filed: April 22, 2003 Abstract: Aminobutylic acid derivatives of the formula (I): 1wherein the symbols are as defined in specification; and non-toxic salts thereof. Because of inhibiting matrix metalloproteinase, the compounds of the formula (I) are useful for prevention and/or treatment of diseases, for example, rheumatoid diseases, arthrosteitis, osteoarthritis, unusual bone resorption, osteoporosis, periodontitis, interstitial nephritis, arteriosclerosis, pulmonary emphysema, cirrhosis, cornea injury, cornea ulcer, metastasis, invasion or growth of tumor cells, autoimmune disease, disease caused by vascular emigration or infiltration of leukocytes, arterialization, multiple sclerosis, arota aneurysm, endometriosis, restenosis after PTCA, unstable angina, acute myocardial infarction, transient ischemic attack. Excerpt(s): This invention relates to aminobutyric acid derivatives, processes for the preparation thereof and pharmaceutical agents comprising aminobutyric acid derivatives as active ingredient. and methyl ester, t-butyl ester, benzyl ester, allyl ester, and non-toxic salts thereof, and pharmaceutical agents comprising the compound and non-toxic salts thereof as active ingredient. The matrix metalloproteinases (MMPs) are neutral metalloproteinases and zinc (Zn.sup.2+) is essential in the active site for their activation. They degrade collagen, laminin, proteoglycans, fibronectin, elastin, gelatin etc. under physiological conditions and therefore, are effective on growth and tissue remodeling of articulation tissue, bone tissue and connective tissue. At least 10 classes of MMPs, which differ in primary structure, are identified. Concretely, there are Interstitial Collagenase (MMP-1), Neutrophil Collagenase (MMP-8), Gelatinase A (MMP-2), Gelatinase B (MMP-9), Stromelysin-1 (MMP-3), Stromelysin-2 (MMP-10), Matrilysin (MMP-7), metalloelastase (MMP-12) etc. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Arteriosclerosis diagnosing apparatus Inventor(s): Ogura, Toshihiko; (Komaki-shi, JP) Correspondence: Oliff & Berridge, Plc; P.O. Box 19928; Alexandria; VA; 22320; US Patent Application Number: 20030109788 Date filed: July 15, 2002 Abstract: An apparatus for diagnosing arteriosclerosis of a living subject, including an inflatable cuff which is adapted to be wound around a first portion of the subject to press the first portion with a pressing pressure, a pulse-wave detecting device which detects a pulse wave that is produced from an artery of the first portion of the subject pressed by the cuff with the pressing pressure and is transmitted to the cuff, and an arteriosclerosis judging device for judging, based on a change of the pulse wave caused by a change of the pressing pressure of the cuff, whether there is an arteriosclerotic

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lesion in a second portion of the subject that is located upstream of the first portion in a direction in which blood flows in the artery. Excerpt(s): The present invention relates to an arteriosclerosis diagnosing apparatus for diagnosing arteriosclerosis or arteriosclerotic lesion, in particular, atherosclerosis. There are known three sorts of arteriosclerosis; atherosclerosis is atheromatous sclerosis of endothelium of large or medium arteries, mediosclerosis is calcification of media of arteries, and arteriolosclerosis is sclerosis of small arteries. Meanwhile, pulse-wavepropagation-velocity-related information that is related to a velocity at which a pulse wave propagates between two regions of a living subject, e.g., pulse-wave propagation velocity itself or pulse-wave propagation time, may be measured to diagnose whether the subject has atherosclerosis or not, or what degree of atherosclerosis the subject has. If a pulse-wave propagation velocity as a sort of pulse-wave-propagation-velocity-related information is measured from an atherosclerotic region of the subject, the measured velocity is higher than a normal velocity, if a degree of the atherosclerosis is low; and the measured velocity is lower than the normal velocity, if the degree of atherosclerosis is medium or high. Thus, the pulse-wave-propagation-veloc- ity-related information can be used to diagnose whether the subject has atherosclerosis, or what degree of atherosclerosis the subject has. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Arteriosclerosis evaluating apparatus Inventor(s): Narimatsu, Kiyoyuki; (Komaki-shi, JP) Correspondence: Oliff & Berridge, Plc; P.O. Box 19928; Alexandria; VA; 22320; US Patent Application Number: 20030120158 Date filed: July 15, 2002 Abstract: An apparatus for evaluating arteriosclerosis of a living subject, including a pulse-wave detecting device which detects a pulse wave from each of a first portion and a second portion of the subject, each of the respective pulse waves detected from the first and second portions containing an incident-wave component, an augmentationindex determining device for determining, based on the pulse wave detected from the first portion by the pulse-wave detecting device, a first augmentation index indicative of a degree of augmentation of an amplitude of the pulse wave detected from the first portion, from an amplitude of the incident-wave component of the pulse wave detected from the first portion, and determining, based on the pulse wave detected from the second portion by the pulse-wave detecting device, a second augmentation index indicative of a degree of augmentation of an amplitude of the pulse wave detected from the second portion, from an amplitude of the incident-wave component of the pulse wave detected from the second portion, and an arteriosclerosis evaluating device for evaluating the arteriosclerosis of the subject, based on a comparison of the first and second augmentation indexes determined by the augmentation-index determining device. Excerpt(s): The present invention relates to an arteriosclerosis evaluating apparatus for evaluating arteriosclerosis based on augmentation index. Augmentation index, AI, is generally calculated as a percentage of a value obtained by diving a difference between a magnitude of a peak of a pulse wave (i.e., a pulse pressure of the pulse wave) and a magnitude of a peak of an incident-wave component contained in the pulse wave (i.e., a pulse pressure of the incident wave), by the pulse pressure of the pulse wave. Since the

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augmentation index increases as arteriosclerosis advances, the augmentation index can be used as an index for evaluating arteriosclerosis. However, the augmentation index is influenced by physiological factors, such as blood pressure or psychological stress, and environmental factors such as temperature, and accordingly the augmentation index may largely change between different living subjects, or between different measuring operations. Thus, a correlation between augmentation index and arteriosclerosis is not so high. Therefore, it is understood that arteriosclerosis cannot be evaluated based on augmentation index only. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Arteriosclerosis examining apparatus Inventor(s): Honda, Takashi; (Komaki-shi, JP), Masuda, Hiroshi; (Komaki-shi, JP), Narimatsu, Kiyoyuki; (Komaki-shi, JP), Ogura, Toshihiko; (Komaki-shi, JP), Tampo, Akira; (Komaki-shi, JP) Correspondence: Oliff & Berridge, Plc; P.O. Box 19928; Alexandria; VA; 22320; US Patent Application Number: 20030114764 Date filed: June 27, 2002 Abstract: An apparatus for examining arteriosclerosis of a living subject, including a pulse-wave detecting device which detects a pulse wave from a first portion of the subject, a stenosis-related-information obtaining device for obtaining, based on a shape of the pulse wave detected by the pulse-wave detecting device, stenosis-related information that changes in relation with stenosis of an artery of a second portion of the subject that is located upstream of the first portion of the subject in a direction in which blood flows in the artery, and a stenosis judging device for making, based on the stenosis-related information obtained by the stenosis-related-information obtaining device, a judgment about the stenosis of the artery of the second portion of the subject. Excerpt(s): The present invention relates to an arteriosclerosis examining apparatus for examining arteriosclerosis, in particular, arteriosclerosis obliterans. There is known, as a sort of arteriosclerosis, atherosclerosis that is arterial atheroma caused by deposit of lipid, such as cholesterol, on inner walls of arteries. Since atherosclerosis causes stenosis of arteries, it is also called arteriostenosis, or arteriosclerosis obliterans. There is known an inferior-and-superior-limb blood-pressure-index measuring apparatus as an apparatus for examining arteriostenosis. This apparatus is disclosed in, e.g., Japanese Patent No. 3,140,007 or its corresponding U.S. Pat. No. 6,355,000. The blood-pressureindex measuring apparatus includes two inflatable cuffs that are adapted to be worn on an inferior limb and a superior limb of a living subject, calculates, as an inferior-andsuperior-limb blood-pressure index, a ratio of one of a superior-limb blood pressure and an inferior-limb blood pressure to the other, and examines arteriostenosis based on the thus calculated inferior-and-superior-limb blood-pressure index. More specifically described, examination of arteriostenosis based on inferior-and-superior-limb bloodpressure index is effected by comparing the index value with a predetermined reference value. For example, in the case where an inferior-and-superior-limb blood-pressure index is calculated by dividing an inferior-limb systolic blood pressure by a superiorlimb systolic blood pressure, if the index value is greater than 0.9, it can be judged that the subject does not have arteriostenosis and, if not, it can be judged that the subject is suspected of having arteriostenosis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Arteriosclerosis inspecting apparatus Inventor(s): Honda, Takashi; (Komaki-shi, JP), Narimatsu, Kiyoyuki; (Komaki-shi, JP), Ogura, Toshihiko; (Komaki-shi, JP), Tampo, Akira; (Komaki-shi, JP) Correspondence: Oliff & Berridge, Plc; P.O. Box 19928; Alexandria; VA; 22320; US Patent Application Number: 20030139675 Date filed: September 9, 2002 Abstract: An apparatus for inspecting arteriosclerosis of a living subject, including a pulse-wave detecting device which detects a pulse wave from a portion of the subject, an augmentation-index determining device for determining, based on the pulse wave detected by the pulse-wave detecting device, an augmentation index indicating a proportion of a reflected-wave component of the pulse wave to an incident-wave component thereof, so that the arteriosclerosis of the subject is inspected based on the augmentation index determined by the augmentation-index determining device, a waveform-related-information obtaining device which obtains waveform-related information that is related to a change of a waveform of the pulse wave detected by the pulse-wave detecting device, a display device, an augmentation-index displaying device for operating the display device to display the augmentation index determined by the augmentation-index determining device, and a waveform-related-information displaying device for operating the display device to display, in addition to the augmentation index, the waveform-related information obtained by the waveformrelated-information obtaining device. Excerpt(s): The present invention relates to an arteriosclerosis inspecting apparatus for inspecting arteriosclerosis of a living subject based on augmentation index. Since a pulse wave that propagates in a blood vessel is reflected at a bifurcated or tapered portion of the blood vessel, a detected waveform of the pulse wave consists of an incident-wave component produced when blood is ejected from subject's heart and propagates toward subject's peripheral portion, and a reflected-wave component produced when an incident wave is reflected. Pulse-wave augmentation index, generally known as AI, indicates a proportion of a reflected-wave component of a pulse wave to an incident-wave component of the same. Usually, augmentation index AI is determined as a percentage of a value obtained by dividing, by a pulse pressure of a detected pulse wave, a difference obtained by subtracting, from a magnitude of the pulse wave at the time of occurrence of a reflected-wave component of the pulse wave, a magnitude of a peak point of an incident-wave component of the pulse wave. As arteriosclerosis advances, the proportion of reflected-wave component of pulse wave increases and accordingly augmentation index increases. Thus, augmentation index is hopeful as an index used to evaluate arteriosclerosis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Arteriosclerosis inspecting apparatus Inventor(s): Ogura, Toshihiko; (Komaki-shi, JP) Correspondence: Oliff & Berridge, Plc; P.O. Box 19928; Alexandria; VA; 22320; US Patent Application Number: 20030167014 Date filed: February 3, 2003

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Abstract: An arteriosclerosis inspecting apparatus including an information obtaining device which obtains information that is related to a velocity at which a pulse wave propagates in a living subject, a blood-pressure measuring device which measures a blood pressure of the subject, a heart-rate measuring device which measures a heart rate of the subject, a pre-ejection-period measuring device which measures a pre-ejection period from a time of starting of contraction of the heart of the subject to a time of starting of ejection of blood from the heart, an ejection-time measuring device which measures an ejection time from the time of starting of ejection of blood from the heart to a time of ending of ejection of blood from the heart, and an arteriosclerosis-inspectionrela- ted-augmentation-index determining means for determining an arteriosclerosisinspection-related augmentation index of the subject, based on the obtained pulse-wavevelocity-related information, the measured blood pressure, the measured heart rate, the measured pre-ejection period, and the measured ejection time, according to a predetermined relationship between (A) (a1) pulse-wave-velocity-related information, (a2) blood pressure, (a3) heart rate, (a4) pre-ejection period and (a5) ejection time, and (B) arteriosclerosis-inspection-relate- d augmentation index. Excerpt(s): The present invention relates to an arteriosclerosis inspecting apparatus for inspecting arteriosclerosis of a living subject based on an augmentation index or pulsewave-velocity-related information. A degree of arteriosclerosis of a living subject can be evaluated based on augmentation index AI or pulse-wave velocity PWV each as a parameter that is related to artery's degree of elasticity or dilation. A pulse wave that propagates through an artery of the subject is reflected at a bifurcated or tapered portion of the artery. Therefore, a shape or form of the pulse wave detected from the artery is defined by the composition of an incident-wave component that is produced when blood is ejected from the heart of the subject and advances toward a peripheral portion of the subject, and a reflected-wave component that is produced when the incidentwave component is reflected. Thus, augmentation index AI is obtained by determining a proportion of a reflected-wave component of a pulse wave detected from an artery, such as a carotid artery or a brachial artery, to an incident-wave component of the detected pulse wave. As the artery hardens, phase or amplitude of the reflected-wave component changes. Usually, augmentation index AI is calculated as a percentage of a value obtained by dividing a difference between a magnitude of the detected pulse wave at the time of detection of a peak point of the reflected-wave component and a magnitude of the detected pulse wave at the time of detection of a peak point of the incident-wave component, by a pulse pressure of the detected pulse wave. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Arteriosclerosis-preventing material, immune-activating material, vertebrate that has eaten such materials, and eggs thereof Inventor(s): Takebe, Minoru; (Shinagawa-ku, JP) Correspondence: Koda & Androlia; Suite 3850; 2029 Century Park East; Los Angeles; CA; 90067; US Patent Application Number: 20030185853 Date filed: March 26, 2003 Abstract: An arteriosclerosis-preventing material, immune-activating material, vertebrate that has eaten these, and eggs of such vertebrate. Such materials are produced by inoculating koji mold on a pulse crop to effect koji preparation and adding water to a product of the koji preparation, thus hydrolyzing proteins and/or saccharides contained

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in the product of said koji preparation and by utilizing the activity common to lactic acid bacteria naturally contained in the starting materials and lactic acid bacteria that is added to the product of the koji preparation. An arteriosclerosis-preventing material possessing arteriosclerosis-preventi- ng capability, an immune-activating material possessing immune-activating capability that are effective in maintaining the health of vertebrates, a vertebrate other than a human being that has been reared by adding these arteriosclerosis-preventing material and immune-activating material to feed, and the egg of such a vertebrate, are obtained. The necessary amount of arteriosclerosispreventing material and immune-activating material that are the product of the present invention is added to, for instance, food products, fodder, feed, etc. and absorbed in vivo from the digestive tract of vertebrates to realize arteriosclerosis-preventing capability and immune-activating capability, thus safely preventing the onset of arteriosclerosis-related disease in such a vertebrate as well as improve immunity of the vertebrate, thus effectively accomplishing a maintenance and promotion of good health and a prevention of disease, etc. Excerpt(s): The present invention relates to an arteriosclerosis-preventing material and an immune-activating material, the starting material of which being pulse crops, and a vertebrate that have eaten these, as well as eggs of such vertebrate; and more particularly to an arteriosclerosis-preventing material possessing arteriosclerosispreventi- ng capability that prevents arteriosclerosis of circulatory system and related diseases caused thereby in vertebrates, including human beings, animals, fowl, and fish (referred to hereafter as "vertebrates"), to an immune-activating material possessing immune-activating capability that improves the immune capability of vertebrates, to a vertebrate other than a human being that has been reared eating feed to which the arteriosclerosis-preventing material and immune-activating material are partially added, and to eggs of such vertebrate. The term pulse crop in the present invention refers to leguminous corps, such as soybeans, etc., and their leguminous crops, processed products, etc. In general, there is a strong demand for products of which starting material is pulse crop, and many types of products are being presented. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Augmentation-index determining apparatus and arteriosclerosis inspecting apparatus Inventor(s): Honda, Takashi; (Komaki-shi, JP), Narimatsu, Kiyoyuki; (Komaki-shi, JP), Ogura, Toshihiko; (Komaki-shi, JP), Tampo, Akira; (Komaki-shi, JP) Correspondence: Oliff & Berridge, Plc; P.O. Box 19928; Alexandria; VA; 22320; US Patent Application Number: 20030130583 Date filed: September 9, 2002 Abstract: An augmentation-index determining apparatus, including a cuff, a cuffpressure changing device which changes a pressing pressure of the cuff, a pulse-wave extracting device which extracts a pulse wave from the cuff, a peak-occurrence-time determining device for determining, based on a high-cuff-pressure pulse wave which is extracted by the pulse-wave extracting device when the cuff-pressure changing device makes the pressing pressure of the cuff higher than a systolic blood pressure of a subject, a time of occurrence of a peak point of an incident-wave component of the highcuff-pressure pulse and a time of occurrence of a peak point of a reflected-wave component of the high-cuff-pressure pulse wave, and an augmentation-index determining device for determining, based on the respective times of occurrence of the respective peak points of the incident-wave and reflected-wave components of the high-

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cuff-pressure pulse, respective times of occurrence of respective peak points of incidentwave and reflected-wave components of a low-cuff-pressure pulse which is extracted by the pulse-wave extracting device when the cuff-pressure changing device makes the pressing pressure of the cuff lower than a mean blood pressure of the subject, and determining an augmentation index based on respective magnitudes of the low-cuffpressure pulse wave at the respective times of occurrence of the respective peak points of the incident-wave and reflected-wave components of the low-cuff-pressure pulse. Excerpt(s): The present invention relates to an augmentation-index determining apparatus which determines an augmentation index of a living subject, and an arteriosclerosis inspecting apparatus which inspects arteriosclerosis of a living subject based on an augmentation index of the subject. Augmentation index, generally known as AI, indicates a proportion of a reflected-wave component of a pulse wave to an incident-wave component of the same, and is used to evaluate compliance of aorta. The greater the compliance is, the smaller the reflected-wave component is, and the smaller the compliance is, the greater the reflected-wave component is. That is, the harder the aorta is, the greater the reflected-wave component of the aortic pulse wave is. Thus, the augmentation index indicates arteriosclerosis and accordingly is used as an index to examine or inspect it. As described above, augmentation index represents a proportion of a reflected-wave component of a pulse wave to an incident-wave component of the same. However, since it is difficult to completely separate a detected pulse wave into an incident-wave component and a reflected-wave component, an augmentation index is determined by first identifying respective times of occurrence of respective peak points of the incident-wave and reflected-wave components of the detected pulse wave, and then dividing a difference between respective magnitudes of the detected pulse wave at the respective times of occurrence of the respective peak points of the incident-wave and reflected-wave components, by a pulse pressure of the detected pulse wave. A time of occurrence of an inflection point or a maximal point of the detected pulse wave between a rising point and a peak point of a heartbeat-synchronous pulse of the detected pulse wave is identified as the time of occurrence of the peak point of the incident-wave component; a time of occurrence of the first or earliest maximal point of the heartbeatsynchronous pulse of the detected pulse wave, subsequent to the peak point of the incident-wave component, is identified as the time of occurrence of the peak point of the reflected-wave component; and a difference between the greatest and smallest magnitudes of the heartbeat-synchronous pulse of the detected pulse wave is determined as the pulse pressure of the detected pulse wave. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Aza-amino acid derivatives (factor Xa inhibitors 15) Inventor(s): Barnes, Christopher; (Bad Soden, DE), Dorsch, Dieter; (Ober-Ramstadt, DE), Gleiltz, Johannes; (Darmstadt, DE), Juraszyk, Horst; (Seeheim-Jugenheim, JP), Mederski, Werner; (Zwingenberg, DE), Tsaklakidis, Christos; (Weinheim, DE) Correspondence: Millen, White, Zelano & Branigan, P.C.; 2200 Clarendon BLVD.; Suite 1400; Arlington; VA; 22201; US Patent Application Number: 20040034072 Date filed: August 4, 2003 Abstract: The invention relates to semicarbazides of the general formula I 1where R.sup.1, R.sup.2, R.sup.3, R.sup.4 and I have the meaning indicated in claim 1.The compounds of the formula I can be employed as pharmaceutical active compounds in

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human and veterinary medicine, in particular for the control and prevention of thromboembolic disorders such as thrombosis, mycocardial infarct, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication. Excerpt(s): and their pharmaceutically tolerable salts and solvates. The invention also relates to the optically active forms, the racemates, the diastereomers and also the hydrates and solvates, e.g. alcoholates, of these compounds. For the control of hemorrhages caused by injuries, the human body has a mechanism by means of which, with the aid of blood clots, a rapid wound closure is achieved. Blood clots are formed by a series of zymogen activations. In the course of this enzymatic cascade, the activated form of a factor in each case catalyzes the activation of the next. Since this process is of catalytic nature, very small amounts of the triggering factor suffice to set the cascade in motion. As a result of the large number of steps, a large amplification is achieved, which guarantees a rapid response to the injury. The plasmatic clotting after a tissue lesion can take place exogenously due to the release of tissue thrombokinase. The corresponding reaction sequence is designated as an extravascular system (extrinsic system) and proceeds within seconds. The clotting can also be triggered endogenously by thrombocytolysis. This reaction sequence, which is designated as an intravascular system, proceeds within minutes. Both systems result in a final common sequence of steps which lead to the formation of a blood clot. The intravascular and the extravascular system have a mutual influence in vivo. Both are necessary for the complete course of blood clotting. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Benzene derivatives and pharmaceutical use thereof Inventor(s): Fujita, Kohichi; (Kawasaki-Shi, JP), Iino, Yukio; (Kawasaki-Shi, JP), Kobayashi, Tsuyoshi; (Kawasaki-Shi, JP), Kodaira, Ariko; (Kawasaki-Shi, JP), Takehana, Kenji; (Kawasaki-Shi, JP), Tsuji, Takashi; (Kawasaki-Shi, JP), Yamamoto, Takashi; (Kawasaki-Shi, JP) Correspondence: Oblon, Spivak, Mcclelland, Maier & Neustadt, P.C.; 1940 Duke Street; Alexandria; VA; 22314; US Patent Application Number: 20030166693 Date filed: March 14, 2003 Abstract: The present invention provides an AP-1 activation inhibitor, NF-kappa B activation inhibitor, inflammatory cytokine production inhibitor, matrix metalloprotease production inhibitor, inflammatory cell adhesion molecule expression inhibitor, antiinflammatory agent, antirheumatic agent, immunosuppressant, cancer metastasis inhibitor, remedy for arteriosclerosis and antiviral agent which contain the benzene derivative of the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. 1 Excerpt(s): The present invention relates to benzene derivatives useful for the treatment of various inflammatory diseases and pharmaceutical compositions containing them. It is known that various inflammatory diseases, rheumatoid diseases, immunoreactive diseases, cancer metastasis and viral diseases are caused by the abnormal production of inflammatory cytokines and matrix metalloprotease and also by the increase in the expression of inflammatory cell adhesion molecules. Although various medicines for

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these diseases were developed in the prior art, further development of a medicine having a stronger efficiency, higher safety and weaker side effects is demanded. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Benzofurylpyrone derivatives Inventor(s): Hamada, Masa; (Tokyo, JP), Ida, Tomohide; (Tokyo, JP), Imai, Hiroshi; (Tokyo, JP), Kitai, Kazuo; (Tokyo, JP), Kosugi, Tomomi; (TYokyo, JP), Muratani, Emiko; (Tokyo, JP), Naniwa, Yoshimitsu; (Tokyo, JP), Sugimoto, Yoshinori; (Tokyo, JP), Takeuchi, Akiko; (Tokyo, JP), Takeuchi, Tomio; (Tokyo, JP), Tomiyama, Takami; (Osaka, JP), Watanabe, Kunihito; (Tokyo, JP) Correspondence: Sughrue Mion,pllc; 2100 Pennsylvania Avenue, NW; Washington; DC; 20037-3213; US Patent Application Number: 20030186976 Date filed: May 12, 2003 Abstract: There is provided benzofuryl-.alpha.-pyrone derivative represented by the following structural formula (I): 1wherein R.sup.1 represents a hydrogen atom or an alkyl group of 1 to 5 carbons;R.sup.2 represents hydrogen, --CO--R.sup.5 or -SO.sub.2R.sup.6;R.sup.3 represents hydrogen, an alkyl group of 1 to 5 carbons, etc.; andR.sup.4 is a substituent attached to the 4-carbon, 5-carbon, 6-carbon or 7 carbon of the benzofuran ring; and their salts. The compounds are useful as therapeutic agent for hypertriglyceridemia, lipid metabolism enhancers, or prophylactic and/or therapeutic agents for arteriosclerosis. Excerpt(s): The present invention relates to novel benzofuryl-.alpha.-pyrone derivatives and to medicines containing them as active ingredients. More specifically, the invention relates to novel benzofuryl-.alpha.-pyrone derivatives and to lipid metabolism enhancers, arteriosclerosis prophylactic agents, arteriosclerosis treatment agents, triglyceride biosynthesis inhibitors, blood triglyceride lowering agents or blood HDL elevating agents containing them as active ingredients. Blood cholesterol and triglycerides (TG) themselves are generally insoluble in blood, and they exist as lipoproteins by binding with apolipoproteins. In the body, triglycerides are biosynthesized primarily in the liver from acetyl CoA as the starting substance which is produced from sugars, etc., by 6 different enzymes and one enzyme group (acetyl CoA carboxylase, the fatty acid synthase group, fatty acyl CoA synthase, glycerophosphoric acid acyl transferase, lysophosphatidic acid acyl transferase, phosphatidic acid phosphatase and diacylglycerol acyl transferase), and are secreted from the liver into the blood as lipoproteins. The condition of a higher-than-normal cholesterol and/or triglyceride blood level is known as hyperlipidemia. The condition termed hyperlipidemia is classified into 6 types based on the lipoproteins in the blood, according to the Fredrickson classification (WHO classification). Types I, IV and V are characterized by increased triglycerides only, type IIa by increased cholesterol, and types IIb and III by increases in both ("Sogo Rinsho", 43, 871(1994)). This means that present hyperlipidemia drugs (that lower only cholesterol or that lower both cholesterol and triglycerides) cannot always be appropriately applied for all hyperlipidemia cases. In particular, type IV accounts for 40 to 50% of male hyperlipidemia patients ("Rinsho to Kenkyu", 69, 318 (1992)). Most secondary onset forms accompanying diabetes are also type IV ("Sogo Rinsho", 43, 878(1994)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Biphenyl derivatives and the use thereof as integrin inhibitors Inventor(s): Goodman, Simon; (Griesheim, DE), Stahle, Wolfgang; (Ingelheim, DE) Correspondence: Millen, White, Zelano & Branigan, P.C.; 2200 Clarendon BLVD.; Suite 1400; Arlington; VA; 22201; US Patent Application Number: 20030187289 Date filed: February 21, 2003 Abstract: Novel biphenyl derivatives of the general formula (I), in which Y, R R.sup.1, R.sup.2, R.sup.3, R.sup.4, m, o and p are as defined in claim 1, and their physiologically acceptable salts and solvates are integrin inhibitors and can be employed for combating thrombosis, cardiac infarction, coronary heart disease, arteriosclerosis, inflammation, tumours, osteoporosis, infections aid restenosis after angioplasty or in pathological processes which are maintained or propagated by angiogenesis. 1 Excerpt(s): and their physiologically acceptable salts and solvates. Partially similar compounds are disclosed in WO 95/32710. The object of the invention was to discover novel compounds having valuable properties, in particular those which are used for the preparation of medicaments. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Biphenyl derivatives and the use thereof as integrin inhibitors Inventor(s): Goodman, Simon; (Griesheim, DE), Holzemann, Gunter; (SeeheimJugenheim, DE), Stahle, Wolfgang; (Ingelheim, DE) Correspondence: Millen, White, Zelano & Branigan, P.C.; 2200 Clarendon BLVD.; Suite 1400; Arlington; VA; 22201; US Patent Application Number: 20040010023 Date filed: February 21, 2003 Abstract: The invention relates to novel biphenyl derivatives of the general formula (I), wherein R.sup.4 represents an aromatic heterocycle, and to the physiologically acceptable salts or solvates thereof. The inventive compounds are integrin inhibitors and are used for combating thromboses, cardiac infarction, coronary heart diseases, arteriosclerosis, inflammations, tumors, osteoporosis, infections and restenosis following angioplasty or for pathological processes that are maintained or propagated by angiogenesis. 1 Excerpt(s): and their physioligically acceptable salts and solvates. Compounds which in some cases are similar are disclosed in WO 97/26250. The invention was based on the object of finding novel compounds having valuable properties, in particular those which can be used for the production of medicaments. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Ceramide kinase and DNA encoding it Inventor(s): Kohama, Takafumi; (Tokyo, JP), Kono, Keita; (Kawasaki-shi, JP), Sugiura, Masako; (Tokyo, JP) Correspondence: Frishauf, Holtz, Goodman & Chick, PC; 767 Third Avenue; 25th Floor; New York; NY; 10017-2023; US Patent Application Number: 20030162206 Date filed: December 10, 2002 Abstract: A protein having ceramide kinase activity which can be a target for a prophylactic or therapeutic medicament against neuronal disease, inflammation, HIV infection, type 2 diabetes mellitus, obesity, septicemia, arteriosclerosis and cancer. Specifically, a protein which comprises an amino acid sequence shown in the amino acid numbers 1-537 of SEQ ID No. 2 of the Sequence Listing, a DNA which encodes the protein, a recombinant vector comprising the DNA, a host cell transformed with the recombinant vector and a method for producing the protein. By using the method of the present invention, a compound is provided having a specifically activating or inhibiting activity to ceramide kinase and is useful as a medicament for treating a neuronal disorder, an anti-inflammatory medicament, a medicament for treating HIV infection, an anti-type 2 diabetes mellitus medicament, an anti-obesity medicament, an antisepticemia medicament, an anti-arteriosclerosis medicament and an anticancer medicament. Excerpt(s): This application is a continuation-in-part of International application PCT/JP01/04889 filed Jun. 11, 2001, the entire contents of which are hereby incorporated by reference herein. The present invention relates to a novel protein having ceramide kinase activity which may be a target of a medicament for preventing or treating neuronal disease, inflammation, HIV infection, type 2 diabetes mellitus, obesity, septicemia, arteriosclerosis and cancer; DNA which encodes the protein; a recombinant DNA vector comprising the DNA; a host transformed with the recombinant DNA vector; a method for producing the ceramide kinase; and use of the protein. Sphingolipids have been conventionally considered to be one of the major components of cell membrane as glycerophospholipids and cholesterol. It has been known that glycerophospholipids not only maintain cell membrane structure, but also let the cells produce many physiologically active substances as metabolites thereof. However, a physiological activity of sphingolipid metabolites has been hardly known until recently. In these years, physiological activities of some sphingolipid metabolites such as induction of apoptosis and cell proliferation-stimulating activity, have come to be known, and the possibility that enzymes metabolizing sphingolipid closely participate in physiological reactions or various diseases has been suggested. Especially, ceramide attracts attention as a regulator which controls many cell mechanisms (See Hannun, Y. A. and Obeid, L. M., (1995), TIBS, 20, 73-77). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Compounds for the treatment of metabolic disorders Inventor(s): Sharma, Shalini; (Gaithersburg, MD), von Borstel, Reid W.; (Potomac, MD) Correspondence: Lewis J. Kreisler; Legal Department; 930 Clopper Road; Gaithersburg; MD; 20878; US Patent Application Number: 20030149107 Date filed: June 12, 2002 Abstract: Compounds useful for the treatment of various metabolic disorders, such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, cachexia, obesity, atherosclerosis and arteriosclerosis, are disclosed. Excerpt(s): This application claims the benefit of U.S. Provisional Patent Application No. 60/297,282, filed Jun. 12, 2001, the contents of which are hereby incorporated by reference. Diabetes mellitus is a major cause of morbidity and mortality. Chronically elevated blood glucose leads to debilitating complications: nephropathy, often necessitating dialysis or renal transplant; peripheral neuropathy; retinopathy leading to blindness; ulceration of the legs and feet, leading to amputation; fatty liver disease, sometimes progressing to cirrhosis; and vulnerability to coronary artery disease and myocardial infarction. There are two primary types of diabetes. Type I, or insulindependent diabetes mellitus (IDDM) is due to autoimmune destruction of insulinproducing beta cells in the pancreatic islets. The onset of this disease is usually in childhood or adolescence. Treatment consists primarily of multiple daily injections of insulin, combined with frequent testing of blood glucose levels to guide adjustment of insulin doses, because excess insulin can cause hypoglycemia and consequent impairment of brain and other functions. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Cyclopropanecarboxylic acid amide compound and pharmaceutical use thereof Inventor(s): Iino, Yukio; (Kawasaki-Shi, JP), Kobayashi, Tsuyoshi; (Kawasaki-Shi, JP), Yamamoto, Takashi; (Kawasaki-Shi, JP) Correspondence: Oblon, Spivak, Mcclelland, Maier & Neustadt, P.C.; 1940 Duke Street; Alexandria; VA; 22314; US Patent Application Number: 20040002521 Date filed: April 30, 2003 Abstract: The present invention provides an NF-kappa B activation inhibitor, an inflammatory cytokine production inhibitor, a matrix metalloprotease production inhibitor, an inflammatory cell adhesion factor expression inhibitor, and an antiinflammatory agent, an antirheumatic agent, an immuno-suppressive agent, an antiallergic agent, an antiviral agent, or a therapeutic agent for arteriosclerosis, which comprise, as the active ingredient, a cyclopropanecarboxylic acid amide compound or a pharmaceutically acceptable salt thereof effective for the treatment of inflammatory diseases. Excerpt(s): The present invention relates to a medicine for treating various inflammatory diseases. It has been known that various kinds of inflammatory diseases, rheumatism, immunoreactive diseases, metastasis of cancer and viral diseases are caused due to, for instance, abnormal production of inflammatory cytokines and matrix metalloproteases and increase in the expression of inflammatory cell adhesion factors. Various substances

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or compounds have conventionally been developed as pharmaceutical agents (or medicines) for treating these diseases, but there have still been desired for the development of pharmaceutical agents having further improved efficacy, a reduced side effect and high safety. In various chronic inflammatory diseases, mediators for inflammation such as various kinds of cytokines (in particular, inflammatory ones include, for instance, IL-1, IL-2, IL-6, IL-8 and TNF), adhesion factors and histoclastic enzymes (such as matrix metalloproteases) are continuously produced by the continuous extra-cellular stimulations and as a result, it has been recognized that the pathema of the chronic inflammatory disease is thus generated. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Diphenylmethane derivatives Inventor(s): Bischoff, Hilmar; (Wuppertal, DE), Faeste, Christiane; (Haan, DE), Haning, Helmut; (Wuppertal, DE), Kretschmer, Axel; (Wuppertal, DE), Pernerstorfer, Josef; (Wuppertal, DE), Schmeck, Carsten; (Wuppertal, DE), Schmidt, Gunter; (Wuppertal, DE), Vohringen, Verena; (Wuppertal, DE), Woltering, Michael; (Wuppertal, DE) Correspondence: Jeffrey M. Greenman; Vice President, Patents And Licensing; Bayer Corporation; 400 Morgan Lane; West Haven; CT; 06516; US Patent Application Number: 20030203898 Date filed: March 11, 2003 Excerpt(s): The invention relates to novel diphenylmethane derivatives, processes for their preparation and their use in medicaments, in particular for the indications of arteriosclerosis and hypercholesterolaemia. European application 580 550 A describes oxamic acid derivatives having cholesterol-lowering properties in mammals. This application describes an in vitro test based on the binding of thyroid hormone cell receptors (called T.sub.3 nuclear receptors). Some of the compounds described therein are stated to have IC-50 values of 0.2 nM and 0.1 nM in the L-triiodothyronine (LT.sub.3) nuclear receptor test. The pharmacological property which is emphasized is the reduction in plasma cholesterol, in particular LDL-cholesterol. Cholesterol-lowering effects are also described in the European application EP-A-188 351 for certain diphenyl ethers with thyroid hormone-like effects. Tripp et al. in J. Med. Chem. 1973, 16(1), 60-64 describe the synthesis of methylene- and carbonyl-bridged analogs of iodothyronine. They found that their thyromimetic activity was less than that of the corresponding Oor S-bridged compounds. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Enzyme inhibitors Inventor(s): Cascon, Mercedes Alonso; (Madrid, ES), Diaz, Isabel Dorronsoro; (Madrid, ES), Gil, Ana Martinez; (Madrid, ES), Jurado, Francisco Wandosell; (Madrid, ES), Morera, Ana Castro; (Madrid, ES), Munoz, Francisco Jose Moreno; (Madrid, ES), Perez, Maria Concepcion Martin; (Madrid, ES) Correspondence: Y. Rocky Tsao; Fish & Richardson P.C.; 225 Franklin Street; Boston; MA; 02110-2804; US Patent Application Number: 20030195238 Date filed: November 8, 2002

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Abstract: Compounds of general formula (I): 1where A, E, G, X, Y and the bond - - - take various meanings are of use in the preparation of a pharmaceutical formulation, for example in the treatment of a disease in which GSK-3 is involved, including Alzheimer's disease or the non-dependent insulin diabetes mellitus, or hyperproliferative disease such as cancer, displasias or metaplasias of tissue, psoriasis, arteriosclerosis or restenosis. Excerpt(s): The present invention relates to enzyme inhibitors, and more particularly to heterocyclic inhibitors of glycogen synthase kinase 3.beta., GSK-3. Alzheimer's disease (AD) is a neurodegenerative process characterised by cognitive disorders associated with a progressive deterioration of the cholinergic function, and neuropathological lesions as senile plaques, formed by the fibrillary.beta.-amyloid, and neurofibrillary tangles, bundles of paired helical filaments. Generally speaking, AD is restricted to groups aged 60 years or more and is the most common cause of dementia in the elderly population. Today, AD affects 23 million people worldwide. As longevity increases, it is estimated that by the year 2050 the number of cases of AD will more than triplicate [Amaduci, L.; Fratiglioni, L. "Epidemiology of AD: Impact on the treatment", in Alzheimer Disease: Therapeutic Strategies, E. Giacobini and R. Becker, Eds., Birhauser, EEUU, 1994, pp. 8]. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Heterocyclic compounds Inventor(s): Aoki, Tomiyoshi; (Harmadacho, JP), Kuwabara, Kenji; (Otsu-shi, JP) Correspondence: Greenberg Traurig, Llp; 885 3rd Avenue; New York; NY; 10022; US Patent Application Number: 20030166697 Date filed: November 18, 2002 Abstract: The present invention provides a preventive or therapeutic agent for hyperlipidemia, comprising as an active ingredient a heterocyclic compound of the formula [1], or a pharmaceutically acceptable salt thereof:R.sup.1-Het-D-E [1]wherein:R.sup.1 is optionally substituted aryl or aromatic heterocyclic group, Het is a divalent aromatic heterocyclic group, D is alkylene, alkenylene, alkynylene, or the like, and E is carboxy, or the like, and novel compounds among the heterocyclic compounds of the formula [1] above, which has blood triglyceride lowering effect, LDL-C lowering effect, and blood glucose lowering effect and blood insulin lowering effect, or HDL-C increasing effect or atherogenic index lowering effect all together, and hence is useful in the prevention or treatment of hyperlipidemia, arteriosclerosis, diabetes mellitus, hypertension, obesity, and the like. Excerpt(s): The present invention is related to novel heterocyclic compounds and pharmaceutically acceptable salts thereof. The compounds of the present invention have blood triglyceride lowering effect, low-density lipoprotein cholesterol (hereinafter, referred to as "LDL-C") lowering effect, and also blood glucose lowering effect, blood insulin lowering effect, or high-density lipoprotein cholesterol (hereinafter, referred to as "HDL-C") increasing effect, atherogenic index lowering effect, which index is the ratio of non-HDL-C to HDL-C calculated according to the formula: (total cholesterol--HDLC)/(HDL-C). Accordingly, the compounds of the present invention are useful in the prevention and treatment of coronary artery disease, cerebral infarction, hyperlipidemia, arteriosclerosis or diabetes mellitus. The insulin resistant syndrome complicated by disorder of carbohydrate and/or lipid metabolism and hypertension

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attracts attention as a multi-risk group of high incidence of ischemic heart disease. The insulin resistant syndrome is found in most of patients suffering from obesity and non insulin-dependent diabetes mellitus (NIDDM). The metabolic disorder of lipids herein recognized is the increase in blood triglycerides mainly due to the increase in chylomicron, very low density lipoproteins, and remnant lipoproteins which are the intermediary metabolites thereof, and the decrease in HDL-C (Diabetes, 37, 15951607(1988); Arch. Intern. Med., 149, 1514-1520(1989); Diabetes Care, 14, 173-194 (1991)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method and composition for inhibiting arteriosclerosis Inventor(s): Fujii, Kenji; (Kobe, JP), Hidaka, Takayoshi; (Kobe, JP), Hosoe, Kazunori; (Takasago, JP), Kawabe, Taizo; (Takasago, JP) Correspondence: Sughrue Mion, Pllc; 2100 Pennsylvania Avenue, N.W.; Washington; DC; 20037; US Patent Application Number: 20040010047 Date filed: July 30, 2003 Abstract: The present invention has for its object to provide a method and a composition for achieving a more efficient recovery of the antioxidant activity of plasma LDL, or even augmentation thereof, which has been depressed by the use of an antihyperlipidemic or cholesterol-lowering drug to thereby insure a potentiated antiarteriosclerotic efficacy.A method for inhibiting arteriosclerosis, which comprises using a combination of a cholesterol-lowering agent and a reduced coenzyme Q.sub.10 represented by the following formula (1), and a composition for inhibiting arteriosclerosis containing both a cholesterol-lowering agent and said reduced coenzyme Q.sub.10. 1 Excerpt(s): The present invention relates to a method for achieving a potentiated effect of inhibiting arteriosclerosis expressed through the concomitant use of a drug having cholesterol-lowering activity, for example a hydroxymethylglutaryl-CoA reductase inhibitor (hereinafter referred to as a statin), and a reduced coenzyme Q.sub.10 occurring in plasma low-density lipoprotein (hereinafter referred to as LDL) and having LDL antioxidant activity and to a composition therefor. Coronary arterial disease is one of the diseases deserving the utmost attention today. It is suspected that a variety of factors contribute in a complex way to arteriosclerosis which triggers coronary arterial disease but an increased blood level of cholesterol is a major factor and the more direct factor is the increase and oxidative degeneration of low-density lipoprotein (LDL) which comprises cholesterol particles. For the prevention of arteriosclerosis, it is important to lower the blood cholesterol level. Statins reportedly produce marked cholesterol lowering effects in patients with hypercholesterolemia. Statins inhibit hydroxymethylglutaryl-CoA reductase, the rate-determining enzyme in cholesterol biosynthesis, to thereby interfere with cholesterol biosynthesis and through the consequent reduction in intrahepatic cholesterol content and ensuing increase in LDL receptors, lower the plasma cholesterol level. However, notwithstanding the fact that it is about a decade since this drug was developed, there has been reportedly no change in the incidence of coronary arterial disease and it is, thus, insufficient to merely lower cholesterol alone for the inhibition of arteriosclerosis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Method and use of extract of a member of Typhaceae's family Inventor(s): Zhou, Tong-Shui; (Shanghai, CN) Correspondence: Raymond Y. Chan; Suite 128; 108 N. Ynez AVE.; Monterey Park; CA; 91754; US Patent Application Number: 20040018261 Date filed: July 16, 2003 Abstract: An extract of Typhae Pollen which is a traditional Chinese medicine consisting of flavonoids as active components includes at least one member of the group selected from kaempferol, quercetin and isorhamnetin and the derivatives of these active components. The present invention also relates to the degraded form of flavonoids, the metal derivatives formed with sodium and potassium salts, and the metal complex formed with a predetermined metal ion. The extract of Typhae Pollen is prepared by a plurality of extraction processes and has a plurality of functions for promoting health including lowering blood lipid level, preventing arteriosclerosis, promoting tolerance of brain and heart tissue under anaerobic condition, preventing blood platelet coagulation, preventing thrombosis and stop bleeding. The extract of Typhae Pollen of the present invention is also used for preventing and treating diseases related to blood vessels in brain and heart, and poor blood circulation induced diseases selecting from the group consisting of chest pain, stomachache, physical injuries, puerperium pain and menstruation. Excerpt(s): The present invention relates to technology in medical and health science, and more particularly to an extract of a Typhae Pollen and its manufacture and application in medicine and health science. `Typhae Pollen` is a common traditional Chinese medicine, which is generally dried pollen of the family Typhaceae such as Typha angustifolia L. and Typha orientalis Presl. According to the principles of the tradition Chinese medicine, Typhae Pollen has the properties of stop bleeding, bruise heeling, and enhancing circulation of the lymphatic system and it has been widely used in the treatment of bleeding, apistaxis, hematemesis, external bleeding, painful menstruation, colic, abscess, painful lymphatic system's disease or discomfort. Recent scientific researches envisage that the extracted components of Typhae Pollen by water extraction or alcohol extraction is capable of substantially increasing the coronary blood flow, improving microcirculation, increasing the tolerance ability of brain and cardiac muscle under anaerobic condition, lowering the consumption of oxygen of brain and heart system, promoting blood vessel dilation, lowering the blood lipid level, preventing arteriosclerosis, and acting as anticoagulant. All the different species of Typhae Pollen comprises organic acid, flavonoids, sterol components, long chain aliphatic components and polysaccharides. The principles and applications of these chemical components were only once disclosed in a Chinese patent 1006015 in China wherein the active mechanism and application of lowering blood lipid level of sterol, long chain aliphatic compounds of Typhae Pollen were described. Since then, there is no related arts relating to Typhae Pollen's extract. A main object of the present invention is to provide an extract of Typhae Pollen and a manufacturing method thereof wherein one of the extract components is flavonol glycosides. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Method for improving the cell protection Inventor(s): Soldati, Fabio; (Savosa, CH) Correspondence: Sterne, Kessler, Goldstein & Fox Pllc; 1100 New York Avenue, N.W.; Washington; DC; 20005; US Patent Application Number: 20040009248 Date filed: July 14, 2003 Abstract: The invention relates to a method for improving the cell protection which comprises the administration of a combination of the extracts of the plants Vitis vinifera and Lycopersicon esculentum with the vitamins C, E, beta-carotene and optionally selenium. Said combination can be used in the prevention of phatological conditions related in part to an overproduction of free radicals like aging, arteriosclerosis and cancer. Excerpt(s): The present application is a divisional of U.S. patent application Ser. No. 09/863,768, Filed on May 24, 2001, which claims benefit of the filing date of U.S. appl. Ser. No. 60/206,945, filed May 25, 2000, the disclosures of which are incorporated herein in entirety by reference. The present invention is related to a novel method of improving the cell protection, which utilises the administration of the combination of the extracts of the plants Vitis vinifera and Lycopersicon esculentum with the vitamins C, E, betacarotene and selenium, as well as the use of such combination for treating or preventing pathologies related to an overproduction of free radicals like aging, arteriosclerosis and cancer. Antioxidants act to protect components of the body against free radical damage (Harman D.; Holliday R. and M. Meydany--Editor, "Towards Prolongation of healthy life span", Annals of the New York Academy of Sciences, Vol. 854, 1998, New York; Sthlin H. B., "The Impact of Antioxidants on Chronic Disease in Aging and Old Age", Int. J. Vitamin. Nutr. Res. 69, 146-149, 1999). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Method for prophylaxis and treatment of diabetic complications with 4[alphahydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic acid and derivatives Inventor(s): Goto, Nobuharu; (Iruma-shi, JP), Hayashi, Yoshiharu; (Iruma-shi, JP) Correspondence: Wenderoth, Lind & Ponack, L.L.P.; 2033 K Street N. W.; Suite 800; Washington; DC; 20006-1021; US Patent Application Number: 20030130332 Date filed: January 30, 2003 Abstract: The present invention relates to an agent for the prophylaxis and treatment of diabetic complications comprising, as an active ingredient, 4-[.alpha.-hydroxy-2-methyl5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic acid, an optically active compound thereof or a pharmaceutically acceptable salt thereof. The present invention further relates to a method for the prophylaxis and treatment of diabetic complications comprising administering an effective amount of this compound. The medicament of the present invention is useful for the prophylaxis and treatment of diabetic complications, namely, diabetic neuropathy, nephropathy, ophthalmopathy, arteriosclerosis and the like. The action of the drug is long-lasting for very small doses and a single administration a day is sufficient.

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Excerpt(s): This is a divisional of Ser. No. 09/091,993, filed Jun. 26, 1998, which is a 371 of PCT/JP96/03776, filed Dec. 24, 1996. The present invention relates to an agent for the prophylaxis and treatment of diabetic complications, namely, to an agent for the prophylaxis and treatment of diabetic neuropathy, nephropathy, ophthalmopathy and arteriosclerosis. More particularly, the present invention relates to an agent for the prophylaxis and treatment of diabetic complications comprising, as an active ingredient, 4-[.alpha.-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic acid, an optically active compound thereof or a pharmaceutically acceptable salt thereof. The present invention further relates to a method for the prophylaxis and treatment of diabetic complications. The discovery of insulin and its clinical application resulted in drastic progress in the treatment of diabetes. Life sustention of the patients with diabetes--which had been a deadly disease until then--was strikingly improved. However, the therapy of chronic complications of diabetes has become a new problem. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method of searching for arteriosclerosis inhibitors and shrinkers Inventor(s): Fuse, Hiromitsu; (Tsukuba-shi, JP), Kita, Shunbun; (Hyogo, JP), Nakamura, Masahira; (Nara, JP), Tozawa, Ryuichi; (Osaka, JP) Correspondence: Takeda Pharmaceuticals North America, Inc; Intellectual Property Department; 475 Half Day Road; Suite 500; Lincolnshire; IL; 60069; US Patent Application Number: 20030139616 Date filed: October 22, 2002 Abstract: It is intended to find an efficient method of searching for drugs affecting the cholesteryl ester cycle and establish a system of efficiently searching for defoaming agents or regression agents artherosclerotic lesion and a system of searching for therapeutic agents remedies for atherosclerosis with a mechanism different from publicly known ones. A method of evaluating effects of a test substance on intracellular cholesteryl ester metabolic regulation which comprises selectively extracting free cholesterol with an aqueous alcohol from cells having been incubated in the presence of the test substance and cells having been incubated in the absence of the test substance, and then comparing the cholesteryl ester content in the cells having been incubated in the presence of the test substance with the cholesteryl ester content in the cells having been incubated in the absence of the test substance; in particular, a method of screening a compound having an activity of regulating the intracellular cholesteryl ester metabolism; and defoaming promoters, antiatherogenic agents or agents for regression of atherosclerotic lesion containing as the active ingredient compounds screened by the above method. Excerpt(s): The present invention relates to a method of searching for compounds useful as antiatherogenic agents and regression agents. More specifically, it relates to a searching method of efficiently evaluating and screening drugs for preventing or treating atherosclerosis as a major cause of ischemic heart diseases such as angina pectoris, myocardial infarction etc., and cerebral infraction ranked highest as a cause of death. Studies on atherosclerosis have been conducted in light of pathogenic morphological features by using experimental atherosclerosis or human dissected preparations. A visual initial change in atherosclerosis lies in spot or linear fat deposition called fatty streak. Histologically, this change has been found to be attributable to accumulation of cells (foam cells) mainly composed of macrophages having cholesterol esters accumulated therein. Fatty streaks turn finally into fibrous

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plaques to be protruded from vascular walls, and infiltration thereof into smooth muscular cells, macrophages, T cells etc., cell necrosis images and accumulation of lipid are histologically recognized. As the morbid state further advances, the fibrous plaques accompanied by calcification and adhesion of thrombi cause vascular cavities to be narrow, or the plaques are ruined to cause thrombotic occlusion, and this is revealed to be closely related to occurrence of the acute coronary syndrome such as acute myocardial infarction, insecurity angina pectoris and ischemic sudden death (Fuster V et al., N. Engl. J. Med., 326, 242-250, 1992). It has also been revealed from a previous study that the readily ruined plaques have thin fibrous capsules, contain a large amount of lipid components such as cholesterol esters, and are instable (Erling F et al., Circulation, 92, 657-671, 1995), and therefore, removal of cholesterol esters, particularly cholesteryl esters from lesions, that is, defoaming, can be expected to stabilize instable plaques and to prevent them from being ruined, thus bringing about stabilization and regressione of atherosclerotic lesions thereby significantly reducing occurrence and recurrence of the acute coronary syndrome attributable to atherosclerosis. As the intracellular cholesterol metabolic system involved in cellular foaming and defoaming, a metabolic cycle participating in exchange of free cholesterol with cholesteryl esters, that is, the cholesteryl ester cycle (Brown M S et al., J. Biol. Chem., 255, 9344-9352 (1980)) is known, and the turnover rate and equilibrated state of the cholesteryl ester cycle are reported to influence an activity of cellular foaming or defoaming (Hakamata H. et al., Arerioscr. Thromb., 14, 1860-1865 (1994)). The intracellular cholesteryl ester cycle is estimated to depend significantly on the activity of ACAT (Acyl-coenzyme A: cholesterol Acyltransferase) contributing to esterification of mainly free cholesterol and on the activity of neutral cholesteryl ester hydrolase contributing to hydrolysis of cholesteryl esters, but there are many unrevealed aspects in this regulatory mechanism. Accordingly, drugs regulating the cholesteryl ester cycle or drugs influencing formation and degradation of cholesteryl esters have the possibility of promoting cellular defoaming or regression of atherosclerotic lesions in a mechanism not known in the past, and are regarded as being effective as novel agents for treating atherosclerosis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods and compounds for influencing beta3-integrin-dependent intracellular processes Inventor(s): Gawaz, Meinrad; (Munchen, DE), Kolanus, Waldemar; (Bonn, DE), Ungerer, Martin; (Munchen, DE) Correspondence: Myers Bigel Sibley & Sajovec; PO Box 37428; Raleigh; NC; 27627; US Patent Application Number: 20040029775 Date filed: July 1, 2003 Abstract: The invention relates to the use of.beta.3-endonexin-long or.beta.3-endonexinshort for finding active substances for the treatment of arteriosclerosis, unstable plaques resulting from the latter, acute coronary thrombosis, cardiac infarct, stroke, peripheral arterial occlusion diseases, chronic venous ulcer and restenosing processes. Excerpt(s): The present invention relates to the influencing of.beta.3-integrin-dependent intracellular processes for the purpose of treating acute and chronic vascular diseases. The present invention relates especially to new uses of the known proteins.beta.3endonexin-short and.beta.3-endonexin-long to find active substances, and to specific methods of identifying active substances for the treatment of acute and chronic vascular diseases. The invention further relates to test mixtures for identifying active substances

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and to specific kits for identifying active substances. The invention relates also to medicaments that comprise active substances for influencing.beta.3-integrin-dependent intracellular processes for the purpose of treating acute and chronic vascular diseases, and to methods of treatment that employ such medicaments. Integrins are.alpha./.beta. heterodimeric surface proteins and belong to a class of adhesion receptors that mediate interactions between cells or between cells and the extracellular matrix.beta.3-Integrins form a sub-class of the integrins and provide dynamic links between cells and the extracellular matrix, with information transfer between the following two key regions of.beta.3-integrin being involved: the binding domains of the extracellular ligand and the intracellular cytoplasmic receptor domains. The signal transmission via.beta.3integrins is bidirectional. "Inside-out" signals regulate the affinity of.beta.3-integrin for the ligand and control cell adhesion. "Outside-in" signals go from the.beta.3-integrin connection to the extracellular matrix and regulate many fundamental intracellular processes, including cell survival and proliferation, cellular differentiation, morphogenesis, cell migration, phagocytosis, gene transcription and integrin localisation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods of treating vascular disease Inventor(s): Bach, Fritz H.; (Mancester-by-the-sea, MA), Choi, Augustine M. K.; (Pittsburgh, PA), Otterbein, Leo E.; (New Kensington, PA), Zuckerbraun, Brian; (Pittsburgh, PA) Correspondence: Fish & Richardson PC; 225 Franklin ST; Boston; MA; 02110; US Patent Application Number: 20030219496 Date filed: February 13, 2003 Abstract: The present invention relates to a method of treating patients suffering from, or at risk for, intimal hyperplasia and/or arteriosclerosis. The treatment includes administering a pharmaceutical composition that includes carbon monoxide to the patient. Excerpt(s): This application claims priority to U.S. Provisional Application No. 60/356,718 filed Feb. 13, 2002, which is incorporated herein by reference in its entirety. This invention generally relates to treating vascular disease. Heme oxygenase-1 (HO-1) catalyzes the first step in the degradation of heme. HO-1 cleaves the.alpha.-meso carbon bridge of b-type heme molecules by oxidation to yield equimolar quantities of biliverdin IXa, carbon monoxide (CO), and free iron. Subsequently, biliverdin is converted to bilirubin via biliverdin reductase, and the free iron is sequestered into ferritin (the production of which is induced by the free iron). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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New biphenyl and biphenyl-analogous compounds as integrin antagonists Inventor(s): Albers, Markus; (Leverkusen, DE), Brueggemeier, Ulf; (Leverkusen, DE), Gerdes, Christoph; (Leverkusen, DE), Harter, Michael; (Leverkusen, DE), Keldenich, Jorg; (Wuppertal, DE), Lustig, Klemens; (Wuppertal, DE), Schmidt, Delf; (Wuppertal, DE), Stahl, Elke; (Bergisch Gladbach, DE), Stelte-Ludwig, Beatrix; (Wulfrath, DE), Urbahns, Klaus; (Wuppertal, DE), Vaupel, Andrea; (Wuppertal, DE) Correspondence: Kurt Briscoe; Norris, Mclaughlin & Marcus, P.A.; 220 East 42nd Street, 30th Floor; New York; NY; 10017; US Patent Application Number: 20040030132 Date filed: October 31, 2002 Abstract: The present invention relates to biphenyl and biphenyl-analogous compounds, their preparation and use as pharmaceutical compositions, as integrin antagonists and in particular for the production of pharmaceutical compositions for the treatment and prophylaxis of cancer, arteriosclerosis, restenosis, osteolytic disorders such as osteoporosis and ophthalmic diseases. The compounds according to the invention have the formula (1) 1whereinR.sup.1, R.sup.2, U, V, A, B, W, R.sup.3, C and R.sup.4 have the meaning as defined in the claims. Excerpt(s): The present invention relates to new biphenyl and biphenyl-analogous compounds, their preparation and use as pharmaceutical compositions, as integrin antagonists and in particular for the production of pharmaceutical compositions for the treatment and prophylaxis of cancer, arteriosclerosis, restenosis, osteolytic disorders such as osteoporosis, rheumatoid arthritis and ophthalmic diseases. Integrins are heterodimeric transmembrane proteins found on the surface of cells, which play an important part in the adhesion of the cells to an extracellular matrix. They recognize extracellular glycoproteins such as fibronectin or vitronectin on the extracellular matrix by means of the RGD sequence occurring in these proteins (RGD is the single letter code for the amino acid sequence arginine-glycine-aspartate). In general, integrins such as, for example, the vitronectin receptor, which is also called the.alpha.sub.v.beta.sub.3 receptor, or alternatively the.alpha.sub.v.beta.sub.5 receptor or the GpIIb/IIIa receptor play an important part in biological processes such as cell migration and cell-matrix adhesion and thus in diseases in which these processes are crucial steps. Cancer, osteoporosis, arteriosclerosis, restenosis (reoccurrence of stenosis after percutaneous transluminal angioplasty) and opthalmia may be mentioned by way of example. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Nitrogen-containing heterocyclic compounds Inventor(s): Fujiwara, Shigeki; (Shizuoka, JP), Ichimura, Michio; (Shizuoka, JP), Ide, Shinichi; (Shizuoka, JP), Irie, Junko; (Shizuoka, JP), Matsuno, Kenji; (Shizuoka, JP), Nomoto, Yuji; (Shizuoka, JP), Oda, Shoji; (Shizuoka, JP), Tsukuda, Eiji; (Kanagawa, JP) Correspondence: Fitzpatrick Cella Harper & Scinto; 30 Rockefeller Plaza; New York; NY; 10112; US Patent Application Number: 20030229077 Date filed: August 26, 2002 Abstract: The present invention provides nitrogen-containing heterocyclic compounds and pharmaceutically acceptable salts thereof which inhibit phosphorylation of PDGF

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receptor to hinder abnormal cell growth and cell wandering and thus are useful for the prevention or treatment of cell-proliferative diseases such as arteriosclerosis, vascular reobstruction, cancer and glomerulosclerosis. The compounds are represented by general formula (I): 1whereinV represents an oxygen atom or a sulfur atom;W represents 1,4-piperazinediyl or 1,4-homopiperazinediyl in which carbons on the ring may be substituted by unsubstituted alkyl groups;X represents a nitrogen atom or C-R.sup.9;Y represents a nitrogen atom or C--R.sup.8;Z represents a nitrogen atom or C-R.sup.7 (provided that at least one of X, Y and Z represents a nitrogen atom);R.sup.1 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alicyclic alkyl group, etc.;R.sup.2 represents a substituted alkyl group, a substituted or unsubstituted alicyclic alkyl group, etc.;R.sup.3, R.sup.4, R.sup.5 and R.sup.6, which may be the same or different, each represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a nitro group, a cyano group, --OR.sup.12, --NR.sup.15R.sup.16, etc.;R.sup.7 represents a halogen atom, etc.;R.sup.8 has the same significance as R.sup.7, andR.sup.9 represents a hydrogen atom or -COR.sup.41. Excerpt(s): This application is a continuation-in-part of application PCT/JP97/03510, filed Oct. 1, 1997. The present invention relates to nitrogen-containing heterocyclic compounds and pharmaceutically acceptable salts thereof which have inhibitory activity on phosphorylation of platelet-derived growth factor (PDGF) receptor and are useful for the treatment of cell-proliferative diseases such as arteriosclerosis, vascular reobstruction, cancer and glomerulosclerosis. PDGF is known to act as an aggravating factor for cell-proliferative diseases such as arteriosclerosis, vascular reobstruction after percutaneous coronary angioplasty and bypass operation, cancer, glomerulonephritis, glomerulosclerosis, psoriasis and articular rheumatism [Cell, 46, 155-169 (1986); Science, 253, 1129-1132 (1991); Nippon Rinsho (Japanese J. of Clinical Medicine), 50, 3038-3045 (1992); Nephrol Dial Transplant, 10, 787-795 (1995); Kidney International, 43 (Suppl. 39), S86-S89 (1993); Journal of Rheumatology, 21, 1507-1511 (1994); Scandinavian Journal of Immunology, 27, 285-294 (1988), etc.]. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Novel imidazonline compounds Inventor(s): Fukami, Takehiro; (Tsukuba-shi, JP), Ishihara, Akane; (Tsukuba-shi, JP), Ishii, Yasuyuki; (Tsukuba-shi, JP), Jitsuoka, Makoto; (Tsukuba-shi, JP), Kanatani, Akio; (Tsukuba-shi, JP), Nagai, Keita; (Tsukuba-shi, JP), Okamoto, Osamu; (Tsukuba-shi, JP), Sato, Nagaaki; (Tsukuba-shi, JP) Correspondence: Wenderoth, Lind & Ponack, L.L.P.; 2033 K Street N. W.; Suite 800; Washington; DC; 20006-1021; US Patent Application Number: 20030158418 Date filed: September 25, 2002 Abstract: Compounds represented by the general formula (I): 1wherein Ar.sup.1 and Ar.sup.2 are each aryl or heteroaryl; R.sup.1 is lower cycloalkyl, --Ar.sup.3, or a group of the general formula (a), (b) or (c): 2and R.sup.2 and R.sup.3 are each hydrogen, lower cycloalkyl, lower alkenyl, or optionally substituted lower alkyl (with the proviso that when R.sup.2 and R.sup.3 are simultaneously hydrogen, Ar.sup.1, Ar.sup.2 and R.sup.1 do not simultaneously represent unsubstituted phenyl). The compounds are useful as treating agents for various NPY-related diseases, for example, circulatory diseases including hypertension, kidney diseases, cardiac diseases, vasospasm and

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arteriosclerosis; central nervous system diseases including hyperphagia, depression, anxiety, convulsion, epilepsy, dementia, pain, alcohol dependence, and withdrawal symptoms due to abstinence from drugs; metabolic diseases including obesity, diabetes, hormonal disorders, hypercholesterolemia, and hyperlipidemia; sexual dysfunction and reproductive function disorders; digestive diseases including enterokinetic disorders; respiratory diseases; inflammation; or glaucoma. Excerpt(s): The present invention is useful in medical fields. In more detail, novel imidazoline compounds of this invention are useful as neuropeptide Y receptor antagonists and as agents for the treatment of various kinds of cardiovascular disorders, central nervous system disorders, metabolic diseases, or the like. Neuropeptide Y (hereinafter referred to as NPY), a peptide consisting of 36 amino acids, was first isolated from porcine brain by Tatemoto et al. in 1982 (Nature, 296: 659(1982)). NPY is widely distributed in the central nervous system and the peripheral nervous system and plays various roles as one of the most abundant peptide in the nervous system. That is, NPY acts as an orexigenic substance in the central nervous system and markedly promotes fat accumulation via the secretion of various hormones or the action of the nervous system. It is known that the continuous intracerebroventricular administration of NPY induces obesity and insulin resistance based on these actions (International Journal of Obesity, vol.19:517(1995); Endocrinology, vol.133: 1753(1993)). It is also known that NPY has central effects, such as depression, anxiety, schizophrenia, pain, dementia, or the like (Drugs, vol.52: 371(1996)). Further, in the periphery, NPY coexists with norepinephrine in sympathetic nerve ending and is involved in the tonicity of the sympathetic nervous system. It is known that peripheral administration of NPY causes vasoconstriction and enhances the effects of other vasoconstrictive substances such as norepinephrine (British Journal of Pharmacology, vol.95: 419(1988)). It is also reported that NPY is involved in the enhancement of cardiac hypertrophy as a result of the acceleration of sympathetic nervous system (Proceeding National Academic Science USA, vol. 97: 1595(2000)). Further, it is reported that NPY is also involved in the secretory function of sexual hormones and growth hormone, sexual and reproductive function, gastrointestinal motility, bronchoconstriction, inflammation and alcohol preference (Life Science, vol. 55: 551(1994); The Journal of Allergy and Immunology, vol. 101: S345(1998); Nature, vol.396: 366(1998)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Novel protein, its production and use Inventor(s): Taniyama, Yoshio; (Ibaraki, JP) Correspondence: Takeda Pharmaceuticals North America, Inc; Intellectual Property Department; 475 Half Day Road; Suite 500; Lincolnshire; IL; 60069; US Patent Application Number: 20030175905 Date filed: December 18, 2002 Abstract: This invention relates to a novel protein having a lecithin-cholesterol acyltransferase-like activity, etc. or its salt, a precursor protein of the protein or its salt, a partial peptide of the protein or its salt; a DNA coding for the protein; a recombinant vector; a transformant; a method for producing the protein, a pharmaceutical composition comprising the protein, the partial peptide or its salt; and an antibody to the protein or the partial peptide. The protein, the partial peptide or its salt, and the DNA are useful as an agent for treating or preventing arteriosclerosis, atherosclerosis, hyperlipidemia, hypercalorism, obesity or hypertriglyceridemia. The antibody can be

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used in assay of the protein, the partial peptide or its salt. The protein, the partial peptide or its salt is useful as a reagent for the screening for candidate medical compounds. Excerpt(s): The present invention relates to a novel protein having a lecithin-cholesterol acyltransferase-like activity etc. and a DNA coding for the protein. Cholesterol is an important lipid constituting the animal cell membrane and defining its character. Moreover, it is a precursor of steroid hormones, thus being a substance essential to animal life. However, due to the recent changes in dietary habit and ecology, arteriosclerosis and other adult diseases arising from pathological intracellular accumulation of cholesterol are now presenting a serious problem so that elucidation of the mechanisms of cholesterol metabolism in the body is being awaited. In the efflux of cholesterol from the peripheral cells, high density lipoprotein (hereinafter sometimes referred to briefly as HDL) is suspected to play a cardinal role and this assumption has been supported by the epidemiologic finding of an inverse correlation between risk for coronary artery disease and plasma HDL levels and the experimental finding that HDL in culture medium stimulates cholesterol efflux from cells and decreases the intracellular concentration of cholesterol (Journal of Lipid Research, 37, 2473, 1996). In the reverse cholesterol transport system, lecithin-cholesterol acyltransferase (hereinafter sometimes referred to briefly as LCAT) is involved to a significant extent. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Novel spiro compounds Inventor(s): Fukami, Takehiro; (Tsukuba-shi, JP), Haga, Yuji; (Tsukuba-shi, JP), Ishihara, Akane; (Tsukuba-shi, JP), Ishii, Yasuyuki; (Tsukuba-shi, JP), Itoh, Takahiro; (Okazakishi, JP), Kanatani, Akio; (Tsukuba-shi, JP), Sakamoto, Toshihiro; (Tsukuba-shi, JP), Takahashi, Toshiyuki; (Tsukuba-shi, JP) Correspondence: Wenderoth, Lind & Ponack, L.L.P.; 2033 K Street N. W.; Suite 800; Washington; DC; 20006-1021; US Patent Application Number: 20030220499 Date filed: June 4, 2003 Abstract: Compounds of the general formula (I): 1(wherein Ar.sup.1 represents optionally substituted aryl or heteroaryl;n represents 0 or 1;T, U, V and W represent independently nitrogen atom or optionally substituted methine group, where at least two of them represent the said methine group;X represents methine or nitrogen;Y represents optionally substituted imino or oxygen atom) exhibit NPY antagonistic activities and are useful as agents for the treatment of various diseases related to NPY, for example, cardiovascular disorders such as hypertension, nephropathy, heart disease, vasospasm, arteriosclerosis and the like, central nervous system disorders such as bulimia, depression, anxiety, seizure, epilepsy, dementia, pain, alcoholism, drug withdrawal and the like, metabolic diseases such as obesity, diabetes, hormone abnormality, hypercholesterolemia, hyperlipidemia and the like, sexual and reproductive dysfunction, gastrointestinal disorder, respiratory disorder, inflammation or glaucoma, and the like. Excerpt(s): The present invention is useful in medical fields. In more detail, novel spiro compounds of this invention are useful as neuropeptide Y receptor antagonists and as agents for the treatment of various kinds of cardiovascular disorders, central nervous system disorders, metabolic diseases, and the like. Neuropeptide Y (hereinafter referred

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to as NPY), a peptide consisting of 36 amino acids, was first Isolated from porcine brain by Tatemoto et al. in 1982 [Nature, 296: 659 (1982)]. NPY is widely distributed in central nervous system and peripheral nervous system and plays various roles as one of the most abundant peptide in the nervous system. That is, NPY acts as an orexigenic substance in the central nervous system and markedly promotes fat accumulation via the mediation of the secretion of various hormones or the action of the nervous system. It is known that the continuous intracerebroventricular administration of NPY induces obesity and insulin resistance based on these actions (International Journal of Obesity, vol.19: 517 (1995); Endocrinology, vol.133: 1753 (1993)). It is also known that NPY has central effects, such as depression, anxiety, schizophrenia, pain, dementia and the like (Drugs, vol.52, 371(1996). Further, in the periphery, NPY coexists with norepinephrine in sympathetic ending and is involved in the tonicity of the sympathetic nervous system. It is known that peripheral administration of NPY causes vasoconstriction and enhances the activities of other vasoconstrictive substances such as norepinephrine (British Journal of Pharmacology, vol.95: 419 (1988)). It is also reported that NPY could participate in the development of cardiac hypertrophy as a result of the sympathic stimulation (Proceeding National Academic Science USA, Vol. 97, 1595(2000)). On the other hand, it is reported that NPY is also involved in the secretory function of sexual hormones and growth hormone, sexual behavior and reproductive function, gastrointestinal motility, bronchoconstriction, inflammation and alcohol preference (Life Science, vol. 55, 551(1994); The Journal of Allergy and Immunology, vol. 101, S345(1998); Nature, vol. 396, 366(1998)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Pharmaceutical agent containing Rho kinase inhibitor Inventor(s): Kawahara, Toshio; (Chikujo-gun, JP), Ono, Takashi; (Iruma-shi, JP), Satoh, Hiroyuki; (Chikujo-gun, JP), Uehata, Masayoshi; (Iruma-shi, JP), Yamagami, Keiji; (Iruma-shi, JP) Correspondence: Wenderoth, Lind & Ponack, L.L.P.; 2033 K Street N. W.; Suite 800; Washington; DC; 20006-1021; US Patent Application Number: 20030134775 Date filed: July 31, 2002 Abstract: A Rho kinase inhibitor is provided as a novel pharmaceutical agent, particularly as a therapeutic agent of hypertension, a therapeutic agent of angina pectoris, a suppressive agent of cerebrovascular contraction, a therapeutic agent of asthma, a therapeutic agent of peripheral circulation disorder, a prophylactic agent of immature birth, a therapeutic agent of arteriosclerosis, an anti-cancer drug, an antiinflammatory agent, an immunosuppressant, a therapeutic agent of autoimmune disease, an anti-AIDS drug, a contraceptive, a prophylactic agent of digestive tract infection, a therapeutic agent of osteoporosis, a therapeutic agent of retinopathy and a brain function improving drug. In addition, the Rho kinase inhibitor is provided as a reagent and a diagnostic. Excerpt(s): The present invention relates to treatment of various diseases by the use of a Rho kinase inhibitor as a pharmaceutical agent. Moreover, the present invention relates to use of a Rho kinase inhibitor as a reagent or a diagnostic. Ever since the discovery of Ras in 1981, a number of small GTP binding proteins (small G proteins) similar to Ras have been found, and many physiological functions they possess have been studied. These small G proteins have a molecular weight of 20,000-30,000 and do not have a

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subunit structure. They all specifically bind GDP and GTP, and hydrolyze the thusbound GTP (GTPase activity) (Hall, A., Science, 249, 635-640, 1990; Bourne, H. R. et al., Nature, 349, 117-127, 1991). To date, more than 50 kinds of genes encoding these small G proteins have been found from yeast to mammals, forming a superfamily. These small G proteins are largely divided into 5 groups of Ras, Rho, Rab, Arf and others, according to the similarity of amino acid sequences. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Photosensitisers Inventor(s): Bell, Andrea Lucille; (Bradford, GB), Brown, Stanley Beames; (West Yorkshire, GB), Griffiths, John; (Leeds, GB), Schofield, Jack; (West Yorkshire, GB) Correspondence: Paul D. Greeley, ESQ.; Ohlandt, Greeley, Ruggiero & Perle; Suite 903; One Landmark Square; Stamford; CT; 06901; US Patent Application Number: 20030180224 Date filed: March 21, 2003 Abstract: According to the present invention there is provided a compound for use as a photosensitiser in PDT, in photochemical internalisation in the production of a cancer vaccine or in the diagnosis or detection of medical conditions, the compound having a photosensitising chromophoric system, a sulphonamido functionality and a carboxy functionality.The compounds used in the present invention are photosensitisers in PDT in vivo, and show phototoxic activity in vitro. The compounds are used to treat precancerous conditions, cancer, ophthalmological disease, vascular problems, arteriosclerosis and restenosis and autoimmune diseases, skin diseases and other benign conditions, and for anti-microbial treatments. Excerpt(s): This application is a continuation-in-part of application no. PCT/GB01/04224 filed 21 Sep. 2001. This invention relates to chemical compounds which act as photosensitisers and may be used in a type of medical treatment known as photodynamic therapy (PDT), as well as for the diagnosis and detection of medical conditions and related uses in photochemical internalisation, in the production of cancer vaccines and in the treatment of bacterial infections including photodisinfections. Photodynamic therapy is used in the treatment of cancer and other diseases. In this treatment a light absorbing compound (the photosensitiser) is applied to a tumour or other lesion. Subsequently laser light is used to activate the photosensitiser and the tumour tissue is destroyed in a process known as the photodynamic effect. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Remedies for ischemic disease Inventor(s): Fukuda, Keiichi; (Tokyo, JP), Hisaka, Yasuyo; (Tokyo, JP), Miyai, Tatsuya; (Tokyo, JP), Tamura, Masahiko; (Tokyo, JP) Correspondence: Browdy And Neimark, P.L.L.C.; 624 Ninth Street, NW; Suite 300; Washington; DC; 20001-5303; US Patent Application Number: 20040019184 Date filed: March 20, 2003

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Abstract: An effective remedy for ischemic disease, which contains human granulocyte colony-stimulating factor (human G-CSF) and hepatocyte growth factor (HGF) as active ingredients, is disclosed. By administering this remedy, an effective therapy particularly for obstructive arteriosclerosis is provided which can eliminate drawbacks with conventional therapies such as kinesitherapy, pharmacotherapy, revascularization and recently proposed therapies such as gene therapy and intramuscular inoculation of bone marrow cells. Furthermore, the remedy of the present invention can become a remedy for ischemic disease such as ischemic cerebrovascular disorder or ischemic heart disease. Excerpt(s): This application is a continuation-in-part of U.S. application as filed under 35 U.S.C.sctn. 371 by entry into the U.S. national stage of a PCT application, PCT/JP01/07946, filed on Sep. 13, 2001. This invention relates to a remedy for ischemic disease which contains human granulocyte colony-stimulating factor (G-CSF) and hepatocyte growth factor (HGF) as active ingredients. The present invention is an invention concerned with remedies for ischemic disease. One typical ischemic disease, obstructive arteriosclerosis, will be described first. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Smooth muscle growth inhibitory arteriosclerosis, and kit therefor

composition,

diagnostic

method

for

Inventor(s): Matsuzawa, Yuji; (Takarazuka-shi, JP), Ohmoto, Yasukazu; (Itano-gun, JP) Correspondence: Sughrue Mion, Pllc; 2100 Pennsylvania Avenue, NW; Washington; DC; 20037-3213; US Patent Application Number: 20030166551 Date filed: July 8, 2002 Abstract: The invention provides not only a smooth muscle growth inhibitory composition and a composition for inhibiting expression of adhesion molecules in vascular endothelial cells, each comprising the adipose tissue-specific secretory factor apM1 as an active ingredient, but also a method for diagnosis of arteriosclerosis which comprises assaying apM1 in a sample, an antibody against apM1, and a diagnostic kit for arteriosclerosis which comprises the antibody as an active component, all of which contribute to the elucidation of obesity-related genes and corresponding expression products which are useful for the etiologic exploration and establishment of therapeutic modalities for various obesity-related diseases, particularly arteriosclerosis inclusive of angina pectoris and myocardial infarction. By utilizing the information thus obtained, therapeutic and diagnostic methods for various diseases can be established. Excerpt(s): This invention relates to a smooth muscle growth inhibitory composition comprising apM1 (adipose most abundant gene transcript 1) as an active ingredient, a method for diagnosis of arteriosclerosis (atherosclerosis) which comprises assaying said apM1 in a sample, and a diagnostic kit for arteriosclerosis which comprises an antibody against said apM1 as an active component. It is well known that, in modern society, obesity or an excessive accumulation of body fat is involved in the development of diabetes mellitus, hyperlipidemia, hypertension, and atherosclerotic diseases inclusive of angina pectoris and myocardial infarction. With obesity, not only genetic factors but also environmental factors are associated. Recently, leptin and many other obesityrelated genes have been isolated from animal models. While the group of these genes thus isolated is suspected to be involved in the establishment of obesity in man, various environmental factors such as the excessive food intake and insufficient physical

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exercise by contemporary man are also considered to be playing a crucial role in the development of diabetes mellitus and atherosclerosis via fat storage. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Synergistic antioxidant combination of delta tocols and polyphenols Inventor(s): Hasler-Nguyen, Nathalie; (Le Muids, CH), Troup, John P.; (Commugny, CH), Zijlstra, Jacob; (Coppet, CH) Correspondence: Thomas Hoxie; Novartis, Corporate Intellectual Property; One Health Plaza 430/2; East Hanover; NJ; 07936-1080; US Patent Application Number: 20040023894 Date filed: July 24, 2003 Abstract: A source of.delta.-tocotrienol and/or-tocopherol acts synergistically with an antioxidant source comprising polyphenols, to effect suppression of LDL oxidation in serum. The combination of these two antioxidant sources has wide-ranging applications in treatment of medical conditions arising from free radical generation, including arteriosclerosis and cancer. Excerpt(s): The present invention relates to compositions comprising a combination of at least one source of.delta.-tocols (tocotrienol and/or tocopherol), with an antioxidant source comprising polyphenolic compounds. Due to synergistic effects, such compositions are useful in treating or preventing disorders caused by free radicals, such as those relating to coronary heart disease, cancer and rheumatism. There is ample evidence suggesting that diets rich in fruit and vegetables protect against the development of chronic illnesses such as Coronary Heart Disease (CHD) and cancer, which are the major killer diseases among affluent populations. It has been recognized for some time that these beneficial effects are due, at least in part, to the antioxidant components of these foodstuffs, which can inhibit cellular damage by free radicals. In the body, free radical damage arises due to reactive oxygen species (ROS) being formed endogenously within the tissues, and also as a result of exposure to radicals arising from cigarette smoke, ionising radiation, air pollution and other environmental insults. These free radicals have the potential to interact with biological molecules such as proteins, lipids and DNA, and they are implicated in the aetiology of diverse diseases. Antioxidants are likely to come into play in many aspects of multi-factorial disease conditions such as cancer or CHD, so it is difficult to establish how their primary effects are exerted. However, in the case of the process of atherogenesis a clear link has been demonstrated between oxidation of low density lipoprotein (LDL) and the formation of occlusive plaque in the arteries. Vitamin E (.alpha.-tocopherol) consumed as part of the diet is naturally present in the blood, where it acts to spare the LDL from oxidation. In vitro experiments have established that other natural sources of antioxidants, such as green tea, can also significantly retard the oxidation of LDL. In vivo studies have confirmed the in vitro tests, showing that increasing dietary intakes of some antioxidants, such as Vitamin E, can increase the resistance of LDL to oxidation and thereby reduce lesions in the arteries. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Use of substituted imidazo[1,2-a]-pyridin-, -pyrimidin-and-pyrazin-3-yl-am- ine derivatives in the preparation of medicaments for inhibiting NOS Inventor(s): Hennies, Hagen-Heinrich; (Simmerath, DE), Maul, Corinna; (Aachen, DE), Schneider, Johannes; (Stolberg, DE), Sundermann, Bernd; (Aachen, DE) Correspondence: Crowell & Moring Llp; Intellectual Property Group; P.O. Box 14300; Washington; DC; 20044-4300; US Patent Application Number: 20040023972 Date filed: April 11, 2003 Abstract: A pharmaceutical composition for the treatment of pain, migraine, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, cerebral ischaemia, diabetes, meningitis, or arteriosclerosis, or a method for healing wounds, the method comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula I 1Also disclosed are methods of preparing the compounds of formula I, and treatment methods using the pharmaceutical compositions. Excerpt(s): The present application is a continuation of International Patent Application No. PCT/EP01/11701, filed Oct. 10, 2001, designating the United States of America and published in German as WO 02/30428 A1, the entire disclosure of which is incorporated herein by reference. Priority is claimed based on Federal Republic of Germany Patent Application No. 100 50 663.1, filed Oct. 13, 2000. The invention relates to the use of substituted imidazo[1,2-a]-pyridin-, -pyrimidin- and -pyrazin-3-yl-amine derivatives in the preparation of medicaments for inhibiting NOS, in the preparation of medicaments for the treatment of migraine and in the preparation of medicaments for the treatment of septic shock, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, inflammations, inflammatory pain, cerebral ischemia, diabetes, meningitis, arteriosclerosis and/or for healing wounds. Nitric oxide (NO) regulates a large number of physiological processes, including neurotransmission, the relaxation and proliferation of smooth muscle, the adhesion and aggregation of thrombocytes, and also tissue damage and inflammation. Owing to the large number of signal functions, NO is associated with a number of diseases (see, for example, L. J. Ignarro, Angew. Chem. (1999), 111, 2002-2013 and F. Murad, Angew. Chem. Int. Ed. (1999), 111, 1976-1989). The enzyme responsible for the physiological formation of NO, NO synthase (NOS), plays an important part in influencing those diseases therapeutically. Hitherto, three different isoforms of NO synthase have been identified, namely the two constitutive forms nNOS and eNOS and the inducible form iNOS (see A. J. Hobbs, A. Higgs, S. Moncada, Annu. Rev. Pharmacol. Toxicol. (1999), 39, 191-220; I. C. Green, P.-E. Chabrier, DDT (1999), 4, 47-49; P.-E. Chabrier et al., Cell. Mol. Life Sci. (1999), 55, 1029-1035). 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 arteriosclerosis, 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

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“arteriosclerosis” (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 arteriosclerosis. You can also use this procedure to view pending patent applications concerning arteriosclerosis. 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 ARTERIOSCLEROSIS Overview This chapter provides bibliographic book references relating to arteriosclerosis. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on arteriosclerosis 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: 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 “arteriosclerosis” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “arteriosclerosis” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “arteriosclerosis” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

Arterial lesions and arteriosclerosis by Harry Jellinek; ISBN: 0306307928; http://www.amazon.com/exec/obidos/ASIN/0306307928/icongroupinterna

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Arterial mesenchyme and arteriosclerosis; [proceedings]; ISBN: 0306390434; http://www.amazon.com/exec/obidos/ASIN/0306390434/icongroupinterna

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Arteriosclerosis of nonhominid primates maintained on a controlled diet by H. L. Ratcliffe; ISBN: 3456003617; http://www.amazon.com/exec/obidos/ASIN/3456003617/icongroupinterna

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Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association by Donald Heistad (Editor); ISBN: 0010795642; http://www.amazon.com/exec/obidos/ASIN/0010795642/icongroupinterna

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Arteriosclerosis: New Insights Into Pathogenetic Mechanisms & Prevention by H. Just, et al; ISBN: 0387914331; http://www.amazon.com/exec/obidos/ASIN/0387914331/icongroupinterna

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Arteriosclerosis: New Insights into Pathogenic Mechanisms and Prevention by H. Just (Editor), et al; ISBN: 3798509379; http://www.amazon.com/exec/obidos/ASIN/3798509379/icongroupinterna

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Arteriosclerosis: Prevention, Treatment, and Regression by Lester M. Morrison, O. Arne Schjeide; ISBN: 039804919X; http://www.amazon.com/exec/obidos/ASIN/039804919X/icongroupinterna

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Atherogenesis; proceedings [Held in] Tokyo, 18-20 May 1972, under the auspices of the Japan Arteriosclerosis Research Foundation; ISBN: 0444150072; http://www.amazon.com/exec/obidos/ASIN/0444150072/icongroupinterna

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Atherosclerosis and Arteriosclerosis by Rodney A. White (Editor), et al; ISBN: 0849363578; http://www.amazon.com/exec/obidos/ASIN/0849363578/icongroupinterna

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Behavior and Arteriosclerosis by J. Alan Herd, Stephen M. Weiss (Editor); ISBN: 0306412810; http://www.amazon.com/exec/obidos/ASIN/0306412810/icongroupinterna

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Beyond Cholesterol: Vitamin B-B6-S, Arteriosclerosis and Your Heart by Edward P. Gruberg, Stephen A. Raymond; ISBN: 0312077793; http://www.amazon.com/exec/obidos/ASIN/0312077793/icongroupinterna

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Dr Morrison's Heart Saver Programme: A Natural, Scientifically Tested Plan for the Prevention of Arteriosclerosis, Heart Attack, and Stroke by Lester Morrison, Nancy Nugent; ISBN: 0722509855; http://www.amazon.com/exec/obidos/ASIN/0722509855/icongroupinterna

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Dr. Morrison's Heart-Saver Program: A Natural, Scientifically Tested Plan for the Prevention of Arteriosclerosis, Heart Attack, and Stroke by Lester M., With Nugent Morrison; ISBN: 0312214812; http://www.amazon.com/exec/obidos/ASIN/0312214812/icongroupinterna

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Graft Arteriosclerosis in Heart Transplantation (Medical Intelligence Unit) by Donald V., Ph.D. Cramer; ISBN: 1879702282; http://www.amazon.com/exec/obidos/ASIN/1879702282/icongroupinterna

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Prognosis of Coronary Heart Disease: Progression of Coronary Arteriosclerosis by H. Roskamm (Editor); ISBN: 0387123679; http://www.amazon.com/exec/obidos/ASIN/0387123679/icongroupinterna

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Recent results of research on arteriosclerosis; ISBN: 3540502882; http://www.amazon.com/exec/obidos/ASIN/3540502882/icongroupinterna

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The artery and the process of arteriosclerosis; proceedings; ISBN: 0306390922; http://www.amazon.com/exec/obidos/ASIN/0306390922/icongroupinterna

Chapters on Arteriosclerosis In order to find chapters that specifically relate to arteriosclerosis, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and arteriosclerosis using the “Detailed Search” option. Go to the following

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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 “arteriosclerosis” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on arteriosclerosis: •

Disorders of Erectile Function Source: in Jequier, A.M. Male Infertility: A Guide for the Clinician. Malden, MA: Blackwell Science, Inc. 2000. p. 200-225. Contact: Available from Blackwell Science, Inc. 350 Main Street, Commerce Place, Malden, MA 02148. (800) 215-1000 or (617) 388-8250. Fax (617) 388-8270. E-mail: [email protected]. Website: www.blackwell-science.com. PRICE: $186.95. ISBN: 0632051299. Summary: Disorders of erectile function are among the most common problems in men. This chapter on disorders of erectile function is from a textbook on male infertility. The author notes that the increase in the average age of patients requiring help with conception and the large numbers of men in second marriages who wish to start a second family raises the numbers of men with disorders of erection in an infertility clinic. The chapter begins with a review of the anatomy of the penis and the erectile tissue that is contained within it. Additional topics include the neuroendocrinology of erection, the mechanism of induction of erection, the etiology of erectile dysfunction (cavernosal smooth muscle dysfunction, arteriosclerosis, psychogenic impotence, endocrine causes, neurological impotence, prostatic surgery, drug effects, chronic illness, venogenic impotence, illicit drugs), the clinical evaluation of men with erectile failure, and treatment strategies, including psychosexual counseling, sildenafil (Viagra), mechanical devices (vacuum erection systems), intracavernosal injection therapy, topical and oral agents, penile prostheses, arterial surgery, and venous ligation. The cause of a patient's erectile failure can often be determined from a careful clinical history and clinical examination. As the treatment may depend for its success on an accurate clinical diagnosis, the clinical assessment of the patient with erectile failure is very important. 6 figures. 42 references.

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Prosthodontic Treatment Planning in Older Adults Source: in Budtz-Jorgensen, E. Prosthodontics for the Elderly: Diagnosis and Treatment. Chicago, IL: Quintessence Publishing Co, Inc. 1999. p. 75-106. Contact: Available from Quintessence Publishing Co, Inc. 551 Kimberly Drive, Carol Stream, IL 60188-9981. (800) 621-0387 or (630) 682-3223. Fax (630) 682-3288. E-mail: [email protected]. Website: www.quintpub.com. PRICE: $89.00 plus shipping and handling. ISBN: 0867153687. Summary: The main objective of prosthetic treatment and care is the maintenance of existing natural functional tooth contacts for life. This chapter on prosthodontic treatment planning in older adults is from a book that offers a comprehensive look at prosthodontics for older patients. The author discusses indications for prosthetic therapy, and the choice of treatment for prosthetic rehabilitation of partially or totally edentulous (without teeth) older patients. The author discusses primary objectives; identification of treatment needs and demands; identification of risk factors, including periodontal situation, caries, residual ridge resorption, function of the masticatory system; risk factors in complete denture wearers; general health, socioeconomic aspects, and attitude, including problems with arteriosclerosis, endocarditis, respiratory

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disorders, diabetes mellitus, arthritis, and cancer; considerations for choice of treatment, including basic criteria for long term success, direct treatment sequelae, long term effects (including failures and complications), and cost effective analyses; fixed versus removable partial dentures; overdentures; complete dentures; and decision making in treatment planning, including the comprehensive oral evaluation and treatment planning, the extraoral and intraoral examinations, and diagnosis. The author concludes that the greatest challenge to the clinician is to make a choice between treating the patient, with the risk of producing iatrogenic disease, or not treating the patient, with the risk of more damage occurring to the masticatory (chewing) system. The chapter is illustrated with numerous full color photographs. 7 figures. 9 tables. 84 references. •

Bowel Disorders Source: in Carlson, K.J.; Eisenstat, S.A.; Ziporyn, T. Harvard Guide to Women's Health. Cambridge, MA: Harvard University Press. 1996. p. 92-97. Contact: Available from Harvard University Press. Customer Service Department, 79 Garden Street, Cambridge, MA 02138. (800) 448-2242. Fax (800) 962-4983. PRICE: $24.95 (paperback). ISBN: 0674367693 (paperback). Summary: This chapter on bowel disorders is from a consumer handbook on women's health. Topics include irritable bowel syndrome (IBS), constipation, diverticular disease, ulcerative colitis, Crohn's disease, celiac disease, arteriosclerosis of the bowel, polyps, and colon cancer. For each disorder, the authors discuss symptoms, etiology, diagnosis, and diagnostic testing. The authors include a brief discussion of the differences in bowel disorders in men versus in women. The chapter concludes with a reference to related chapters in the book.

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Hemodynamics and Circulatory Disturbances Source: in Miller, R.L., et al. General and Oral Pathology for the Dental Hygienist. St. Louis, MO: Mosby-Year Book, Inc. 1995. p. 143-168. Contact: Available from Mosby-Year Book, Inc. 11830 Westline Industrial Drive, St. Louis, MO 63146-9934. (800) 426-4545 or (314) 872-8370; Fax (800) 535-9935 or (314) 4321380; E-mail: [email protected]; http://www.mosby.com. PRICE: $43.00 plus shipping and handling. ISBN: 0801670241. Stock Number 07024. Summary: This chapter, from a textbook on pathology for dental hygiene students, covers hemodynamics and circulatory disturbances. Topics covered include the common causes of edema in tissues and spaces; the etiology and pathogenesis of heart failure; common causes of hemorrhage; blood pressure regulation, including hypertension, shock, and syncope; vascular disease, including atherosclerosis and other types of arteriosclerosis; arterial thrombosis and phlebothrombosis; ischemia and infarction; venous embolism and arterial embolism; and ischemic heart disease and valvular heart disease, especially the conditions of heart valves that call for premedication of a patient before dental treatment. The chapter includes a list of learning objectives; illustrative case studies; and recommended readings. 11 figures. 1 table.

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CHAPTER 8. PERIODICALS ARTERIOSCLEROSIS

AND

NEWS

ON

Overview In this chapter, we suggest a number of news sources and present various periodicals that cover arteriosclerosis.

News Services and Press Releases One of the simplest ways of tracking press releases on arteriosclerosis 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 “arteriosclerosis” (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 arteriosclerosis. 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 “arteriosclerosis” (or synonyms). The following was recently listed in this archive for arteriosclerosis: •

Transplant arteriosclerosis linked to repair efforts gone awry Source: Reuters Medical News Date: March 21, 2003

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•

Pioglitazone prevents coronary arteriosclerosis in rat model Source: Reuters Industry Breifing Date: December 02, 2002

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Garlic blocks very earliest stages of arteriosclerosis Source: Reuters Medical News Date: April 12, 2002

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Antioxidant vitamins slow arteriosclerosis in heart transplant recipients Source: Reuters Medical News Date: March 28, 2002

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Interleukin-4 pivotal in development of transplant arteriosclerosis Source: Reuters Medical News Date: August 10, 2001

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Interferon-gamma induces arteriosclerosis in mice via effects on smooth muscle Source: Reuters Medical News Date: January 13, 2000 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 “arteriosclerosis” (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

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

Academic Periodicals covering Arteriosclerosis Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to arteriosclerosis. In addition to these sources, you can search for articles covering arteriosclerosis that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”

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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 Institute11: •

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/

11

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

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

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

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

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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/

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

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

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

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

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

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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

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

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

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

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

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

•

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

•

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

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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.12 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:13 •

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

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

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

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

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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

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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

12

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). 13 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

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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 Gateway14 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.15 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “arteriosclerosis” (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 73862 1244 244 78 72 75500

HSTAT16 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.17 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.18 Simply search by “arteriosclerosis” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

14

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

15

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). 16 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 17 18

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 Biologists19 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.20 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.21 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

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

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

•

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

The Genome Project and Arteriosclerosis In the following section, we will discuss databases and references which relate to the Genome Project and arteriosclerosis. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).22 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. 19 Adapted 20

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. 21 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. 22 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.

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

Arteriosclerosis, Severe Juvenile Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=208060 Genes and Disease (NCBI - Map)

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

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

•

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

•

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

•

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

•

Nervous System: Mind and body. Examples: Alzheimer disease, amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, fragile X syndrome, Friedreich’s ataxia, Huntington disease, Niemann-Pick disease, Parkinson disease, Prader-Willi syndrome, Rett syndrome, spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html

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•

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

•

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

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

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

•

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

•

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

•

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

•

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

•

OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

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PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset

•

ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

•

Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein

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PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed

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Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure

•

Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy

To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=genome, and then

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select the database that you would like to search. The databases available are listed in the drop box next to “Search.” Enter “arteriosclerosis” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database23 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html. The Genome Database24 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “arteriosclerosis” (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms).

23

Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 24 Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.

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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on arteriosclerosis 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 arteriosclerosis. 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 arteriosclerosis. 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 “arteriosclerosis”:

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Other guides Circulatory Disorders http://www.nlm.nih.gov/medlineplus/circulatorydisorders.html Coronary Disease http://www.nlm.nih.gov/medlineplus/coronarydisease.html Diagnostic Imaging http://www.nlm.nih.gov/medlineplus/diagnosticimaging.html Heart Diseases http://www.nlm.nih.gov/medlineplus/heartdiseases.html Stroke http://www.nlm.nih.gov/medlineplus/stroke.html

Within the health topic page dedicated to arteriosclerosis, the following was listed: •

General/Overviews Coronary Artery Disease Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=DS00064 Coronary Artery Disease Source: National Women's Health Information Center http://www.4woman.gov/faq/coronary.htm

•

Diagnosis/Symptoms Chest X-Rays: Helping Detect Heart and Lung Conditions Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=HB00019 Coronary Angiography Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=11222 Coronary Angiography and Angioplasty http://www.nlm.nih.gov/medlineplus/tutorials/coronaryangiographyandangiopl astyloader.html Echocardiogram http://www.nlm.nih.gov/medlineplus/tutorials/echocardiogramloader.html Echocardiogram Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=HB00012 Echocardiography Stress Test http://www.nlm.nih.gov/medlineplus/tutorials/echocardiographystresstestloader .html Exercise Testing and Nuclear Scanning http://circ.ahajournals.org/cgi/reprint/107/16/e100.pdf

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Treatment MedlinePlus: Angioplasty Source: National Library of Medicine http://www.nlm.nih.gov/medlineplus/angioplasty.html MedlinePlus: Heart Bypass Surgery Source: National Library of Medicine http://www.nlm.nih.gov/medlineplus/heartbypasssurgery.html

•

Nutrition Supplements for Heart Health Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=HB00018

•

Specific Conditions/Aspects Acute Coronary Occlusion: A Common Cause of Heart Attack Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=AN00462 Alcohol Alert: Alcohol and Coronary Heart Disease Source: National Institute on Alcohol Abuse and Alcoholism http://www.niaaa.nih.gov/publications/aa45-text.htm Atherosclerosis Source: National Women's Health Information Center http://www.4woman.gov/faq/atheroscle.htm Coronary Artery Spasm Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=4520 Occlusive Peripheral Arterial Disease Source: Merck & Co., Inc. http://www.merck.com/mrkshared/mmanual_home2/sec03/ch034/ch034b.jsp

•

From the National Institutes of Health Facts about Coronary Heart Disease Source: National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/health/public/heart/other/chdfacts2.htm What Is Atherosclerosis? Source: National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/health/dci/Diseases/Atherosclerosis/Atherosclerosis_ WhatIs.html What Is Coronary Artery Disease? Source: National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/health/dci/Diseases/Cad/CAD_WhatIs.html

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Latest News Intensive Therapy Benefits Stable Heart Patients Source: 03/03/2004, Reuters Health http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_16381 .html More News on Coronary Disease http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/alphanews_c.html#C oronaryDisease More Potent Therapy Slows Plaque Build-up in Arteries Source: 03/02/2004, Reuters Health http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_16362 .html New Marker Linked with Heart Disease in Women Source: 02/17/2004, American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3019176 New Stats Show Heart Disease Still America's No. 1 Killer, Stroke No. 3 Source: 01/01/2004, American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3018015 Poor Oral Health Associated with Coronary Heart Disease Source: 02/17/2004, American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3019173 Simple Test Points to Diabetics' Heart Risks Source: 02/05/2004, Reuters Health http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_15920 .html

•

Organizations American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=1200000 National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/

•

Prevention/Screening Coronary Heart Disease: Reducing Your Risk Source: American Academy of Family Physicians http://familydoctor.org/239.xml MedlinePlus: Heart Diseases--Prevention Source: National Library of Medicine http://www.nlm.nih.gov/medlineplus/heartdiseasesprevention.html Risk Assessment Tool for Heart Attack or Coronary Heart Disease Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3003499 Scanning for Heart Disease: Help or Hype? Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=HB00015

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Use of New Imaging Techniques to Screen for Coronary Artery Disease http://circ.ahajournals.org/cgi/reprint/108/8/e50.pdf •

Research Arthritis Drugs May Help the Heart Source: American Heart Association http://www.americanheart.org/presenter.jhtml%3Bjsessionid=?identifier=3007523 Cognitive Function and Carotid Artery Disease Source: American College of Physicians http://www.annals.org/cgi/content/full/140/4/I-34 Early Heart Disease in Parents Linked to Thicker Artery Walls in Offspring Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3014026 Elevated Homocysteine in Heart Patients Linked with Higher Stroke Risk Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3008854 Evaluation Needed to Gauge Silent Threat Lurking within Stroke Patients Source: American Heart Association http://www.americanheart.org/presenter.jhtml%3Bjsessionid=?identifier=3015082 Lack of Studies on Women Limits Usefulness of Research on Coronary Heart Disease Source: Agency for Healthcare Research and Quality http://www.ahrq.gov/news/press/pr2003/chdwmpr.htm Men with 3 of 5 Metabolic Abnormalities Risk Diabetes, Heart Disease Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3013637 Parents of Large Families May Be at Higher Heart Risk Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3008817 Surgery Better Than Drugs for Serious Lack of Blood Flow to the Heart Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3012085 Tight Glucose Control in Diabetes Lowers Risk of Atherosclerosis Source: National Institute of Diabetes and Digestive and Kidney Diseases http://www.nih.gov/news/pr/jun2003/niddk-04.htm Vitamin C, Fish, and a Gout Drug Target Artery Damage from Smoking Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3007365

•

Statistics New Stats Show Heart Disease Still America's No. 1 Killer, Stroke No. 3 Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3018015

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Women What's Important about Elderly Women's Fat? Amount or Location? Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3010084

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 arteriosclerosis. 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: •

Understanding the Complications of Diabetes Mellitus Source: Toronto, Ontario: Canadian Diabetes Association. 1992. 8 p. Contact: Available from Canadian Diabetes Association. National Office, 15 Toronto Street, Suite 1001, Toronto, Ontario M5C 2E3. (416) 363-3373. PRICE: $0.25 each. Summary: This brochure presents a brief guide to understanding the complications of diabetes mellitus. Topics include risk factors for complications, including poor control of blood glucose, high levels of cholesterol, hypertension, cigarette smoking, and lack of knowledge; diseases of the small blood vessels, including retinopathy, nephropathy, and neuropathy; and diseases of the large blood vessels, including arteriosclerosis. The brochure concludes with a checklist for a regular diabetes routine that will help to maintain good health and prevent complications.

•

ABCs of PXE, The Source: Sharon, MA: PXE International. 2001. 8 p. Contact: Available from PXE International. 23 Mountain Street, Sharon, MA 02067. (781) 784-3817. Fax (781) 784-6672. E-mail: [email protected]. Website: www.pxe.org. PRICE: Single copy free. Summary: This fact sheet provides people who have pseudoxanthoma elasticum (PXE) with definitions of terms associated with this condition. Terms are ABCC6, acquired PXE, allele, angioid streaks, angina pectoris, arteries, arteriosclerosis, autosomal, axilla, biopsy, blood and tissue bank, Bruch's membrane, calcium, central vision, chelation therapy, choroidal neovascularization, collagen, consanguinity, dermis, dominant, drusen, elastic fibers, electron microscope, expressivity, fibroblasts, flexural creases, fluorescein angiography, and fovea. Other terms are gastrointestinal bleeding, genes,

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genetic counseling, genome, genotype, Gronblad-Strandberg, heterozygote, homozygotes, hypertension, intermittent claudication, laser therapy, legal blindness, mutation, myocardial infarction, oral lesions, peau d'orange, penetrance, phenocopy, phenotype, pseudoxanthoma, recessive, retina, Trental, visual aids, and x-ray. •

Diabetes and Erectile Dysfunction Source: Augusta, GA: Geddings D. Osbon, Sr. Foundation. 1995. 1 p. Contact: Available from Geddings D. Osbon, Sr. Foundation. 121 Twelfth Street, P.O. Box 1593, Augusta, GA 30903. (800) 433-4215. PRICE: Single copy free. Summary: This simple fact sheet lists facts about diabetes mellitus and erectile dysfunction. Topics include a definition of impotence; the epidemiology of erectile dysfunction; the evaluation of impotence; how autonomic and peripheral neuropathy can affect erection in men with diabetes; impotence related to arteriosclerosis; smoking as a risk factor for impotence; and treatment options. The fact sheet includes the toll-free telephone number of the Geddings Osbon Sr. Foundation, a resource organization on impotence. 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: •

Arteriosclerosis, Thrombosis, and Vascular Biology (Journal) Summary: One of five monthly Journals written for the general public and healthcare professionals and published by the American Heart Association. Source: American Heart Association http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=1939 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 arteriosclerosis. 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.

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Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats

•

Family Village: http://www.familyvillage.wisc.edu/specific.htm

•

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

•

Med Help International: http://www.medhelp.org/HealthTopics/A.html

•

Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/

•

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

•

WebMD®Health: http://my.webmd.com/health_topics

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to arteriosclerosis. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with arteriosclerosis. 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 arteriosclerosis. 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 “arteriosclerosis” (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

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your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “arteriosclerosis”. 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 “arteriosclerosis” (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 “arteriosclerosis” (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.25

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

25

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)26: •

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)

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Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

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California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html

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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

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California: Gateway Health Library (Sutter Gould Medical Foundation)

•

California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/

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California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp

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California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

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California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/

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California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/

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California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/

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California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html

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California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/

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Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/

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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/

26

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

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Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm

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Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html

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Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

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Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp

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Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/

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Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm

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Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html

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Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/

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Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm

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Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/

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Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/

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Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/

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Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm

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Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html

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Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

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Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

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Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

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Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

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Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/

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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

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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

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Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

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Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

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Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

•

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

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Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

•

Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

•

National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

•

National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

•

National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

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•

Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm

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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

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New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

•

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

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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

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Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

•

Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

•

Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

•

MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

•

Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

•

Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

•

On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

•

Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

•

Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on arteriosclerosis: •

Basic Guidelines for Arteriosclerosis Arteriosclerosis of the extremities Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000170.htm

•

Signs & Symptoms for Arteriosclerosis Absent pulse Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003078.htm Claudication Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003184.htm Cyanosis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm Fever Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003090.htm

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General ill feeling Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003089.htm Impotence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003164.htm Joint pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003261.htm Leg pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003182.htm Loss of hair Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003246.htm Muscle pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003178.htm Numbness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003206.htm Obesity Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003101.htm Paleness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003244.htm Pulse, weak or absent Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003078.htm Walking/gait abnormalities Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003199.htm •

Diagnostics and Tests for Arteriosclerosis Angiography Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003327.htm Blood pressure Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003398.htm Doppler ultrasound exam of an extremity Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003775.htm Hemodialysis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003421.htm MRI Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003335.htm Total cholesterol Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003492.htm

Online Glossaries 177

Ulcers Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003228.htm •

Nutrition for Arteriosclerosis Cholesterol Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002472.htm

•

Surgery and Procedures for Arteriosclerosis Balloon angioplasty Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002953.htm Bypass surgery Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002946.htm

•

Background Topics for Arteriosclerosis Analgesics Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002123.htm Emboli Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001124.htm Exercise Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001941.htm Kidney disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000457.htm Peripheral Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002273.htm Smoking Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002032.htm Stent Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002303.htm Thrombi Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001124.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

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•

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

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ARTERIOSCLEROSIS DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 1-phosphate: A drug that halts cell suicide in human white blood cells. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal fat: Fat (adipose tissue) that is centrally distributed between the thorax and pelvis and that induces greater health risk. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Abscess: A localized, circumscribed collection of pus. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acid Phosphatase: An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. EC 3.1.3.2. [NIH] Acne: A disorder of the skin marked by inflammation of oil glands and hair glands. [NIH] Acoustic: Having to do with sound or hearing. [NIH] Acrylonitrile: A highly poisonous compound used widely in the manufacture of plastics, adhesives and synthetic rubber. [NIH] Actin: Essential component of the cell skeleton. [NIH] Activities of Daily Living: The performance of the basic activities of self care, such as dressing, ambulation, eating, etc., in rehabilitation. [NIH] Acuity: Clarity or clearness, especially of the vision. [EU] Acute Disease: Disease having a short and relatively severe course. [NIH] Acyl: Chemical signal used by bacteria to communicate. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adhesions: Pathological processes consisting of the union of the opposing surfaces of a wound. [NIH] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH]

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Adipose Tissue: Connective tissue composed of fat cells lodged in the meshes of areolar tissue. [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] Adoptive Transfer: Form of passive immunization where previously sensitized immunologic agents (cells or serum) are transferred to non-immune recipients. When transfer of cells is used as a therapy for the treatment of neoplasms, it is called adoptive immunotherapy (immunotherapy, adoptive). [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [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] Aerobic Exercise: A type of physical activity that includes walking, jogging, running, and dancing. Aerobic training improves the efficiency of the aerobic energy-producing systems that can improve cardiorespiratory endurance. [NIH] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]

Aetiology: Study of the causes of disease. [EU] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]

Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH]

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Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] 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] Aldehydes: Organic compounds containing a carbonyl group in the form -CHO. [NIH] Aldosterone: (11 beta)-11,21-Dihydroxy-3,20-dioxopregn-4-en-18-al. A hormone secreted by the adrenal cortex that functions in the regulation of electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkaline Phosphatase: An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. EC 3.1.3.1. [NIH] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allo: A female hormone. [NIH] Allogeneic: Taken from different individuals of the same species. [NIH] Allograft: An organ or tissue transplant between two humans. [NIH] Allylamine: Possesses an unusual and selective cytotoxicity for vascular smooth muscle cells in dogs and rats. Useful for experiments dealing with arterial injury, myocardial fibrosis or cardiac decompensation. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] 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] Alveolar Process: The thickest and spongiest part of the maxilla and mandible hollowed out into deep cavities for the teeth. [NIH] Alveoli: Tiny air sacs at the end of the bronchioles in the lungs. [NIH] Ameliorating: A changeable condition which prevents the consequence of a failure or

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accident from becoming as bad as it otherwise would. [NIH] Amenorrhea: Absence of menstruation. [NIH] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] Amino Acid Motifs: Commonly observed structural components of proteins formed by simple combinations of adjacent secondary structures. A commonly observed structure may be composed of a conserved sequence which can be represented by a consensus sequence. [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] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Amputation: Surgery to remove part or all of a limb or appendage. [NIH] Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH] Anaerobic: 1. Lacking molecular oxygen. 2. Growing, living, or occurring in the absence of molecular oxygen; pertaining to an anaerobe. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] 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]

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Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angina Pectoris: The symptom of paroxysmal pain consequent to myocardial ischemia usually of distinctive character, location and radiation, and provoked by a transient stressful situation during which the oxygen requirements of the myocardium exceed the capacity of the coronary circulation to supply it. [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] Angiogram: An x-ray of blood vessels; the person receives an injection of dye to outline the vessels on the x-ray. [NIH] Angiography: Radiography of blood vessels after injection of a contrast medium. [NIH] Angioid Streaks: Small breaks in the elastin-filled tissue of the retina. [NIH] Angiopathy: Disease of the blood vessels (arteries, veins, and capillaries) that occurs when someone has diabetes for a long time. There are two types of angiopathy: macroangiopathy and microangiopathy. In macroangiopathy, fat and blood clots build up in the large blood vessels, stick to the vessel walls, and block the flow of blood. In microangiopathy, the walls of the smaller blood vessels become so thick and weak that they bleed, leak protein, and slow the flow of blood through the body. Then the cells, for example, the ones in the center of the eye, do not get enough blood and may be damaged. [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] Angiotensin converting enzyme inhibitor: A drug used to decrease pressure inside blood vessels. [NIH] Angiotensinogen: An alpha-globulin of which a fragment of 14 amino acids is converted by renin to angiotensin I, the inactive precursor of angiotensin II. It is a member of the serpin superfamily. [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] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Ankle: That part of the lower limb directly above the foot. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]

Anovulation: Suspension or cessation of ovulation in animals and humans. [NIH]

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Anterior Cerebral Artery: Artery formed by the bifurcation of the internal carotid artery. Branches of the anterior cerebral artery supply the caudate nucleus, internal capsule, putamen, septal nuclei, gyrus cinguli, and surfaces of the frontal lobe and parietal lobe. [NIH] Antiallergic: Counteracting allergy or allergic conditions. [EU] Anti-Anxiety Agents: Agents that alleviate anxiety, tension, and neurotic symptoms, promote sedation, and have a calming effect without affecting clarity of consciousness or neurologic conditions. Some are also effective as anticonvulsants, muscle relaxants, or anesthesia adjuvants. Adrenergic beta-antagonists are commonly used in the symptomatic treatment of anxiety but are not included here. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibiotic Prophylaxis: Use of antibiotics before, during, or after a diagnostic, therapeutic, or surgical procedure to prevent infectious complications. [NIH] Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are 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] Antithrombotic: Preventing or interfering with the formation of thrombi; an agent that so acts. [EU]

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Antiviral: Destroying viruses or suppressing their replication. [EU] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Aorta: The main trunk of the systemic arteries. [NIH] Apheresis: Components plateletpheresis. [NIH]

being

separated

out,

as

leukapheresis,

plasmapheresis,

Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Aqueous: Having to do with water. [NIH] Arachidonate 12-Lipoxygenase: An enzyme that catalyzes the oxidation of arachidonic acid to yield 12-hydroperoxyarachidonate (12-HPETE) which is itself rapidly converted by a peroxidase to 12-hydroxy-5,8,10,14-eicosatetraenoate (12-HETE). The 12-hydroperoxides are preferentially formed in platelets. EC 1.13.11.31. [NIH] Arachidonate 15-Lipoxygenase: An enzyme that catalyzes the oxidation of arachidonic acid to yield 15-hydroperoxyarachidonate (15-HPETE) which is rapidly converted to 15-hydroxy5,8,11,13-eicosatetraenoate (15-HETE). The 15-hydroperoxides are preferentially formed in neutrophils and lymphocytes. EC 1.13.11.33. [NIH] Arachidonate Lipoxygenases: Enzymes catalyzing the oxidation of arachidonic acid to hydroperoxyarachidonates (HPETES). These products are then rapidly converted by a peroxidase to hydroxyeicosatetraenoic acids (HETES). The positional specificity of the enzyme reaction varies from tissue to tissue. The final lipoxygenase pathway leads to the leukotrienes. EC 1.13.11.- . [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [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] Arteriography: A procedure to x-ray arteries. The arteries can be seen because of an injection of a dye that outlines the vessels on an x-ray. [NIH] Arteriolar: Pertaining to or resembling arterioles. [EU] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriolosclerosis: Sclerosis and thickening of the walls of the smaller arteries (arterioles). Hyaline arteriolosclerosis, in which there is homogeneous pink hyaline thickening of the arteriolar walls, is associated with benign nephrosclerosis. Hyperplastic arteriolosclerosis, in which there is a concentric thickening with progressive narrowing of the lumina may be associated with malignant hypertension, nephrosclerosis, and scleroderma. [EU] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the

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intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Arteriosclerosis Obliterans: Arteriosclerosis in which proliferation of the intima leads to occlusion of the lumen of the arteries. [NIH] Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Articular: Of or pertaining to a joint. [EU] Articulation: The relationship of two bodies by means of a moveable joint. [NIH] Aseptic: Free from infection or septic material; sterile. [EU] Aspartate: A synthetic amino acid. [NIH] Aspirin: A drug that reduces pain, fever, inflammation, and blood clotting. Aspirin belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied in cancer prevention. [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] 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] Atherogenic: Causing the formation of plaque in the lining of the arteries. [NIH] Atrial: Pertaining to an atrium. [EU] Atrial Fibrillation: Disorder of cardiac rhythm characterized by rapid, irregular atrial impulses and ineffective atrial contractions. [NIH] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] 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]

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Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] 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] Autoradiography: A process in which radioactive material within an object produces an image when it is in close proximity to a radiation sensitive emulsion. [NIH] Autosuggestion: Suggestion coming from the subject himself. [NIH] Axilla: The underarm or armpit. [NIH] Axillary: Pertaining to the armpit area, including the lymph nodes that are located there. [NIH]

Axillary Artery: The continuation of the subclavian artery; it distributes over the upper limb, axilla, chest and shoulder. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Infections: Infections by bacteria, general or unspecified. [NIH] 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] 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

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basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Benzene: Toxic, volatile, flammable liquid hydrocarbon biproduct of coal distillation. It is used as an industrial solvent in paints, varnishes, lacquer thinners, gasoline, etc. Benzene causes central nervous system damage acutely and bone marrow damage chronically and is carcinogenic. It was formerly used as parasiticide. [NIH] Beta-pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Beta-sheet: Two or more parallel or anti-parallel strands are arranged in rows. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bile Ducts: Tubes that carry bile from the liver to the gallbladder for storage and to the small intestine for use in digestion. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biliary Tract: The gallbladder and its ducts. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biomolecular: A scientific field at the interface between advanced computing and biotechnology. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] 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

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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] Bladder: The organ that stores urine. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Coagulation Factors: Endogenous substances, usually proteins, that are involved in the blood coagulation process. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Body Composition: The relative amounts of various components in the body, such as percent body fat. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [NIH] Body Regions: Anatomical areas of the body. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone Marrow Cells: Cells contained in the bone marrow including fat cells, stromal cells, megakaryocytes, and the immediate precursors of most blood cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [NIH] Bone Resorption: Bone loss due to osteoclastic activity. [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]

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Brachial: All the nerves from the arm are ripped from the spinal cord. [NIH] Brachial Artery: The continuation of the axillary artery; it branches into the radial and ulnar arteries. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Brain Stem: The part of the brain that connects the cerebral hemispheres with the spinal cord. It consists of the mesencephalon, pons, and medulla oblongata. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Breakdown: A physical, metal, or nervous collapse. [NIH] Bridged Compounds: Cyclic hydrocarbons that contain multiple rings and share one or more atoms. [NIH] Bronchioles: The tiny branches of air tubes in the lungs. [NIH] Bronchoconstriction: Diminution of the caliber of a bronchus physiologically or as a result of pharmacological intervention. [NIH] Bronchus: A large air passage that leads from the trachea (windpipe) to the lung. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Buffers: A chemical system that functions to control the levels of specific ions in solution. When the level of hydrogen ion in solution is controlled the system is called a pH buffer. [NIH]

Bulimia: Episodic binge eating. The episodes may be associated with the fear of not being able to stop eating, depressed mood, or self-deprecating thoughts (binge-eating disorder) and may frequently be terminated by self-induced vomiting (bulimia nervosa). [NIH] Burns: Injuries to tissues caused by contact with heat, steam, chemicals (burns, chemical), electricity (burns, electric), or the like. [NIH] Burns, Electric: Burns produced by contact with electric current or from a sudden discharge of electricity. [NIH] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Cacao: A tree of the family Sterculiaceae (or Byttneriaceae), usually Theobroma cacao, or its seeds, which after fermentation and roasting, yield cocoa and chocolate. [NIH] Cachexia: General ill health, malnutrition, and weight loss, usually associated with chronic disease. [NIH] Cadaver: A dead body, usually a human body. [NIH] Cadherins: A group of functionally related glycoproteins responsible for the calciumdependent cell-to-cell adhesion mechanism. They are divided into subclasses E-, P-, and Ncadherins, which are distinct in immunological specificity and tissue distribution. They promote cell adhesion via a homophilic mechanism. These compounds play a role in the construction of tissues and of the whole animal body. [NIH]

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Calcification: Deposits of calcium in the tissues of the breast. Calcification in the breast can be seen on a mammogram, but cannot be detected by touch. There are two types of breast calcification, macrocalcification and microcalcification. Macrocalcifications are large deposits and are usually not related to cancer. Microcalcifications are specks of calcium that may be found in an area of rapidly dividing cells. Many microcalcifications clustered together may be a sign of cancer. [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] Cancer vaccine: A vaccine designed to prevent or treat cancer. [NIH] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capillary Fragility: The lack of resistance, or susceptibility, of capillaries to damage or disruption under conditions of increased stress. [NIH] Capillary Permeability: Property of blood capillary walls that allows for the selective exchange of substances. Small lipid-soluble molecules such as carbon dioxide and oxygen move freely by diffusion. Water and water-soluble molecules cannot pass through the endothelial walls and are dependent on microscopic pores. These pores show narrow areas (tight junctions) which may limit large molecule movement. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carboxy: Cannabinoid. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinogens: Substances that increase the risk of neoplasms in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. [NIH] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Cardiac: Having to do with the heart. [NIH] Cardiology: The study of the heart, its physiology, and its functions. [NIH] Cardiorespiratory: Relating to the heart and lungs and their function. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high

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blood pressure). [NIH] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [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] Carotenoids: Substance found in yellow and orange fruits and vegetables and in dark green, leafy vegetables. May reduce the risk of developing cancer. [NIH] Carotid Arteries: Either of the two principal arteries on both sides of the neck that supply blood to the head and neck; each divides into two branches, the internal carotid artery and the external carotid artery. [NIH] Carotid Stenosis: The constriction or narrowing of an orifice or the lumen of a hollow or tubular organ. [NIH] Cataracts: In medicine, an opacity of the crystalline lens of the eye obstructing partially or totally its transmission of light. [NIH] Catechin: Extracted from Uncaria gambier, Acacia catechu and other plants; it stabilizes collagen and is therefore used in tanning and dyeing; it prevents capillary fragility and abnormal permeability, but was formerly used as an antidiarrheal. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [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] Catheters: A small, flexible tube that may be inserted into various parts of the body to inject or remove liquids. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Celiac Disease: A disease characterized by intestinal malabsorption and precipitated by gluten-containing foods. The intestinal mucosa shows loss of villous structure. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Adhesion Molecules: Surface ligands, usually glycoproteins, that mediate cell-to-cell adhesion. Their functions include the assembly and interconnection of various vertebrate systems, as well as maintenance of tissue integration, wound healing, morphogenic movements, cellular migrations, and metastasis. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH]

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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 motility: The ability of a cell to move. [NIH] Cell Polarity: Orientation of intracellular structures especially with respect to the apical and basolateral domains of the plasma membrane. Polarized cells must direct proteins from the Golgi apparatus to the appropriate domain since tight junctions prevent proteins from diffusing between the two domains. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] 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 Diseases: Diseases of any component of the brain (including the cerebral hemispheres, diencephalon, brain stem, and cerebellum) or the spinal cord. [NIH] Central Nervous System Infections: Pathogenic infections of the brain, spinal cord, and meninges. DNA virus infections; RNA virus infections; bacterial infections; mycoplasma infections; Spirochaetales infections; fungal infections; protozoan infections; helminthiasis; and prion diseases may involve the central nervous system as a primary or secondary process. [NIH] Ceramide: A type of fat produced in the body. It may cause some types of cells to die, and is being studied in cancer treatment. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral hemispheres: The two halves of the cerebrum, the part of the brain that controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. The right hemisphere controls muscle movement on the left side of the body, and the left hemisphere controls muscle movement on the right side of the body. [NIH] Cerebral Infarction: The formation of an area of necrosis in the cerebrum caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial

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distribution (e.g., infarction, anterior cerebral artery), and etiology (e.g., embolic infarction). [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] Chaperonins: A class of sequence-related molecular chaperones found in bacteria, mitochondria, and plastids. Chaperonins are abundant constitutive proteins that increase in amount after stresses such as heat shock, bacterial infection of macrophages, and an increase in the cellular content of unfolded proteins. Bacterial chaperonins are major immunogens in human bacterial infections because of their accumulation during the stress of infection. Two members of this class of chaperones are chaperonin 10 and chaperonin 60. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chelation: Combination with a metal in complexes in which the metal is part of a ring. [EU] Chelation Therapy: Therapy of heavy metal poisoning using agents which sequester the metal from organs or tissues and bind it firmly within the ring structure of a new compound which can be eliminated from the body. [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] Chest Pain: Pressure, burning, or numbness in the chest. [NIH] Child Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders in children. [NIH] Choleretic: A choleretic agent. [EU] 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] Cholic Acid: A major primary bile acid produced in the liver and usually conjugated with glycine or taurine. It facilitates fat absorption and cholesterol excretion. [NIH] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chorea: Involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement. Hypotonia and pendular

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reflexes are often associated. Conditions which feature recurrent or persistent episodes of chorea as a primary manifestation of disease are referred to as choreatic disorders. Chorea is also a frequent manifestation of basal ganglia diseases. [NIH] Choreatic Disorders: Acquired and hereditary conditions which feature chorea as a primary manifestation of the disease process. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Choroidal Neovascularization: A pathological process consisting of the formation of new blood vessels in the choroid. [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 renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Circadian: Repeated more or less daily, i. e. on a 23- to 25-hour cycle. [NIH] Circadian Rhythm: The regular recurrence, in cycles of about 24 hours, of biological processes or activities, such as sensitivity to drugs and stimuli, hormone secretion, sleeping, feeding, etc. This rhythm seems to be set by a 'biological clock' which seems to be set by recurring daylight and darkness. [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] Claudication: Limping or lameness. [EU] 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 study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH]

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Clonal Deletion: Removal, via cell death, of immature lymphocytes that interact with antigens during maturation. For T-lymphocytes this occurs in the thymus and ensures that mature T-lymphocytes are self tolerant. B-lymphocytes may also undergo clonal deletion. [NIH]

Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]

Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Clot Retraction: Retraction of a clot resulting from contraction of platelet pseudopods attached to fibrin strands that is dependent on the contractile protein thrombosthenin. Used as a measure of platelet function. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Coal: A natural fuel formed by partial decomposition of vegetable matter under certain environmental conditions. [NIH] Coal Tar: A by-product of the destructive distillation of coal used as a topical antieczematic. It is an antipruritic and keratoplastic agent used also in the treatment of psoriasis and other skin conditions. Occupational exposure to soots, tars, and certain mineral oils is known to be carcinogenic according to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985) (Merck Index, 11th ed). [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] Cognitive restructuring: A method of identifying and replacing fear-promoting, irrational beliefs with more realistic and functional ones. [NIH] Colestipol: Highly crosslinked and insoluble basic anion exchange resin used as anticholesteremic. It may also may reduce triglyceride levels. [NIH] Colic: Paroxysms of pain. This condition usually occurs in the abdominal region but may occur in other body regions as well. [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Colloidal: Of the nature of a colloid. [EU]

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Colony-Stimulating Factors: Glycoproteins found in a subfraction of normal mammalian plasma and urine. They stimulate the proliferation of bone marrow cells in agar cultures and the formation of colonies of granulocytes and/or macrophages. The factors include interleukin-3 (IL-3), granulocyte colony-stimulating factor (G-CSF), macrophage colonystimulating factor (M-CSF), and granulocyte-macrophage colony-stimulating factor (GMCSF). [NIH] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complement Activation: The sequential activation of serum components C1 through C9, initiated by an erythrocyte-antibody complex or by microbial polysaccharides and properdin, and producing an inflammatory response. [NIH] 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] 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,

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taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Concentric: Having a common center of curvature or symmetry. [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] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjugation: 1. The act of joining together or the state of being conjugated. 2. A sexual process seen in bacteria, ciliate protozoa, and certain fungi in which nuclear material is exchanged during the temporary fusion of two cells (conjugants). In bacterial genetics a form of sexual reproduction in which a donor bacterium (male) contributes some, or all, of its DNA (in the form of a replicated set) to a recipient (female) which then incorporates differing genetic information into its own chromosome by recombination and passes the recombined set on to its progeny by replication. In ciliate protozoa, two conjugants of separate mating types exchange micronuclear material and then separate, each now being a fertilized cell. In certain fungi, the process involves fusion of two gametes, resulting in union of their nuclei and formation of a zygote. 3. In chemistry, the joining together of two compounds to produce another compound, such as the combination of a toxic product with some substance in the body to form a detoxified product, which is then eliminated. [EU] 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] Consensus Sequence: A theoretical representative nucleotide or amino acid sequence in which each nucleotide or amino acid is the one which occurs most frequently at that site in the different sequences which occur in nature. The phrase also refers to an actual sequence which approximates the theoretical consensus. A known conserved sequence set is represented by a consensus sequence. Commonly observed supersecondary protein structures (amino acid motifs) are often formed by conserved sequences. [NIH] Conserved Sequence: A sequence of amino acids in a polypeptide or of nucleotides in DNA or RNA that is similar across multiple species. A known set of conserved sequences is represented by a consensus sequence. Amino acid motifs are often composed of conserved sequences. [NIH]

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Constipation: Infrequent or difficult evacuation of feces. [NIH] Constriction: The act of constricting. [NIH] Constriction, Pathologic: The condition of an anatomical structure's being constricted beyond normal dimensions. [NIH] Consumption: Pulmonary tuberculosis. [NIH] Contraceptive: An agent that diminishes the likelihood of or prevents conception. [EU] Contractility: Capacity for becoming short in response to a suitable stimulus. [EU] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] 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 clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Conventional therapy: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional treatment. [NIH] Conventional treatment: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional therapy. [NIH] Convulsion: A violent involuntary contraction or series of contractions of the voluntary muscles. [EU] 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 Angiography: Radiography of the vascular system of the heart muscle after injection of a contrast medium. [NIH] Coronary Arteriosclerosis: Thickening and loss of elasticity of the coronary arteries. [NIH] Coronary Artery Bypass: Surgical therapy of ischemic coronary artery disease achieved by grafting a section of saphenous vein, internal mammary artery, or other substitute between the aorta and the obstructed coronary artery distal to the obstructive lesion. [NIH] Coronary Circulation: The circulation of blood through the coronary vessels of the heart. [NIH]

Coronary Disease: Disorder of cardiac function due to an imbalance between myocardial function and the capacity of the coronary vessels to supply sufficient flow for normal function. It is a form of myocardial ischemia (insufficient blood supply to the heart muscle) caused by a decreased capacity of the coronary vessels. [NIH] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a

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myocardial infarction. [NIH] Coronary Vessels: The veins and arteries of the heart. [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] Corticosteroid: Any of the steroids elaborated by the adrenal cortex (excluding the sex hormones of adrenal origin) in response to the release of corticotrophin (adrenocorticotropic hormone) by the pituitary gland, to any of the synthetic equivalents of these steroids, or to angiotensin II. They are divided, according to their predominant biological activity, into three major groups: glucocorticoids, chiefly influencing carbohydrate, fat, and protein metabolism; mineralocorticoids, affecting the regulation of electrolyte and water balance; and C19 androgens. Some corticosteroids exhibit both types of activity in varying degrees, and others exert only one type of effect. The corticosteroids are used clinically for hormonal replacement therapy, for suppression of ACTH secretion by the anterior pituitary, as antineoplastic, antiallergic, and anti-inflammatory agents, and to suppress the immune response. Called also adrenocortical hormone and corticoid. [EU] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [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] Crowns: A prosthetic restoration that reproduces the entire surface anatomy of the visible natural crown of a tooth. It may be partial (covering three or more surfaces of a tooth) or complete (covering all surfaces). It is made of gold or other metal, porcelain, or resin. [NIH] Crystallization: The formation of crystals; conversion to a crystalline form. [EU] 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] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH] Cystathionine beta-Synthase: A multifunctional pyridoxal phosphate enzyme. In the second stage of cysteine biosynthesis it catalyzes the reaction of homocysteine with serine to form cystathionine with the elimination of water. Deficiency of this enzyme leads to

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hyperhomocysteinemia and homocystinuria. EC 4.2.1.22. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]

Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytomegalovirus: A genus of the family Herpesviridae, subfamily Betaherpesvirinae, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS. [NIH] 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] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Dairy Products: Raw and processed or manufactured milk and milk-derived products. These are usually from cows (bovine) but are also from goats, sheep, reindeer, and water buffalo. [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] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Decision Making: The process of making a selective intellectual judgment when presented with several complex alternatives consisting of several variables, and usually defining a course of action or an idea. [NIH] Decompensation: Failure of compensation; cardiac decompensation is marked by dyspnea, venous engorgement, and edema. [EU] Decompression: Decompression external to the body, most often the slow lessening of external pressure on the whole body (especially in caisson workers, deep sea divers, and persons who ascend to great heights) to prevent decompression sickness. It includes also sudden accidental decompression, but not surgical (local) decompression or decompression applied through body openings. [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] Dementia: An acquired organic mental disorder with loss of intellectual abilities of

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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] Demethylation: Process that releases substantial amounts of carbon dioxide in the liver. [NIH]

Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dendritic cell: A special type of antigen-presenting cell (APC) that activates T lymphocytes. [NIH]

Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dental Abutments: Natural teeth or teeth roots used as anchorage for a fixed or removable denture or other prosthesis (such as an implant) serving the same purpose. [NIH] Dental Caries: Localized destruction of the tooth surface initiated by decalcification of the enamel followed by enzymatic lysis of organic structures and leading to cavity formation. If left unchecked, the cavity may penetrate the enamel and dentin and reach the pulp. The three most prominent theories used to explain the etiology of the disase are that acids produced by bacteria lead to decalcification; that micro-organisms destroy the enamel protein; or that keratolytic micro-organisms produce chelates that lead to decalcification. [NIH]

Dentures: An appliance used as an artificial or prosthetic replacement for missing teeth and adjacent tissues. It does not include crowns, dental abutments, nor artificial teeth. [NIH] Deoxycholic Acid: A bile acid formed by bacterial action from cholate. It is usually conjugated with glycine or taurine. Deoxycholic acid acts as a detergent to solubilize fats for intestinal absorption, is reabsorbed itself, and is used as a choleretic and detergent. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Dermatitis: Any inflammation of the skin. [NIH] DES: Diethylstilbestrol. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who used DES. DES may also increase the risk of breast cancer in women who used DES. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Developed Countries: Countries that have reached a level of economic achievement through an increase of production, per capita income and consumption, and utilization of natural and human resources. [NIH] Developing Countries: Countries in the process of change directed toward economic growth, that is, an increase in production, per capita consumption, and income. The process of economic growth involves better utilization of natural and human resources, which

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results in a change in the social, political, and economic structures. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diabetic Retinopathy: Retinopathy associated with diabetes mellitus, which may be of the background type, progressively characterized by microaneurysms, interretinal punctuate macular edema, or of the proliferative type, characterized by neovascularization of the retina and optic disk, which may project into the vitreous, proliferation of fibrous tissue, vitreous hemorrhage, and retinal detachment. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Diastolic pressure: The lowest pressure to which blood pressure falls between contractions of the ventricles. [NIH] Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [NIH] Dietary Fiber: The remnants of plant cell walls that are resistant to digestion by the alimentary enzymes of man. It comprises various polysaccharides and lignins. [NIH] Dietitian: An expert in nutrition who helps people plan what and how much food to eat. [NIH]

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] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dihydroxy: AMPA/Kainate antagonist. [NIH] Dilatation: The act of dilating. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilate: Relax; expand. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dilator: A device used to stretch or enlarge an opening. [NIH] Diploid: Having two sets of chromosomes. [NIH] Dipyridamole: A drug that prevents blood cell clumping and enhances the effectiveness of fluorouracil and other chemotherapeutic agents. [NIH]

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Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] 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] Diving: An activity in which the organism plunges into water. It includes scuba and bell diving. Diving as natural behavior of animals goes here, as well as diving in decompression experiments with humans or animals. [NIH] Dose-dependent: Refers to the effects of treatment with a drug. If the effects change when the dose of the drug is changed, the effects are said to be dose dependent. [NIH] 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 Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Drusen: Tiny yellow or white deposits in the retina or optic nerve head. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dura mater: The outermost, toughest, and most fibrous of the three membranes (meninges) covering the brain and spinal cord; called also pachymeninx. [EU] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dynamometer: An instrument for measuring the force of muscular contraction. [NIH] Dyskinesia: Impairment of the power of voluntary movement, resulting in fragmentary or incomplete movements. [EU] Dyslipidemia: Disorders in the lipoprotein metabolism; classified as hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, and low levels of high-density lipoprotein (HDL) cholesterol. All of the dyslipidemias can be primary or secondary. Both elevated levels of low-density lipoprotein (LDL) cholesterol and low levels of HDL cholesterol

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predispose to premature atherosclerosis. [NIH] Dyspareunia: Painful sexual intercourse. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Ectopic: Pertaining to or characterized by ectopia. [EU] Eczema: A pruritic papulovesicular dermatitis occurring as a reaction to many endogenous and exogenous agents (Dorland, 27th ed). [NIH] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Electrocardiogram: Measurement of electrical activity during heartbeats. [NIH] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electron microscope: A microscope (device used to magnify small objects) that uses electrons (instead of light) to produce an enlarged image. An electron microscopes shows tiny details better than any other type of microscope. [NIH] 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]

Electroporation: A technique in which electric pulses of intensity in kilovolts per centimeter and of microsecond-to-millisecond duration cause a temporary loss of the semipermeability of cell membranes, thus leading to ion leakage, escape of metabolites, and increased uptake by cells of drugs, molecular probes, and DNA. Some applications of electroporation include introduction of plasmids or foreign DNA into living cells for transfection, fusion of cells to prepare hybridomas, and insertion of proteins into cell membranes. [NIH] Emboli: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embolism: Blocking of a blood vessel by a blood clot or foreign matter that has been

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transported from a distant site by the blood stream. [NIH] Embolization: The blocking of an artery by a clot or foreign material. Embolization can be done as treatment to block the flow of blood to a tumor. [NIH] Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Enamel: A very hard whitish substance which covers the dentine of the anatomical crown of a tooth. [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] Endocarditis: Exudative and proliferative inflammatory alterations of the endocardium, characterized by the presence of vegetations on the surface of the endocardium or in the endocardium itself, and most commonly involving a heart valve, but sometimes affecting the inner lining of the cardiac chambers or the endocardium elsewhere. It may occur as a primary disorder or as a complication of or in association with another disease. [EU] Endocardium: The innermost layer of the heart, comprised of endothelial cells. [NIH] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endoderm: The inner of the three germ layers of the embryo. [NIH] 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] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have

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filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] 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] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Energy balance: Energy is the capacity of a body or a physical system for doing work. Energy balance is the state in which the total energy intake equals total energy needs. [NIH] Enhancers: Transcriptional element in the virus genome. [NIH] Enteritis: Inflammation of the intestine, applied chiefly to inflammation of the small intestine; see also enterocolitis. [EU] Enterocolitis: Inflammation of the intestinal mucosa of the small and large bowel. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] 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] Epidemiological: Relating to, or involving epidemiology. [EU] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which

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covers the inner or outer surfaces of the body. [NIH] Epitopes: Sites on an antigen that interact with specific antibodies. [NIH] Erectile: The inability to get or maintain an erection for satisfactory sexual intercourse. Also called impotence. [NIH] Erection: The condition of being made rigid and elevated; as erectile tissue when filled with blood. [EU] Erythema: Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of causes. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [NIH] Esterification: The process of converting an acid into an alkyl or aryl derivative. Most frequently the process consists of the reaction of an acid with an alcohol in the presence of a trace of mineral acid as catalyst or the reaction of an acyl chloride with an alcohol. Esterification can also be accomplished by enzymatic processes. [NIH] Estrogen: One of the two female sex hormones. [NIH] Estrogen Replacement Therapy: The use of hormonal agents with estrogen-like activity in postmenopausal or other estrogen-deficient women to alleviate effects of hormone deficiency, such as vasomotor symptoms, dyspareunia, and progressive development of osteoporosis. This may also include the use of progestational agents in combination therapy. [NIH]

Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evacuation: An emptying, as of the bowels. [EU] Excipients: Usually inert substances added to a prescription in order to provide suitable consistency to the dosage form; a binder, matrix, base or diluent in pills, tablets, creams, salves, etc. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Exercise Test: Controlled physical activity, more strenuous than at rest, which is performed in order to allow assessment of physiological functions, particularly cardiovascular and pulmonary, but also aerobic capacity. Maximal (most intense) exercise is usually required but submaximal exercise is also used. The intensity of exercise is often graded, using criteria such as rate of work done, oxygen consumption, and heart rate. Physiological data obtained from an exercise test may be used for diagnosis, prognosis, and evaluation of disease severity, and to evaluate therapy. Data may also be used in prescribing exercise by determining a person's exercise capacity. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [NIH]

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External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH] 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] Extravascular: Situated or occurring outside a vessel or the vessels. [EU] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Farnesyl: Enzyme which adds 15 carbon atoms to the Ras precursor protein. [NIH] Fat: Total lipids including phospholipids. [NIH] 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]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Fatty Liver: The buildup of fat in liver cells. The most common cause is alcoholism. Other causes include obesity, diabetes, and pregnancy. Also called steatosis. [NIH] Febrile: Pertaining to or characterized by fever. [EU] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Femoral: Pertaining to the femur, or to the thigh. [EU] Femoral Artery: The main artery of the thigh, a continuation of the external iliac artery. [NIH] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [NIH] Fermentation: An enzyme-induced chemical change in organic compounds that takes place in the absence of oxygen. The change usually results in the production of ethanol or lactic acid, and the production of energy. [NIH]

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Ferritin: An iron-containing protein complex that is formed by a combination of ferric iron with the protein apoferritin. [NIH] Fibrillation: A small, local, involuntary contraction of muscle, invisible under the skin, resulting from spontaneous activation of single muscle cells or muscle fibres. [EU] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibrinolysis: The natural enzymatic dissolution of fibrin. [NIH] Fibroblast Growth Factor: Peptide isolated from the pituitary gland and from the brain. It is a potent mitogen which stimulates growth of a variety of mesodermal cells including chondrocytes, granulosa, and endothelial cells. The peptide may be active in wound healing and animal limb regeneration. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibronectin: An adhesive glycoprotein. One form circulates in plasma, acting as an opsonin; another is a cell-surface protein which mediates cellular adhesive interactions. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Flow Cytometry: Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. [NIH] Fluorescein Angiography: Visualization of a vascular system after intravenous injection of a fluorescein solution. The images may be photographed or televised. It is used especially in studying the retinal and uveal vasculature. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorescent Dyes: Dyes that emit light when exposed to light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags. They are used as markers in biochemistry and immunology. [NIH] Fluorouracil: A pyrimidine analog that acts as an antineoplastic antimetabolite and also has immunosuppressant. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. [NIH] Foam Cells: Lipid-laden macrophages originating from monocytes or from smooth muscle cells. [NIH]

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Focal Adhesions: An anchoring junction of the cell to a non-cellular substrate. It is composed of a specialized area of the plasma membrane where bundles of microfilaments terminate and attach to the transmembrane linkers, integrins, which in turn attach through their extracellular domains to extracellular matrix proteins. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fovea: The central part of the macula that provides the sharpest vision. [NIH] Frontal Lobe: The anterior part of the cerebral hemisphere. [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] Gadolinium: An element of the rare earth family of metals. It has the atomic symbol Gd, atomic number 64, and atomic weight 157.25. Its oxide is used in the control rods of some nuclear reactors. [NIH] Gait: Manner or style of walking. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gallstones: The solid masses or stones made of cholesterol or bilirubin that form in the gallbladder or bile ducts. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gangrene: Death and putrefaction of tissue usually due to a loss of blood supply. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gasoline: Volative flammable fuel (liquid hydrocarbons) derived from crude petroleum by processes such as distillation reforming, polymerization, etc. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] 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] Gemfibrozil: A lipid-regulating agent that lowers elevated serum lipids primarily by decreasing serum triglycerides with a variable reduction in total cholesterol. These decreases occur primarily in the VLDL fraction and less frequently in the LDL fraction. Gemfibrozil increases HDL subfractions HDL2 and HDL3 as well as apolipoproteins A-I and A-II. Its mechanism of action has not been definitely established. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Targeting: The integration of exogenous DNA into the genome of an organism at sites

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where its expression can be suitably controlled. This integration occurs as a result of homologous recombination. [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 Counseling: Advising families of the risks involved pertaining to birth defects, in order that they may make an informed decision on current or future pregnancies. [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. [NIH]

Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Gestational: Psychosis attributable to or occurring during pregnancy. [NIH] Gifted: As used in child psychiatry, this term is meant to refer to a child whose intelligence is in the upper 2 per cent of the total population of his age. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Glomeruli: Plural of glomerulus. [NIH] Glomerulonephritis: Glomerular disease characterized by an inflammatory reaction, with leukocyte infiltration and cellular proliferation of the glomeruli, or that appears to be the result of immune glomerular injury. [NIH] Glomerulosclerosis: Scarring of the glomeruli. It may result from diabetes mellitus (diabetic glomerulosclerosis) or from deposits in parts of the glomerulus (focal segmental glomerulosclerosis). The most common signs of glomerulosclerosis are proteinuria and kidney failure. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glucocorticoids: A group of corticosteroids that affect carbohydrate metabolism (gluconeogenesis, liver glycogen deposition, elevation of blood sugar), inhibit corticotropin secretion, and possess pronounced anti-inflammatory activity. They also play a role in fat and protein metabolism, maintenance of arterial blood pressure, alteration of the connective tissue response to injury, reduction in the number of circulating lymphocytes, and

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functioning of the central nervous system. [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] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucose tolerance: The power of the normal liver to absorb and store large quantities of glucose and the effectiveness of intestinal absorption of glucose. The glucose tolerance test is a metabolic test of carbohydrate tolerance that measures active insulin, a hepatic function based on the ability of the liver to absorb glucose. The test consists of ingesting 100 grams of glucose into a fasting stomach; blood sugar should return to normal in 2 to 21 hours after ingestion. [NIH] Glucose Tolerance Test: Determination of whole blood or plasma sugar in a fasting state before and at prescribed intervals (usually 1/2 hr, 1 hr, 3 hr, 4 hr) after taking a specified amount (usually 100 gm orally) of glucose. [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] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

Glutamine: A non-essential amino acid present abundantly throught the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. [NIH] Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]

Gluten: The protein of wheat and other grains which gives to the dough its tough elastic character. [EU] Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]

Glycerophospholipids: Derivatives of phosphatidic acid in which the hydrophobic regions are composed of two fatty acids and a polar alcohol is joined to the C-3 position of glycerol through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. [NIH] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] 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] Glycogen Synthase: An enzyme that catalyzes the transfer of D-glucose from UDPglucose into 1,4-alpha-D-glucosyl chains. EC 2.4.1.11. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH]

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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] Gonadal: Pertaining to a gonad. [EU] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]

Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] 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 Survival: The survival of a graft in a host, the factors responsible for the survival and the changes occurring within the graft during growth in the host. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Granulocyte Colony-Stimulating Factor: A glycoprotein of MW 25 kDa containing internal disulfide bonds. It induces the survival, proliferation, and differentiation of neutrophilic granulocyte precursor cells and functionally activates mature blood neutrophils. Among the family of colony-stimulating factors, G-CSF is the most potent inducer of terminal differentiation to granulocytes and macrophages of leukemic myeloid cell lines. [NIH] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [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] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [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]

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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 Promotion: Encouraging consumer behaviors most likely to optimize health potentials (physical and psychosocial) through health information, preventive programs, and access to medical care. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heart Transplantation: The transference of a heart from one human or animal to another. [NIH]

Heart Valves: Flaps of tissue that prevent regurgitation of blood from the ventricles to the atria or from the pulmonary arteries or aorta to the ventricles. [NIH] Heartbeat: One complete contraction of the heart. [NIH] Heat-Shock Proteins: Proteins which are synthesized in eukaryotic organisms and bacteria in response to hyperthermia and other environmental stresses. They increase thermal tolerance and perform functions essential to cell survival under these conditions. [NIH] Heat-Shock Proteins 90: A class of molecular chaperones whose members act in the mechanism of signal transduction by steroid receptors. [NIH] Hematemesis: Vomiting of blood. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemodynamics: The movements of the blood and the forces involved in systemic or regional blood circulation. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [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]

Heparan Sulfate Proteoglycan: A substance released by astrocytes, which is critical in stopping nervous fibers in their tracks. [NIH] Heparin: Heparinic acid. A highly acidic mucopolysaccharide formed of equal parts of

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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] Hepatic: Refers to the liver. [NIH] Hepatocyte: A liver cell. [NIH] Hepatocyte Growth Factor: Multifunctional growth factor which regulates both cell growth and cell motility. It exerts a strong mitogenic effect on hepatocytes and primary epithelial cells. Its receptor is proto-oncogene protein C-met. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] 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]

Heterozygote: An individual having different alleles at one or more loci in homologous chromosome segments. [NIH] Hippocampus: A curved elevation of gray matter extending the entire length of the floor of the temporal horn of the lateral ventricle (Dorland, 28th ed). The hippocampus, subiculum, and dentate gyrus constitute the hippocampal formation. Sometimes authors include the entorhinal cortex in the hippocampal formation. [NIH] Hirudin: The active principle in the buccal gland secretion of leeches. It acts as an antithrombin and as an antithrombotic agent. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homicide: The killing of one person by another. [NIH] Homodimer: Protein-binding "activation domains" always combine with identical proteins. [NIH]

Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homozygotes: An individual having a homozygous gene pair. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hormone Replacement Therapy: Therapeutic use of hormones to alleviate the effects of hormone deficiency. [NIH] 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]

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Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] 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] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperglycemia: Abnormally high blood sugar. [NIH] Hyperhomocysteinemia: An inborn error of methionone metabolism which produces an excess of homocysteine in the blood. It is often caused by a deficiency of cystathionine betasynthase and is a risk factor for coronary vascular disease. [NIH] Hyperlipidemia: An excess of lipids in the blood. [NIH] Hyperlipoproteinemia: Metabolic disease characterized by elevated plasma cholesterol and/or triglyceride levels. The inherited form is attributed to a single gene mechanism. [NIH] Hyperphagia: Ingestion of a greater than optimal quantity of food. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [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] Hyperthyroidism: Excessive functional activity of the thyroid gland. [NIH]

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Hypertriglyceridemia: Condition of elevated triglyceride concentration in the blood; an inherited form occurs in familial hyperlipoproteinemia IIb and hyperlipoproteinemia type IV. It has been linked to higher risk of heart disease and arteriosclerosis. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hypesthesia: Absent or reduced sensitivity to cutaneous stimulation. [NIH] Hypodermic: Applied or administered beneath the skin. [EU] Hypoglycemia: Abnormally low blood sugar [NIH] Hypotensive: Characterized by or causing diminished tension or pressure, as abnormally low blood pressure. [EU] Iatrogenic: Resulting from the activity of physicians. Originally applied to disorders induced in the patient by autosuggestion based on the physician's examination, manner, or discussion, the term is now applied to any adverse condition in a patient occurring as the result of treatment by a physician or surgeon, especially to infections acquired by the patient during the course of treatment. [EU] Iatrogenic Disease: Any adverse condition in a patient occurring as the result of treatment by a physician, surgeon, or other health professional, especially infections acquired by the patient during the course of treatment. [NIH] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Iliac Artery: Either of two large arteries originating from the abdominal aorta; they supply blood to the pelvis, abdominal wall and legs. [NIH] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH]

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Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] Impotence: The inability to perform sexual intercourse. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incubated: Grown in the laboratory under controlled conditions. (For instance, white blood cells can be grown in special conditions so that they attack specific cancer cells when returned to the body.) [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] 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]

Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH]

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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] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inlay: In dentistry, a filling first made to correspond with the form of a dental cavity and then cemented into the cavity. [NIH] 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] 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] Interindividual: Occurring between two or more individuals. [EU] Intermediate Filaments: Cytoplasmic filaments intermediate in diameter (about 10 nanometers) between the microfilaments and the microtubules. They may be composed of any of a number of different proteins and form a ring around the cell nucleus. [NIH]

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Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intervention Studies: Epidemiologic investigations designed to test a hypothesized causeeffect relation by modifying the supposed causal factor(s) in the study population. [NIH] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intracranial Pressure: Pressure within the cranial cavity. It is influenced by brain mass, the circulatory system, CSF dynamics, and skull rigidity. [NIH] Intrahepatic: Within the liver. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intraocular: Within the eye. [EU] Intraocular pressure: Pressure of the fluid inside the eye; normal IOP varies among individuals. [NIH] Intravascular: Within a vessel or vessels. [EU] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Intubation: Introduction of a tube into a hollow organ to restore or maintain patency if obstructed. It is differentiated from catheterization in that the insertion of a catheter is usually performed for the introducing or withdrawing of fluids from the body. [NIH] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Involuntary: Reaction occurring without intention or volition. [NIH] Ionization: 1. Any process by which a neutral atom gains or loses electrons, thus acquiring a net charge, as the dissociation of a substance in solution into ions or ion production by the passage of radioactive particles. 2. Iontophoresis. [EU] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body

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(external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Irritable Bowel Syndrome: A disorder that comes and goes. Nerves that control the muscles in the GI tract are too active. The GI tract becomes sensitive to food, stool, gas, and stress. Causes abdominal pain, bloating, and constipation or diarrhea. Also called spastic colon or mucous colitis. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Islet: Cell producing insulin in pancreas. [NIH] Isoflavones: 3-Phenylchromones. Isomeric form of flavones in which the benzene group is attached to the 3 position of the benzopyran ring instead of the 2 position. [NIH] Isoprenoid: Molecule that might anchor G protein to the cell membrane as it is hydrophobic. [NIH]

Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Kallidin: A decapeptide bradykinin homolog produced by the action of tissue and glandular kallikreins on low-molecular-weight kininogen. It is a smooth-muscle stimulant and hypotensive agent that functions through vasodilatation. [NIH] Kallikrein-Kinin System: A system produced in the distal nephron of the kidney. Its components are kallikrein, kinins, kininase I and II, and enkephalinase. It is involved in mediation and modulation of the renin-angiotensin-aldosterone system, prostaglandins, vasopressins, and in the regulation of sodium-water balance, renal hemodynamics, and particularly blood pressure. The system participates in the control of renal functions and the physiopathology of renal diseases. [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] Keratolytic: An agent that promotes keratolysis. [EU] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [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] Lag: The time elapsing between application of a stimulus and the resulting reaction. [NIH] Laminin: Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion. [NIH]

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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] Laser therapy: The use of an intensely powerful beam of light to kill cancer cells. [NIH] Latency: The period of apparent inactivity between the time when a stimulus is presented and the moment a response occurs. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] 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] Legal blindness: In the U.S., (1) visual acuity of 20/200 or worse in the better eye with corrective lenses (20/200 means that a person must be at 20 feet from an eye chart to see what a person with normal vision can see at 200 feet) or (2) visual field restricted to 20 d [NIH]

Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Lentivirus: A genus of the family Retroviridae consisting of non-oncogenic retroviruses that produce multi-organ diseases characterized by long incubation periods and persistent infection. Lentiviruses are unique in that they contain open reading frames (ORFs) between the pol and env genes and in the 3' env region. Five serogroups are recognized, reflecting the mammalian hosts with which they are associated. HIV-1 is the type species. [NIH] Leptin: A 16-kD peptide hormone secreted from white adipocytes and implicated in the regulation of food intake and energy balance. Leptin provides the key afferent signal from fat cells in the feedback system that controls body fat stores. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leukapheresis: The preparation of leukocyte concentrates with the return of red cells and 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] Libido: The psychic drive or energy associated with sexual instinct in the broad sense (pleasure and love-object seeking). It may also connote the psychic energy associated with instincts in general that motivate behavior. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] 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]

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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] Lipid Peroxides: Peroxides produced in the presence of a free radical by the oxidation of unsaturated fatty acids in the cell in the presence of molecular oxygen. The formation of lipid peroxides results in the destruction of the original lipid leading to the loss of integrity of the membranes. They therefore cause a variety of toxic effects in vivo and their formation is considered a pathological process in biological systems. Their formation can be inhibited by antioxidants, such as vitamin E, structural separation or low oxygen tension. [NIH] Lipodystrophy: A collection of rare conditions resulting from defective fat metabolism and characterized by atrophy of the subcutaneous fat. They include total, congenital or acquired, partial, abdominal infantile, and localized lipodystrophy. [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] Lipoxygenase: An enzyme of the oxidoreductase class that catalyzes reactions between linoleate and other fatty acids and oxygen to form hydroperoxy-fatty acid derivatives. Related enzymes in this class include the arachidonate lipoxygenases, arachidonate 5lipoxygenase, arachidonate 12-lipoxygenase, and arachidonate 15-lipoxygenase. EC 1.13.11.12. [NIH] Lithotripsy: The destruction of a calculus of the kidney, ureter, bladder, or gallbladder by physical forces, including crushing with a lithotriptor through a catheter. Focused percutaneous ultrasound and focused hydraulic shock waves may be used without surgery. Lithotripsy does not include the dissolving of stones by acids or litholysis. Lithotripsy by laser is laser lithotripsy. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] 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

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numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Lovastatin: A fungal metabolite isolated from cultures of Aspergillus terreus. The compound is a potent anticholesteremic agent. It inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase (hydroxymethylglutaryl CoA reductases), which is the rate-limiting enzyme in cholesterol biosynthesis. It also stimulates the production of low-density lipoprotein receptors in the liver. [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] Lubricants: Oily or slippery substances. [NIH] Lucida: An instrument, invented by Wollaton, consisting essentially of a prism or a mirror through which an object can be viewed so as to appear on a plane surface seen in direct view and on which the outline of the object may be traced. [NIH] Lumen: The cavity or channel within a tube or tubular organ. [EU] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lycopene: A red pigment found in tomatoes and some fruits. [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]

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] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphokines: Soluble protein factors generated by activated lymphocytes that affect other cells, primarily those involved in cellular immunity. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] 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]

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Macrophage Activation: The process of altering the morphology and functional activity of macrophages so that they become avidly phagocytic. It is initiated by lymphokines, such as the macrophage activation factor (MAF) and the macrophage migration-inhibitory factor (MMIF), immune complexes, C3b, and various peptides, polysaccharides, and immunologic adjuvants. [NIH] Macula: A stain, spot, or thickening. Often used alone to refer to the macula retinae. [EU] 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] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Mammary: Pertaining to the mamma, or breast. [EU] Mammogram: An x-ray of the breast. [NIH] Mandible: The largest and strongest bone of the face constituting the lower jaw. It supports the lower teeth. [NIH] Mania: Excitement of psychotic proportions manifested by mental and physical hyperactivity, disorganization of behaviour, and elevation of mood. [EU] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] 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] Mean blood pressure: The average blood pressure, taking account of the rise and fall that occurs with each heartbeat. It is often estimated by multiplying the diastolic pressure by two, adding the systolic pressure, and then dividing this sum by three. [NIH] Meat: The edible portions of any animal used for food including domestic mammals (the major ones being cattle, swine, and sheep) along with poultry, fish, shellfish, and game. [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 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]

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Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Megakaryocytes: Very large bone marrow cells which release mature blood platelets. [NIH] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [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] Menopause: Permanent cessation of menstruation. [NIH] 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] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [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] Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Mesoderm: The middle germ layer of the embryo. [NIH]

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Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] 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] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Metastatic cancer: Cancer that has spread from the place in which it started to other parts of the body. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] Methyltransferase: A drug-metabolizing enzyme. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microcalcifications: Tiny deposits of calcium in the breast that cannot be felt but can be detected on a mammogram. A cluster of these very small specks of calcium may indicate that cancer is present. [NIH] Microcirculation: The vascular network lying between the arterioles and venules; includes capillaries, metarterioles and arteriovenous anastomoses. Also, the flow of blood through this network. [NIH] Microfibrils: Components of the extracellular matrix consisting primarily of fibrillin. They are essential for the integrity of elastic fibers. [NIH] Microfilaments: The smallest of the cytoskeletal filaments. They are composed chiefly of actin. [NIH] Micronuclei: Nuclei, separate from and additional to the main nucleus of a cell, produced during the telophase of mitosis or meiosis by lagging chromosomes or chromosome fragments derived from spontaneous or experimentally induced chromosomal structural changes. This concept also includes the smaller, reproductive nuclei found in multinucleate protozoans. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Micro-organism: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microtubule-Associated Proteins: High molecular weight proteins found in the microtubules of the cytoskeletal system. Under certain conditions they are required for

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tubulin assembly into the microtubules and stabilize the assembled microtubules. [NIH] Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Mineralocorticoids: A group of corticosteroids primarily associated with the regulation of water and electrolyte balance. This is accomplished through the effect on ion transport in renal tubules, resulting in retention of sodium and loss of potassium. Mineralocorticoid secretion is itself regulated by plasma volume, serum potassium, and angiotensin II. [NIH] 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] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] 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] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Chaperones: A family of cellular proteins that mediate the correct assembly or disassembly of other polypeptides, and in some cases their assembly into oligomeric structures, but which are not components of those final structures. It is believed that chaperone proteins assist polypeptides to self-assemble by inhibiting alternative assembly pathways that produce nonfunctional structures. Some classes of molecular chaperones are the nucleoplasmins, the chaperonins, the heat-shock proteins 70, and the heat-shock proteins 90. [NIH] Molecular Conformation: The characteristic three-dimensional shape of a molecule. [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] Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. [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] Monocyte: A type of white blood cell. [NIH] Mononuclear: A cell with one nucleus. [NIH]

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Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH]

Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Motility: The ability to move spontaneously. [EU] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] 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] Muscle Contraction: A process leading to shortening and/or development of tension in muscle tissue. Muscle contraction occurs by a sliding filament mechanism whereby actin filaments slide inward among the myosin filaments. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagenicity: Ability to damage DNA, the genetic material; the power to cause mutations. [NIH]

Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Mutate: To change the genetic material of a cell. Then changes (mutations) can be harmful, beneficial, or have no effect. [NIH] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result

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in necrosis of cardiac muscle (myocardial infarction). [NIH] Myocardial Reperfusion: Generally, restoration of blood supply to heart tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. Reperfusion can be induced to treat ischemia. Methods include chemical dissolution of an occluding thrombus, administration of vasodilator drugs, angioplasty, catheterization, and artery bypass graft surgery. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing myocardial reperfusion injury. [NIH] Myocardial Reperfusion Injury: Functional, metabolic, or structural changes in ischemic heart muscle thought to result from reperfusion to the ischemic areas. Changes can be fatal to muscle cells and may include edema with explosive cell swelling and disintegration, sarcolemma disruption, fragmentation of mitochondria, contraction band necrosis, enzyme washout, and calcium overload. Other damage may include hemorrhage and ventricular arrhythmias. One possible mechanism of damage is thought to be oxygen free radicals. Treatment currently includes the introduction of scavengers of oxygen free radicals, and injury is thought to be prevented by warm blood cardioplegic infusion prior to reperfusion. [NIH]

Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Naphthalenes: Two-ring crystalline hydrocarbons isolated from coal tar. They are used as intermediates in chemical synthesis, as insect repellents, fungicides, lubricants, preservatives, and, formerly, as topical antiseptics. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] 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] Neocortex: The largest portion of the cerebral cortex. It is composed of neurons arranged in six layers. [NIH] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephritis: Inflammation of the kidney; a focal or diffuse proliferative or destructive process which may involve the glomerulus, tubule, or interstitial renal tissue. [EU] Nephron: A tiny part of the kidneys. Each kidney is made up of about 1 million nephrons, which are the working units of the kidneys, removing wastes and extra fluids from the

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blood. [NIH] Nephropathy: Disease of the kidneys. [EU] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neuritis: A general term indicating inflammation of a peripheral or cranial nerve. Clinical manifestation may include pain; paresthesias; paresis; or hypesthesia. [NIH] Neuroendocrinology: The study of the anatomical and functional relationships between the nervous system and the endocrine system. [NIH] Neurofibrillary Tangles: Abnormal structures located in various parts of the brain and composed of dense arrays of paired helical filaments (neurofilaments and microtubules). These double helical stacks of transverse subunits are twisted into left-handed ribbon-like filaments that likely incorporate the following proteins: (1) the intermediate filaments: medium- and high-molecular-weight neurofilaments; (2) the microtubule-associated proteins map-2 and tau; (3) actin; and (4) ubiquitin. As one of the hallmarks of Alzheimer disease, the neurofibrillary tangles eventually occupy the whole of the cytoplasm in certain classes of cell in the neocortex, hippocampus, brain stem, and diencephalon. The number of these tangles, as seen in post mortem histology, correlates with the degree of dementia during life. Some studies suggest that tangle antigens leak into the systemic circulation both in the course of normal aging and in cases of Alzheimer disease. [NIH] Neurofilaments: Bundle of neuronal fibers. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH] Neuroses: Functional derangement due to disorders of the nervous system which does not affect the psychic personality of the patient. [NIH] Neurosis: Functional derangement due to disorders of the nervous system which does not affect the psychic personality of the patient. [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] Neutron Capture Therapy: A technique for the treatment of neoplasms in which an isotope

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is introduced into target cells followed by irradiation with thermal neutrons. [NIH] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophil: A type of white blood cell. [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Nitrates: Inorganic or organic salts and esters of nitric acid. These compounds contain the NO3- radical. [NIH] Nitric acid: A toxic, corrosive, colorless liquid used to make fertilizers, dyes, explosives, and other chemicals. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH] Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Nitroglycerin: A highly volatile organic nitrate that acts as a dilator of arterial and venous smooth muscle and is used in the treatment of angina. It provides relief through improvement of the balance between myocardial oxygen supply and demand. Although total coronary blood flow is not increased, there is redistribution of blood flow in the heart when partial occlusion of coronary circulation is effected. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the

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chromosomes. [NIH] Nutritional Status: State of the body in relation to the consumption and utilization of nutrients. [NIH] Observational study: An epidemiologic study that does not involve any intervention, experimental or otherwise. Such a study may be one in which nature is allowed to take its course, with changes in one characteristic being studied in relation to changes in other characteristics. Analytical epidemiologic methods, such as case-control and cohort study designs, are properly called observational epidemiology because the investigator is observing without intervention other than to record, classify, count, and statistically analyze results. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Odds Ratio: The ratio of two odds. The exposure-odds ratio for case control data is the ratio of the odds in favor of exposure among cases to the odds in favor of exposure among noncases. The disease-odds ratio for a cohort or cross section is the ratio of the odds in favor of disease among the exposed to the odds in favor of disease among the unexposed. The prevalence-odds ratio refers to an odds ratio derived cross-sectionally from studies of prevalent cases. [NIH] Odour: A volatile emanation that is perceived by the sense of smell. [EU] Ointments: Semisolid preparations used topically for protective emollient effects or as a vehicle for local administration of medications. Ointment bases are various mixtures of fats, waxes, animal and plant oils and solid and liquid hydrocarbons. [NIH] Oligomenorrhea: Abnormally infrequent menstruation. [NIH] Omega-3 fatty acid: A type of fat obtained in the diet and involved in immunity. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Open Reading Frames: Reading frames where successive nucleotide triplets can be read as codons specifying amino acids and where the sequence of these triplets is not interrupted by stop codons. [NIH] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Ophthalmic: Pertaining to the eye. [EU] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [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

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the central nervous system. [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] Organ Transplantation: Transference of an organ between individuals of the same species or between individuals of different species. [NIH] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Osteoarthritis: A progressive, degenerative joint disease, the most common form of arthritis, especially in older persons. The disease is thought to result not from the aging process but from biochemical changes and biomechanical stresses affecting articular cartilage. In the foreign literature it is often called osteoarthrosis deformans. [NIH] Osteoblasts: Bone-forming cells which secrete an extracellular matrix. Hydroxyapatite crystals are then deposited into the matrix to form bone. [NIH] Osteocalcin: Vitamin K-dependent calcium-binding protein synthesized by osteoblasts and found primarily in bone. Serum osteocalcin measurements provide a noninvasive specific marker of bone metabolism. The protein contains three residues of the amino acid gammacarboxyglutamic acid (GLA), which, in the presence of calcium, promotes binding to hydroxyapatite and subsequent accumulation in bone matrix. [NIH] Osteogenic sarcoma: A malignant tumor of the bone. Also called osteosarcoma. [NIH] Osteolytic: Causing the breakdown of bone. [NIH] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Osteosarcoma: A cancer of the bone that affects primarily children and adolescents. Also called osteogenic sarcoma. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overexpress: An excess of a particular protein on the surface of a cell. [NIH] Overweight: An excess of body weight but not necessarily body fat; a body mass index of 25 to 29.9 kg/m2. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxamic Acid: Amino-substituted glyoxylic acid derivative. [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

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bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oxides: Binary compounds of oxygen containing the anion O(2-). The anion combines with metals to form alkaline oxides and non-metals to form acidic oxides. [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Oxygenase: Enzyme which breaks down heme, the iron-containing oxygen-carrying constituent of the red blood cells. [NIH] P53 gene: A tumor suppressor gene that normally inhibits the growth of tumors. This gene is altered in many types of cancer. [NIH] Pachymeningitis: Inflammation of the dura mater of the brain, the spinal cord or the optic nerve. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] 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] Panic: A state of extreme acute, intense anxiety and unreasoning fear accompanied by disorganization of personality function. [NIH] Paraffin: A mixture of solid hydrocarbons obtained from petroleum. It has a wide range of uses including as a stiffening agent in ointments, as a lubricant, and as a topical antiinflammatory. It is also commonly used as an embedding material in histology. [NIH] Parenchyma: The essential elements of an organ; used in anatomical nomenclature as a general term to designate the functional elements of an organ, as distinguished from its framework, or stroma. [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] Paresthesia: Subjective cutaneous sensations (e.g., cold, warmth, tingling, pressure, etc.) that are experienced spontaneously in the absence of stimulation. [NIH] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Particle: A tiny mass of material. [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]

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Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Peau d'orange: A dimpled condition of the skin of the breast, resembling the skin of an orange, sometimes found in inflammatory breast cancer. [NIH] Pelvic: Pertaining to the pelvis. [EU] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Periodontitis: Inflammation of the periodontal membrane; also called periodontitis simplex. [NIH]

Perioperative: Around the time of surgery; usually lasts from the time of going into the hospital or doctor's office for surgery until the time the patient goes home. [NIH] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peripheral Neuropathy: Nerve damage, usually affecting the feet and legs; causing pain, numbness, or a tingling feeling. Also called "somatic neuropathy" or "distal sensory polyneuropathy." [NIH] Peripheral Vascular Disease: Disease in the large blood vessels of the arms, legs, and feet. People who have had diabetes for a long time may get this because major blood vessels in their arms, legs, and feet are blocked and these limbs do not receive enough blood. The signs of PVD are aching pains in the arms, legs, and feet (especially when walking) and foot sores that heal slowly. Although people with diabetes cannot always avoid PVD, doctors say they have a better chance of avoiding it if they take good care of their feet, do not smoke, and keep both their blood pressure and diabetes under good control. [NIH] Perivascular: Situated around a vessel. [EU]

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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] Personality Disorders: A major deviation from normal patterns of behavior. [NIH] Petroleum: Naturally occurring complex liquid hydrocarbons which, after distillation, yield combustible fuels, petrochemicals, and lubricants. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharmacotherapy: A regimen of using appetite suppressant medications to manage obesity by decreasing appetite or increasing the feeling of satiety. These medications decrease appetite by increasing serotonin or catecholamine—two brain chemicals that affect mood and appetite. [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Photodynamic therapy: Treatment with drugs that become active when exposed to light. These drugs kill cancer cells. [NIH]

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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] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other 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] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasmapheresis: Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. [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]

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Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelet-Derived Growth Factor: Mitogenic peptide growth hormone carried in the alphagranules of platelets. It is released when platelets adhere to traumatized tissues. Connective tissue cells near the traumatized region respond by initiating the process of replication. [NIH] Plateletpheresis: The preparation of platelet concentrates with the return of red cells and platelet-poor plasma to the donor. [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] Pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Pollen: The male fertilizing element of flowering plants analogous to sperm in animals. It is released from the anthers as yellow dust, to be carried by insect or other vectors, including wind, to the ovary (stigma) of other flowers to produce the embryo enclosed by the seed. The pollens of many plants are allergenic. [NIH] Polyarteritis Nodosa: A form of necrotizing vasculitis involving small- and medium-sized arteries. The signs and symptoms result from infarction and scarring of the affected organ system. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polycystic Ovary Syndrome: Clinical symptom complex characterized by oligomenorrhea or amenorrhea, anovulation, and regularly associated with bilateral polycystic ovaries. [NIH] Polylysine: A peptide which is a homopolymer of lysine. [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]

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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] 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] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potentiate: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Pravastatin: An antilipemic fungal metabolite isolated from cultures of Nocardia autotrophica. It acts as a competitive inhibitor of HMG CoA reductase (hydroxymethylglutaryl CoA reductases). [NIH] Precipitation: The act or process of precipitating. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Prekallikrein: A plasma protein which is the precursor of kallikrein. Plasma that is deficient in prekallikrein has been found to be abnormal in thromboplastin formation, kinin generation, evolution of a permeability globulin, and plasmin formation. The absence of prekallikrein in plasma leads to Fletcher factor deficiency, a congenital disease. [NIH] Premedication: Preliminary administration of a drug preceding a diagnostic, therapeutic, or surgical procedure. The commonest types of premedication are antibiotics (antibiotic prophylaxis) and anti-anxiety agents. It does not include preanesthetic medication. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH]

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Primary endpoint: The main result that is measured at the end of a study to see if a given treatment worked (e.g., the number of deaths or the difference in survival between the treatment group and the control group). What the primary endpoint will be is decided before the study begins. [NIH] Primary Prevention: Prevention of disease or mental disorders in susceptible individuals or populations through promotion of health, including mental health, and specific protection, as in immunization, as distinguished from the prevention of complications or after-effects of existing disease. [NIH] Primary tumor: The original tumor. [NIH] 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] Progeny: The offspring produced in any generation. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] 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] Progressive disease: Cancer that is increasing in scope or severity. [NIH] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Prokaryotic Cells: Cells, such as those of bacteria and the blue green algae, which lack a nuclear membrane so that the nuclear material is either scattered in the cytoplasm or collected in a nucleoid region. [NIH] Proliferative Retinopathy: A disease of the small blood vessels of the retina of the eye. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] 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 Studies: Observation of a population for a sufficient number of persons over a sufficient number of years to generate incidence or mortality rates subsequent to the selection of the study group. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandins: A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes

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a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Prosthodontics: A dental specialty concerned with the restoration and maintenance of oral function by the replacement of missing teeth and structures by artificial devices or prostheses. [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] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [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]

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] Prothrombin: A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. Deficiency of prothrombin leads to hypoprothrombinemia. [NIH]

Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Pruritic: Pertaining to or characterized by pruritus. [EU] Pseudoxanthoma: A rare disease of the skin characterized by the appearance of elevated yellowish papules or plaques, particularly on the neck, chest an abdomen and infrequently on the eyelids. [NIH] Pseudoxanthoma Elasticum: A rare, progressive inherited disorder resulting from extensive basophilic degeneration of elastic tissue, usually presenting after puberty and involving the skin, eye, and cardiovascular system. Characteristic manifestations are small, circumscribed yellowish patches at sites of considerable movement of the skin, angioid streaks in the retina, and a tendency towards hemorrhage and arterial insufficiency. [NIH] Psoriasis: A common genetically determined, chronic, inflammatory skin disease

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characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychogenic: Produced or caused by psychic or mental factors rather than organic factors. [EU]

Psychosexual: Pertaining to the mental aspects of sex. [NIH] Puberty: The period during which the secondary sex characteristics begin to develop and the capability of sexual reproduction is attained. [EU] 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]

Puerperium: Period from delivery of the placenta until return of the reproductive organs to their normal nonpregnant morphologic state. In humans, the puerperium generally lasts for six to eight weeks. [NIH] Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Embolism: Embolism in the pulmonary artery or one of its branches. [NIH] Pulmonary Emphysema: Condition of the lungs characterized by increase beyond normal in the size of air spaces distal to the terminal bronchioles, either from dilatation of the alveoli or from destruction of their walls. [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]

Pupil: The aperture in the iris through which light passes. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Putrefaction: The process of decomposition of animal and vegetable matter by living organisms. [NIH] Pyrexia: A fever, or a febrile condition; abnormal elevation of the body temperature. [EU] Quercetin: Aglucon of quercetrin, rutin, and other glycosides. It is widely distributed in the plant kingdom, especially in rinds and barks, clover blossoms, and ragweed pollen. [NIH] Quiescent: Marked by a state of inactivity or repose. [EU] Quinolones: Quinolines which are substituted in any position by one or more oxo groups. These compounds can have any degree of hydrogenation, any substituents, and fused ring systems. [NIH]

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Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Reactivation: The restoration of activity to something that has been inactivated. [EU] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reading Frames: The sequence of codons by which translation may occur. A segment of mRNA 5'AUCCGA3' could be translated in three reading frames, 5'AUC. or 5'UCC. or 5'CCG., depending on the location of the start codon. [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] Receptors, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH]

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Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reference point: The midpoint of a line connecting the centers of the two end faces of the acoustic test fixture. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] 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] Regurgitation: A backward flowing, as the casting up of undigested food, or the backward flowing of blood into the heart, or between the chambers of the heart when a valve is incompetent. [EU] Relative risk: The ratio of the incidence rate of a disease among individuals exposed to a specific risk factor to the incidence rate among unexposed individuals; synonymous with risk ratio. Alternatively, the ratio of the cumulative incidence rate in the exposed to the cumulative incidence rate in the unexposed (cumulative incidence ratio). The term relative risk has also been used synonymously with odds ratio. This is because the odds ratio and relative risk approach each other if the disease is rare ( 5 percent of population) and the number of subjects is large. [NIH] Relaxation Techniques: The use of muscular relaxation techniques in treatment. [NIH] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Renin: An enzyme which is secreted by the kidney and is formed from prorenin in plasma and kidney. The enzyme cleaves the Leu-Leu bond in angiotensinogen to generate angiotensin I. EC 3.4.23.15. (Formerly EC 3.4.99.19). [NIH] Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH] Repressor: Any of the specific allosteric protein molecules, products of regulator genes,

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which bind to the operator of operons and prevent RNA polymerase from proceeding into the operon to transcribe messenger RNA. [NIH] Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] 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] 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] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoid: Vitamin A or a vitamin A-like compound. [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] Retinopathy: 1. Retinitis (= inflammation of the retina). 2. Retinosis (= degenerative, noninflammatory condition of the retina). [EU] Retrovirus: A member of a group of RNA viruses, the RNA of which is copied during viral replication into DNA by reverse transcriptase. The viral DNA is then able to be integrated into the host chromosomal DNA. [NIH] 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] 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] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU]

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Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Risk patient: Patient who is at risk, because of his/her behaviour or because of the type of person he/she is. [EU] Rods: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide side vision and the ability to see objects in dim light (night vision). [NIH] Rubber: A high-molecular-weight polymeric elastomer derived from the milk juice (latex) of Hevea brasiliensis and other trees. It is a substance that can be stretched at room temperature to atleast twice its original length and after releasing the stress, retractrapidly, and recover its original dimensions fully. Synthetic rubber is made from many different chemicals, including styrene, acrylonitrile, ethylene, propylene, and isoprene. [NIH] Rutin: 3-((6-O-(6-Deoxy-alpha-L-mannopyranosyl)-beta-D-glucopyranosyl)oxy)-2-(3,4dihydroxyphenyl)-5,7-dihydroxy-4H-1-benzopyran-4-one. Found in many plants, including buckwheat, tobacco, forsythia, hydrangea, pansies, etc. It has been used therapeutically to decrease capillary fragility. [NIH] Saline: A solution of salt and water. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Saphenous: Applied to certain structures in the leg, e. g. nerve vein. [NIH] Saphenous Vein: The vein which drains the foot and leg. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Sarcoma: A connective tissue neoplasm formed by proliferation of mesodermal cells; it is usually highly malignant. [NIH] Saturated fat: A type of fat found in greatest amounts in foods from animals, such as fatty cuts of meat, poultry with the skin, whole-milk dairy products, lard, and in some vegetable oils, including coconut, palm kernel, and palm oils. Saturated fat raises blood cholesterol more than anything else eaten. On a Step I Diet, no more than 8 to 10 percent of total calories should come from saturated fat, and in the Step II Diet, less than 7 percent of the day's total calories should come from saturated fat. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] 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]

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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] Sclerotic: Pertaining to the outer coat of the eye; the sclera; hard, indurated or sclerosed. [NIH]

Screening: Checking for disease when there are no symptoms. [NIH] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sedentary: 1. Sitting habitually; of inactive habits. 2. Pertaining to a sitting posture. [EU] Segmental: Describing or pertaining to a structure which is repeated in similar form in successive segments of an organism, or which is undergoing segmentation. [NIH] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Self Care: Performance of activities or tasks traditionally performed by professional health care providers. The concept includes care of oneself or one's family and friends. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Senile Plaques: Spherical masses consisting of amyloid fibrils and neuronal processes. [NIH] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU] Septicemia: Systemic disease associated with the presence and persistence of pathogenic microorganisms or their toxins in the blood. Called also blood poisoning. [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] Sequester: A portion of dead bone which has become detached from the healthy bone tissue,

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as occurs in necrosis. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH]

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Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Social Support: Support systems that provide assistance and encouragement to individuals with physical or emotional disabilities in order that they may better cope. Informal social support is usually provided by friends, relatives, or peers, while formal assistance is provided by churches, groups, etc. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Sound wave: An alteration of properties of an elastic medium, such as pressure, particle displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] 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] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] 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 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]

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Spiro Compounds: A group of compounds consisting in part of two rings sharing one carbon atom in common. [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] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Stabilization: The creation of a stable state. [EU] Standard therapy: A currently accepted and widely used treatment for a certain type of cancer, based on the results of past research. [NIH] Standardize: To compare with or conform to a standard; to establish standards. [EU] Steatosis: Fatty degeneration. [EU] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stent: A device placed in a body structure (such as a blood vessel or the gastrointestinal tract) to provide support and keep the structure open. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stress management: A set of techniques used to help an individual cope more effectively with difficult situations in order to feel better emotionally, improve behavioral skills, and often to enhance feelings of control. Stress management may include relaxation exercises, assertiveness training, cognitive restructuring, time management, and social support. It can be delivered either on a one-to-one basis or in a group format. [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] Stroma: The middle, thickest layer of tissue in the cornea. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [NIH]

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Styrene: A colorless, toxic liquid with a strong aromatic odor. It is used to make rubbers, polymers and copolymers, and polystyrene plastics. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts. [NIH] Sudden death: Cardiac arrest caused by an irregular heartbeat. The term "death" is somewhat misleading, because some patients survive. [NIH] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Sunburn: An injury to the skin causing erythema, tenderness, and sometimes blistering and resulting from excessive exposure to the sun. The reaction is produced by the ultraviolet radiation in sunlight. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Suppositories: A small cone-shaped medicament having cocoa butter or gelatin at its basis and usually intended for the treatment of local conditions in the rectum. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] Surface Plasmon Resonance: A biosensing technique in which biomolecules capable of binding to specific analytes or ligands are first immobilized on one side of a metallic film. Light is then focused on the opposite side of the film to excite the surface plasmons, that is, the oscillations of free electrons propagating along the film's surface. The refractive index of light reflecting off this surface is measured. When the immobilized biomolecules are bound by their ligands, an alteration in surface plasmons on the opposite side of the film is created which is directly proportional to the change in bound, or adsorbed, mass. Binding is measured by changes in the refractive index. The technique is used to study biomolecular interactions, such as antigen-antibody binding. [NIH] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral

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column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Syncope: A temporary suspension of consciousness due to generalized cerebral schemia, a faint or swoon. [EU] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Systolic blood pressure: The maximum pressure in the artery produced as the heart contracts and blood begins to flow. [NIH] Systolic pressure: The highest pressure to which blood pressure rises with the contraction of the ventricles. [NIH] Tardive: Marked by lateness, late; said of a disease in which the characteristic lesion is late in appearing. [EU] Taurine: 2-Aminoethanesulfonic acid. A conditionally essential nutrient, important during mammalian development. It is present in milk but is isolated mostly from ox bile and strongly conjugates bile acids. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Telophase: The final phase of cell division, in which two daughter nuclei are formed, the cytoplasm divides, and the chromosomes lose their distinctness and are transformed into chromatin networks. [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] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [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]

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Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] 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]

Thromboplastin: Constituent composed of protein and phospholipid that is widely distributed in many tissues. It serves as a cofactor with factor VIIa to activate factor X in the extrinsic pathway of blood coagulation. [NIH] Thromboses: The formation or presence of a blood clot within a blood vessel during life. [NIH]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]

Thymidine Kinase: An enzyme that catalyzes the conversion of ATP and thymidine to ADP and thymidine 5'-phosphate. Deoxyuridine can also act as an acceptor and dGTP as a donor. (From Enzyme Nomenclature, 1992) EC 2.7.1.21. [NIH] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] 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] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tic: An involuntary compulsive, repetitive, stereotyped movement, resembling a purposeful movement because it is coordinated and involves muscles in their normal synergistic relationships; tics usually involve the face and shoulders. [EU] Time Management: Planning and control of time to improve efficiency and effectiveness.

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[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] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tonicity: The normal state of muscular tension. [NIH] Topical: On the surface of the body. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transforming Growth Factor beta: A factor synthesized in a wide variety of tissues. It acts synergistically with TGF-alpha in inducing phenotypic transformation and can also act as a negative autocrine growth factor. TGF-beta has a potential role in embryonal development, cellular differentiation, hormone secretion, and immune function. TGF-beta is found mostly as homodimer forms of separate gene products TGF-beta1, TGF-beta2 or TGF-beta3. Heterodimers composed of TGF-beta1 and 2 (TGF-beta1.2) or of TGF-beta2 and 3 (TGF-

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beta2.3) have been isolated. The TGF-beta proteins are synthesized as precursor proteins. [NIH]

Transgenes: Genes that are introduced into an organism using gene transfer techniques. [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] 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] Trees: Woody, usually tall, perennial higher plants (Angiosperms, Gymnosperms, and some Pterophyta) having usually a main stem and numerous branches. [NIH] Triglyceride: A lipid carried through the blood stream to tissues. Most of the body's fat tissue is in the form of triglycerides, stored for use as energy. Triglycerides are obtained primarily from fat in foods. [NIH] Troglitazone: A drug used in diabetes treatment that is being studied for its effect on reducing the risk of cancer cell growth in fat tissue. [NIH] Trypsin: A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tumor suppressor gene: Genes in the body that can suppress or block the development of cancer. [NIH] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH]

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Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ulceration: 1. The formation or development of an ulcer. 2. An ulcer. [EU] Ulcerative colitis: Chronic inflammation of the colon that produces ulcers in its lining. This condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and mucus from the bowel. [NIH] Ultrasound test: A test that bounces sound waves off tissues and internal organs and changes the echoes into pictures (sonograms). [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] 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]

Ureter: One of a pair of thick-walled tubes that transports urine from the kidney pelvis to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] 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] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular Surgical Procedures: Operative procedures for the treatment of vascular disorders. [NIH]

Vasculitis: Inflammation of a blood vessel. [NIH] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vasomotor: 1. Affecting the calibre of a vessel, especially of a blood vessel. 2. Any element or agent that effects the calibre of a blood vessel. [EU] Vasopressins: Octapeptide antidiuretic hormones released by the neurohypophysis of all vertebrates (chemical composition varies with species). They control water metabolism and balance by regulating lung, gill, kidney, etc., and water loss, and also contract smooth muscle. They may also be neurotransmitters. Also included are synthetic vasopressin derivatives. Vasopressins are used pharmacologically as renal agents, vasoconstrictor

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agents, and hemostatics. [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] Venom: That produced by the poison glands of the mouth and injected by the fangs of poisonous snakes. [NIH] Venous: Of or pertaining to the veins. [EU] Venous blood: Blood that has given up its oxygen to the tissues and carries carbon dioxide back for gas exchange. [NIH] Venous Thrombosis: The formation or presence of a thrombus within a vein. [NIH] 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] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Villous: Of a surface, covered with villi. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Load: The quantity of measurable virus in the blood. Change in viral load, measured in plasma, is used as a surrogate marker in HIV disease progression. [NIH] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] 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] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Visceral fat: One of the three compartments of abdominal fat. Retroperitoneal and subcutaneous are the other two compartments. [NIH] 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] Vitelline Membrane: The plasma membrane of the egg. [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]

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Vitreous Hemorrhage: Hemorrhage into the vitreous body. [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] Warfarin: An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] 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] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Yolk Sac: An embryonic membrane formed from endoderm and mesoderm. In reptiles and birds it incorporates the yolk into the digestive tract for nourishing the embryo. In placental mammals its nutritional function is vestigial; however, it is the source of most of the intestinal mucosa and the site of formation of the germ cells. It is sometimes called the vitelline sac, which should not be confused with the vitelline membrane of the egg. [NIH] Zygote: The fertilized ovum. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

261

INDEX 1 1-phosphate, 23, 179 A Abdomen, 179, 189, 207, 214, 221, 224, 236, 243, 252 Abdominal, 179, 196, 218, 222, 224, 236, 258, 259 Abdominal fat, 179, 259 Abdominal Pain, 179, 222, 258 Aberrant, 10, 12, 179 Abscess, 125, 179 Acceptor, 179, 224, 235, 255 Acetylcholine, 179, 194, 233 Acid Phosphatase, 118, 179 Acne, 109, 179 Acoustic, 179, 246 Acrylonitrile, 179, 248 Actin, 5, 8, 10, 23, 49, 179, 228, 230, 231, 232 Activities of Daily Living, 179 Acuity, 179 Acute Disease, 52, 179 Acyl, 54, 108, 118, 128, 179, 208 Adaptability, 179, 192, 193 Adenovirus, 5, 11, 17, 26, 28, 44, 46, 49, 105, 106, 179 Adhesions, 8, 179 Adipocytes, 179, 198, 223 Adipose Tissue, 136, 179, 180 Adjustment, 121, 180 Adjuvant, 180, 211 Adolescence, 121, 180 Adoptive Transfer, 42, 180 Adrenal Cortex, 180, 181, 200, 242 Adrenal Medulla, 180, 192, 207, 233 Adverse Effect, 180, 250 Aerobic, 24, 180, 208 Aerobic Exercise, 24, 180 Aerosol, 101, 180 Aetiology, 137, 180 Afferent, 180, 223 Affinity, 91, 92, 129, 180, 181, 186, 251 Agar, 180, 197, 239 Age of Onset, 180, 257 Agonist, 7, 181 Albumin, 37, 50, 181, 239 Aldehydes, 53, 107, 181 Aldosterone, 30, 181, 222

Algorithms, 181, 189 Alimentary, 181, 203 Alkaline, 11, 181, 182, 191, 236 Alkaline Phosphatase, 11, 181 Alkaloid, 21, 181 Alleles, 181, 216 Allergen, 181, 202 Allo, 6, 13, 22, 35, 181 Allogeneic, 12, 16, 40, 42, 181 Allograft, 5, 6, 11, 13, 17, 32, 34, 35, 36, 42, 64, 181 Allylamine, 32, 181, 182 Alpha Particles, 181, 245 Alternative medicine, 146, 181 Alveolar Process, 181, 247 Alveoli, 181, 244 Ameliorating, 42, 109, 181 Amenorrhea, 182, 240 Amine, 138, 182 Amino Acid Motifs, 182, 198 Amino Acid Sequence, 26, 120, 130, 135, 182, 184, 198, 212 Ammonia, 182, 213 Amplification, 52, 117, 182 Amputation, 14, 121, 182 Amyloid, 57, 123, 182, 249 Anaerobic, 125, 182 Anaesthesia, 182, 219 Anal, 96, 182, 224 Analogous, 9, 105, 130, 182, 240, 256 Analytes, 182, 253 Anaphylatoxins, 182, 197 Anatomical, 183, 189, 199, 203, 206, 219, 232, 236, 249 Androgens, 72, 180, 183, 200 Anemia, 157, 183 Aneurysm, 110, 183, 258 Angina, 70, 97, 107, 110, 117, 127, 134, 136, 164, 183, 233 Angina Pectoris, 97, 107, 117, 127, 134, 136, 164, 183 Angiogenesis, 16, 23, 27, 119, 183, 226 Angiogram, 84, 183 Angiography, 14, 34, 81, 84, 176, 183 Angioid Streaks, 164, 183, 243 Angiopathy, 57, 183 Angioplasty, 44, 45, 49, 85, 107, 117, 119, 130, 131, 160, 161, 177, 183, 231

262

Arteriosclerosis

Angiotensin converting enzyme inhibitor, 103, 183 Angiotensinogen, 183, 246 Animal model, 5, 11, 20, 30, 36, 40, 52, 54, 106, 136, 183 Anions, 181, 183, 221 Ankle, 8, 183 Annealing, 183, 240 Anovulation, 183, 240 Anterior Cerebral Artery, 184, 194 Antiallergic, 121, 184, 200 Anti-Anxiety Agents, 184, 241 Antibacterial, 184, 251 Antibiotic, 99, 184, 241, 251 Antibiotic Prophylaxis, 184, 241 Antibodies, 8, 13, 22, 26, 34, 43, 53, 184, 186, 208, 214, 217, 218, 225, 239 Anticoagulant, 125, 184, 243, 260 Antigen, 22, 31, 41, 42, 180, 184, 197, 202, 208, 216, 217, 218, 219, 220, 226, 253 Antigen-Antibody Complex, 184, 197 Antigen-presenting cell, 184, 202 Anti-inflammatory, 43, 91, 94, 117, 120, 121, 134, 184, 186, 200, 212, 236 Anti-Inflammatory Agents, 91, 184, 186, 200 Antineoplastic, 184, 200, 210 Antioxidant, 41, 79, 86, 124, 137, 146, 184, 235 Antithrombotic, 184, 216 Antiviral, 117, 121, 185, 220, 237 Anxiety, 94, 109, 132, 133, 134, 184, 185, 236 Aorta, 11, 102, 116, 185, 199, 215, 218, 259 Apheresis, 57, 185 Apolipoproteins, 50, 101, 118, 185, 211, 224 Apoptosis, 21, 22, 36, 40, 41, 120, 185 Aqueous, 127, 185, 187, 201, 206, 217, 223 Arachidonate 12-Lipoxygenase, 185, 224 Arachidonate 15-Lipoxygenase, 185, 224 Arachidonate Lipoxygenases, 185, 224 Arginine, 32, 130, 182, 185, 233, 257 Aromatic, 108, 109, 119, 123, 185, 238, 253 Arteriography, 84, 185 Arteriolar, 185, 190 Arterioles, 185, 186, 189, 191, 228, 230 Arteriolosclerosis, 111, 185, 186 Arteriosclerosis Obliterans, 56, 57, 112, 186 Arteriovenous, 15, 186, 228 Articular, 131, 186, 235

Articulation, 110, 186 Aseptic, 186, 235, 252 Aspartate, 130, 186 Aspirin, 70, 79, 186 Assay, 53, 99, 133, 186 Astrocytes, 186, 215 Asymptomatic, 76, 80, 97, 186, 236 Ataxia, 156, 157, 186, 254 Atherogenic, 53, 103, 123, 186 Atrial, 186, 260 Atrial Fibrillation, 186, 260 Atrophy, 20, 156, 186, 224 Autoantibodies, 53, 186 Autoantigens, 16, 186 Autodigestion, 186, 236 Autoimmune disease, 100, 108, 109, 110, 134, 135, 186, 187, 230 Autoimmunity, 16, 187 Autologous, 16, 40, 187 Autonomic, 165, 179, 187, 233, 237, 253 Autonomic Nervous System, 187, 237, 253 Autoradiography, 34, 187 Autosuggestion, 187, 218 Axilla, 164, 187 Axillary, 187, 190 Axillary Artery, 187, 190 B Bacterial Infections, 135, 187, 193, 194 Bacteriophage, 187, 239, 256 Bacterium, 187, 198 Basal Ganglia, 186, 187, 195 Basal Ganglia Diseases, 186, 187, 195 Base, 8, 15, 20, 187, 202, 208, 212, 222, 254, 258 Basement Membrane, 187, 209, 222 Basophils, 187, 214, 223 Benign, 105, 106, 135, 185, 188, 214, 231, 245 Benzene, 117, 188, 222 Beta-pleated, 182, 188 Beta-sheet, 29, 188 Bilateral, 188, 236, 240 Bile, 38, 90, 94, 188, 194, 202, 211, 217, 224, 252, 254 Bile Acids, 38, 91, 94, 188, 252, 254 Bile Acids and Salts, 188 Bile Ducts, 188, 211 Biliary, 188, 236 Biliary Tract, 188, 236 Bilirubin, 129, 181, 188, 211 Bioavailability, 5, 188

Index 263

Biochemical, 5, 15, 29, 30, 32, 38, 48, 181, 188, 210, 212, 223, 235, 250 Biological response modifier, 188, 220 Biological therapy, 188, 214 Biomarkers, 37, 188 Biomolecular, 188, 253 Biopsy, 9, 15, 51, 164, 188, 237 Biopsy specimen, 9, 51, 188 Biosynthesis, 26, 94, 97, 100, 118, 124, 188, 200, 225, 250 Biotechnology, 55, 56, 101, 146, 153, 155, 156, 157, 188, 189 Bladder, 189, 224, 230, 242, 258 Blastocyst, 189, 198, 239 Bloating, 189, 222 Blood Coagulation, 25, 189, 191, 255 Blood Coagulation Factors, 189 Blood Glucose, 109, 121, 123, 164, 189, 215, 220 Blood Platelets, 189, 227, 250 Body Composition, 19, 24, 189 Body Fluids, 188, 189, 190, 204, 251, 257 Body Mass Index, 189, 235 Body Regions, 189, 196 Bone Marrow, 25, 71, 136, 188, 189, 197, 200, 218, 225, 227, 251, 252 Bone Marrow Cells, 136, 189, 197, 227 Bone Marrow Transplantation, 26, 189 Bone Resorption, 110, 189 Bowel, 54, 144, 182, 189, 203, 207, 221, 252, 258 Bowel Movement, 189, 203, 252 Brachial, 8, 71, 72, 82, 114, 190 Brachial Artery, 114, 190 Brachytherapy, 190, 221, 222, 245, 260 Bradykinin, 37, 190, 222, 233, 239 Brain Stem, 190, 193, 232 Branch, 173, 190, 225, 236, 251, 255 Breakdown, 190, 203, 211, 234, 235 Bridged Compounds, 122, 190 Bronchioles, 181, 190, 244 Bronchoconstriction, 132, 134, 190 Bronchus, 190 Buccal, 190, 216, 225 Buffers, 91, 190 Bulimia, 133, 190 Burns, 91, 92, 190 Burns, Electric, 190 Bypass, 81, 83, 85, 131, 161, 177, 190, 231 C Cacao, 92, 93, 190 Cachexia, 109, 121, 190

Cadaver, 14, 190 Cadherins, 10, 190 Calcification, 11, 20, 73, 78, 111, 128, 186, 191 Calcium, 7, 14, 72, 77, 78, 101, 164, 190, 191, 197, 226, 228, 231, 235, 243, 250 Cancer vaccine, 135, 191 Capillary, 47, 190, 191, 192, 248, 259 Capillary Fragility, 191, 192, 248 Capillary Permeability, 190, 191 Capsules, 128, 191, 211 Carbohydrate, 123, 191, 200, 212, 213, 241 Carbon Dioxide, 191, 202, 239, 247, 259 Carboxy, 123, 135, 191 Carcinogenic, 188, 191, 196, 220, 234, 242, 252 Carcinogens, 191, 196, 234 Carcinoma, 191 Cardiology, 30, 41, 191 Cardiorespiratory, 180, 191 Cardiovascular disease, 4, 11, 24, 30, 41, 42, 53, 75, 76, 79, 81, 93, 102, 191 Cardiovascular System, 192, 243 Carotene, 74, 79, 126, 192, 247 Carotenoids, 41, 74, 192 Carotid Arteries, 80, 81, 192 Carotid Stenosis, 80, 192 Cataracts, 108, 109, 192 Catechin, 91, 192 Catecholamine, 192, 238 Catheterization, 84, 183, 192, 221, 231 Catheters, 84, 192, 219, 221 Cations, 192, 221 Causal, 97, 192, 221 Cause of Death, 35, 36, 40, 43, 54, 100, 127, 192 Celiac Disease, 144, 192 Cell Adhesion, 21, 27, 117, 121, 129, 190, 192, 220 Cell Adhesion Molecules, 27, 117, 192 Cell Cycle, 51, 192 Cell Death, 21, 185, 192, 196, 231 Cell Differentiation, 4, 193, 250 Cell Division, 156, 187, 192, 193, 214, 227, 229, 239, 249, 254 Cell membrane, 99, 120, 133, 193, 202, 205, 222, 238 Cell motility, 4, 193, 216 Cell Polarity, 4, 193 Cell proliferation, 8, 10, 40, 51, 54, 120, 186, 193, 250 Cell Size, 193, 210

264

Arteriosclerosis

Cell Survival, 21, 129, 193, 214, 215 Cellulose, 193, 239 Central Nervous System, 132, 133, 179, 187, 188, 193, 211, 213, 214, 230, 235, 250 Central Nervous System Diseases, 132, 193 Central Nervous System Infections, 193, 214 Ceramide, 120, 193 Cerebellar, 186, 193, 246 Cerebellum, 193, 246 Cerebral hemispheres, 187, 190, 193, 194 Cerebral Infarction, 103, 123, 193 Cerebrovascular, 56, 75, 76, 79, 80, 81, 100, 134, 136, 187, 191, 194, 254 Cerebrum, 193, 194, 257 Chaperonins, 194, 229 Character, 99, 133, 183, 194, 201, 213 Chelation, 65, 164, 194 Chelation Therapy, 65, 164, 194 Chemokines, 12, 54, 55, 194 Chemotactic Factors, 194, 197 Chemotaxis, 23, 194 Chest Pain, 70, 72, 125, 194 Child Psychiatry, 194, 212 Choleretic, 194, 202 Cholesterol Esters, 127, 194, 224 Cholic Acid, 39, 194 Choline, 29, 194 Cholinergic, 123, 194 Chorea, 94, 194, 195 Choreatic Disorders, 195 Choroid, 195, 247 Choroidal Neovascularization, 164, 195 Chromatin, 185, 195, 207, 254 Chromosomal, 9, 182, 195, 212, 228, 239, 247 Chromosome, 10, 12, 195, 198, 214, 216, 223, 228, 249 Chronic Disease, 82, 126, 190, 195 Chronic renal, 195, 240, 258 Chylomicrons, 195, 224 Circadian, 109, 195 Circadian Rhythm, 109, 195 Circulatory system, 115, 195, 206, 221 CIS, 44, 47, 48, 96, 195, 247 Claudication, 7, 14, 117, 165, 175, 195 Clear cell carcinoma, 195, 202 Clinical Medicine, 131, 195, 241 Clinical study, 195, 199 Clinical trial, 4, 14, 36, 43, 69, 86, 153, 195, 199, 200, 245

Clonal Deletion, 12, 196 Clone, 39, 94, 196 Cloning, 189, 196 Clot Retraction, 196, 239 Coagulation, 107, 125, 189, 196, 215, 239, 255, 260 Coal, 188, 196, 231 Coal Tar, 196, 231 Coenzyme, 124, 128, 196, 225 Cofactor, 29, 196, 243, 255 Cognitive restructuring, 196, 252 Colestipol, 81, 196 Colic, 125, 196 Colitis, 196, 222 Collagen, 14, 32, 37, 110, 164, 187, 192, 196, 209, 210, 211, 226, 240, 242 Colloidal, 181, 196, 205 Colony-Stimulating Factors, 197, 214 Combination Therapy, 197, 208 Complement, 15, 22, 40, 41, 43, 182, 197, 220, 226, 239 Complement Activation, 22, 182, 197 Complementary and alternative medicine, 63, 66, 197 Complementary medicine, 63, 197 Computational Biology, 153, 155, 197 Computed tomography, 78, 197, 198 Computerized axial tomography, 198 Computerized tomography, 198 Concentric, 35, 54, 185, 198 Conception, 143, 198, 199, 252 Concomitant, 124, 198 Cones, 198, 247 Conjugated, 188, 194, 198, 202 Conjugation, 90, 198 Connective Tissue, 37, 110, 189, 196, 198, 210, 211, 212, 225, 243, 247, 248, 252 Connective Tissue Cells, 198 Consciousness, 184, 198, 202, 204, 254 Consensus Sequence, 25, 182, 198 Conserved Sequence, 182, 198 Constipation, 144, 199, 222 Constriction, 102, 192, 199, 222, 258 Constriction, Pathologic, 199, 258 Consumption, 125, 199, 202, 234, 236 Contraceptive, 134, 199 Contractility, 36, 48, 199 Contraindications, ii, 199 Control group, 199, 242 Controlled clinical trial, 53, 199 Conventional therapy, 84, 199 Conventional treatment, 199

Index 265

Convulsion, 132, 199 Coordination, 193, 199, 230 Cornea, 110, 199, 214, 248, 252 Coronary Angiography, 16, 160, 199 Coronary Artery Bypass, 44, 199 Coronary Circulation, 183, 199, 233 Coronary Disease, 69, 73, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 160, 162, 199 Coronary heart disease, 4, 55, 69, 75, 78, 85, 91, 95, 97, 119, 137, 191, 199 Coronary Thrombosis, 128, 199, 228, 230 Coronary Vessels, 22, 199, 200 Corpus, 200, 237, 242 Corpus Luteum, 200, 242 Cortex, 5, 186, 200, 216, 231, 246 Cortical, 23, 200, 249, 254 Corticosteroid, 53, 200 Cortisol, 181, 200 Cranial, 193, 200, 214, 221, 232, 234, 237 Craniocerebral Trauma, 187, 200, 214, 254 Crossing-over, 200, 245 Crowns, 200, 202 Crystallization, 91, 200 Cues, 10, 200 Cultured cells, 19, 200 Curative, 101, 200, 233, 255 Cutaneous, 200, 218, 225, 236 Cyclic, 23, 95, 96, 190, 200, 214, 233 Cyclosporine, 22, 40, 200 Cystathionine beta-Synthase, 200, 217 Cysteine, 30, 45, 194, 200, 201, 253 Cystine, 201 Cytokine, 13, 15, 31, 35, 42, 52, 117, 121, 201 Cytomegalovirus, 13, 40, 46, 51, 52, 54, 201 Cytoplasm, 185, 187, 193, 201, 207, 214, 232, 242, 247, 254 Cytoskeleton, 8, 10, 23, 201, 220, 229 Cytotoxic, 9, 40, 201, 245, 250 Cytotoxicity, 9, 181, 201 D Dairy Products, 201, 248 Databases, Bibliographic, 153, 201 De novo, 26, 201 Decision Making, 144, 201 Decompensation, 181, 201 Decompression, 201, 204 Defense Mechanisms, 201, 220 Degenerative, 96, 201, 235, 247 Deletion, 43, 185, 196, 201 Dementia, 123, 132, 133, 134, 201, 232 Demethylation, 30, 202

Denaturation, 100, 202, 240 Dendrites, 202, 232 Dendritic, 22, 202, 227 Dendritic cell, 22, 202 Dental Abutments, 202 Dental Caries, 92, 202 Dentures, 144, 202 Deoxycholic Acid, 39, 202 Depolarization, 202, 250 Dermatitis, 202, 205 DES, 94, 182, 202 Desensitization, 7, 202 Deuterium, 25, 202, 217 Developed Countries, 100, 202 Developing Countries, 100, 202 Diabetic Retinopathy, 27, 51, 76, 203, 238 Diagnostic procedure, 89, 146, 203 Dialyzer, 203, 215 Diarrhea, 94, 203, 222 Diastolic, 203, 217, 226 Diastolic pressure, 203, 217, 226 Diencephalon, 193, 203, 232 Dietary Fiber, 93, 203 Dietitian, 70, 203 Diffusion, 191, 203, 220 Digestion, 94, 181, 188, 189, 203, 221, 224, 252 Digestive system, 87, 203, 230 Digestive tract, 115, 134, 203, 251, 260 Dihydrotestosterone, 203, 246 Dihydroxy, 105, 107, 181, 203, 248 Dilatation, 183, 203, 242, 244, 258 Dilatation, Pathologic, 203, 258 Dilate, 70, 203 Dilation, 114, 125, 190, 203, 258 Dilator, 203, 233 Diploid, 203, 239 Dipyridamole, 72, 203 Direct, iii, 6, 12, 15, 22, 31, 44, 54, 90, 92, 100, 105, 106, 124, 144, 193, 195, 204, 225, 246 Disease Progression, 54, 204, 259 Dissociation, 180, 204, 221 Distal, 199, 204, 222, 237, 244 Diving, 111, 204 Dose-dependent, 23, 204 Drive, ii, vi, 59, 106, 143, 144, 204, 223 Drug Interactions, 204 Drug Tolerance, 204, 256 Drusen, 164, 204 Duct, 192, 204, 208, 248 Duodenum, 188, 204, 252

266

Arteriosclerosis

Dura mater, 204, 227, 236 Dyes, 10, 182, 188, 204, 210, 233 Dynamometer, 71, 204 Dyskinesia, 94, 204 Dyslipidemia, 4, 19, 24, 28, 54, 204 Dyspareunia, 205, 208 Dysplasia, 157, 205 Dystrophy, 156, 205 E Ectopic, 20, 205 Eczema, 109, 205 Edema, 144, 201, 203, 205, 222, 231, 258 Effector, 9, 31, 35, 42, 51, 179, 197, 205, 232 Effector cell, 31, 42, 205, 232 Efficacy, 13, 28, 34, 36, 70, 122, 124, 205 Elasticity, 102, 114, 185, 199, 205 Elastin, 11, 110, 183, 196, 205, 209 Electrocardiogram, 70, 205 Electrocoagulation, 196, 205 Electrolyte, 181, 200, 205, 229, 241, 251, 258 Electron microscope, 164, 205 Electrons, 184, 187, 205, 221, 235, 245, 253 Electrophoresis, 31, 205 Electroporation, 101, 205 Emboli, 177, 205, 206, 260 Embolism, 144, 205, 244, 260 Embolization, 206, 260 Embolus, 206, 219 Embryo, 27, 93, 189, 193, 206, 219, 227, 240, 260 Emulsion, 187, 206 Enamel, 202, 206 Endarterectomy, 183, 206 Endemic, 52, 206, 252 Endocarditis, 143, 206 Endocardium, 206 Endocrine System, 206, 232 Endoderm, 206, 260 Endometrial, 206 Endometriosis, 110, 206 Endometrium, 206, 227 Endothelium, 5, 8, 9, 22, 27, 70, 91, 92, 111, 206, 207, 233, 239 Endothelium, Lymphatic, 206 Endothelium, Vascular, 206, 207 Endothelium-derived, 207, 233 Endotoxic, 207, 224 Endotoxins, 197, 207 End-stage renal, 28, 195, 207, 240 Energy balance, 207, 223 Enhancers, 118, 207

Enteritis, 109, 207 Enterocolitis, 207 Environmental Exposure, 207, 234 Environmental Health, 152, 154, 207 Enzymatic, 51, 117, 191, 192, 197, 202, 207, 208, 210, 240, 247 Enzyme, 20, 25, 26, 29, 103, 118, 122, 123, 124, 138, 179, 181, 185, 196, 200, 205, 207, 209, 213, 214, 224, 225, 228, 231, 236, 238, 239, 240, 243, 246, 250, 253, 255, 256, 260 Enzyme Inhibitors, 103, 123, 207, 239 Eosinophils, 207, 214, 223 Epidemiological, 28, 46, 53, 55, 207 Epigastric, 207, 236 Epinephrine, 207, 233, 257 Epithelial, 207, 216, 222 Epithelial Cells, 207, 216, 222 Epithelium, 187, 206, 207, 221 Epitopes, 16, 31, 40, 208 Erectile, 143, 165, 208, 237 Erection, 143, 165, 208 Erythema, 208, 253 Erythrocytes, 183, 189, 208, 246 Esophagus, 203, 208, 252 Essential Tremor, 156, 208 Esterification, 128, 208 Estrogen, 78, 83, 86, 208 Estrogen Replacement Therapy, 83, 208 Ethnic Groups, 43, 208 Eukaryotic Cells, 98, 208, 219, 258 Evacuation, 199, 208 Excipients, 91, 208 Excitation, 208, 210 Exercise Test, 71, 72, 160, 208 Exocrine, 208, 236 Exogenous, 40, 205, 208, 211, 257 Extensor, 208, 244 External-beam radiation, 209, 222, 245, 260 Extracellular Matrix, 10, 11, 29, 32, 45, 47, 49, 129, 130, 198, 209, 210, 211, 220, 226, 228, 235 Extracellular Matrix Proteins, 209, 211, 226 Extracellular Space, 209 Extraction, 91, 125, 209 Extravascular, 117, 209 Extremity, 14, 176, 209, 236 Eye Infections, 179, 209 F Family Planning, 153, 209

Index 267

Farnesyl, 26, 209 Fatigue, 72, 209, 215 Fatty acids, 50, 90, 94, 96, 181, 209, 213, 224, 242 Fatty Liver, 108, 109, 121, 209 Febrile, 209, 244 Feces, 199, 209, 252 Femoral, 14, 81, 209 Femoral Artery, 14, 81, 209 Femur, 209 Fermentation, 190, 209 Ferritin, 129, 210 Fibrillation, 210 Fibrin, 22, 25, 189, 196, 210, 239, 255 Fibrinogen, 24, 25, 37, 210, 239, 255 Fibrinolysis, 17, 210 Fibroblast Growth Factor, 51, 210 Fibroblasts, 26, 164, 198, 210 Fibronectin, 110, 130, 210 Fibrosis, 47, 98, 157, 181, 210, 249 Flow Cytometry, 8, 210 Fluorescein Angiography, 164, 210 Fluorescence, 29, 210 Fluorescent Dyes, 210 Fluorouracil, 203, 210 Foam Cells, 127, 210 Focal Adhesions, 8, 11, 211 Fold, 29, 41, 211 Forearm, 71, 82, 189, 211 Fovea, 164, 211 Frontal Lobe, 184, 193, 211 Fungi, 198, 209, 211, 228, 260 G Gadolinium, 72, 85, 211 Gait, 176, 211 Gallbladder, 91, 94, 179, 188, 203, 211, 224 Gallstones, 90, 97, 188, 211 Ganglia, 179, 187, 211, 232, 237, 254 Gangrene, 211 Gas, 182, 191, 203, 211, 217, 222, 233, 259 Gasoline, 188, 211 Gastrin, 211, 216 Gastrointestinal, 50, 94, 132, 133, 164, 190, 207, 211, 250, 252, 253, 257 Gastrointestinal tract, 211, 250, 252, 257 Gelatin, 110, 211, 213, 253, 255 Gemfibrozil, 75, 211 Gene Expression, 27, 32, 44, 45, 46, 52, 106, 157, 211 Gene Targeting, 6, 211 Genetic Code, 212, 233 Genetic Counseling, 165, 212

Genetic Screening, 31, 212 Genetic Techniques, 6, 212 Genetic testing, 72, 212, 240 Genetics, 17, 19, 27, 28, 43, 75, 198, 212, 229 Genomics, 19, 38, 76, 212 Genotype, 165, 212, 238 Germ Cells, 101, 212, 227, 235, 260 Gestational, 108, 109, 212 Gifted, 41, 212 Gland, 180, 212, 216, 225, 236, 239, 242, 249, 252, 255 Glomerular, 28, 212, 246 Glomeruli, 29, 212 Glomerulonephritis, 131, 212 Glomerulosclerosis, 29, 131, 212 Glomerulus, 212, 231 Glucocorticoids, 180, 200, 212 Glucose, 19, 24, 97, 98, 108, 109, 121, 156, 163, 189, 193, 203, 213, 215, 220, 248 Glucose Intolerance, 203, 213 Glucose tolerance, 24, 97, 108, 109, 213 Glucose Tolerance Test, 24, 213 Glucuronic Acid, 213, 216 Glutamic Acid, 213, 242 Glutamine, 25, 213 Glutathione Peroxidase, 213, 249 Gluten, 192, 213 Glycerol, 213, 238 Glycerophospholipids, 120, 213, 238 Glycine, 32, 130, 188, 194, 202, 213, 250 Glycogen, 123, 212, 213 Glycogen Synthase, 123, 213 Glycoprotein, 210, 213, 214, 222, 255 Glycosaminoglycan, 19, 214 Gonadal, 214, 252 Governing Board, 214, 241 Gp120, 214, 237 Grade, 24, 214 Graft Survival, 55, 214 Grafting, 199, 214, 219 Granulocyte Colony-Stimulating Factor, 136, 197, 214 Granulocytes, 197, 214, 250, 260 Groin, 84, 214 Growth factors, 41, 82, 214 Guanylate Cyclase, 214, 233 H Habitual, 194, 214 Haploid, 214, 239 Haptens, 180, 214 Headache, 82, 214, 215

268

Arteriosclerosis

Headache Disorders, 214, 215 Health Promotion, 24, 215 Heart attack, 39, 70, 102, 191, 215 Heart failure, 7, 9, 144, 215 Heart Transplantation, 5, 9, 56, 142, 215 Heart Valves, 144, 215 Heartbeat, 72, 116, 215, 226, 253 Heat-Shock Proteins, 215, 229 Heat-Shock Proteins 90, 215, 229 Hematemesis, 125, 215 Heme, 129, 188, 215, 236 Hemodialysis, 57, 176, 203, 215, 222 Hemodynamics, 144, 215, 222 Hemoglobin, 183, 208, 215 Hemoglobinuria, 156, 215 Hemorrhage, 102, 144, 200, 205, 214, 215, 231, 243, 252, 260 Hemostasis, 57, 215, 220, 250 Heparan Sulfate Proteoglycan, 18, 215 Heparin, 29, 49, 85, 215 Hepatic, 25, 181, 213, 216 Hepatocyte, 26, 136, 216 Hepatocyte Growth Factor, 136, 216 Hereditary, 195, 216, 238, 247 Heredity, 211, 212, 216 Heterodimers, 216, 220, 256 Heterogeneity, 180, 216 Heterozygote, 165, 216 Hippocampus, 216, 232 Hirudin, 29, 216 Histology, 17, 18, 216, 232, 236 Homeostasis, 22, 38, 216 Homicide, 77, 216 Homodimer, 216, 256 Homogeneous, 185, 216 Homologous, 45, 181, 200, 212, 216, 249, 254 Homozygotes, 49, 165, 216 Hormonal, 86, 132, 186, 200, 208, 216 Hormone Replacement Therapy, 83, 216 Host, 13, 34, 39, 40, 42, 51, 54, 120, 187, 214, 216, 218, 219, 247, 259 Humoral, 17, 20, 216 Humour, 216, 217 Hybrid, 196, 217 Hybridization, 49, 52, 217, 229 Hybridomas, 205, 217 Hydrogen Peroxide, 213, 217, 224 Hydrolysis, 94, 128, 217, 238, 241, 243, 257 Hydrophobic, 94, 213, 217, 222, 224 Hydroxylysine, 196, 217 Hydroxyproline, 196, 217

Hypercholesterolemia, 45, 84, 93, 96, 97, 103, 124, 132, 133, 204, 217 Hyperglycemia, 37, 217 Hyperhomocysteinemia, 28, 30, 201, 217 Hyperlipidemia, 28, 93, 99, 118, 121, 123, 132, 133, 136, 204, 217 Hyperlipoproteinemia, 217, 218 Hyperphagia, 132, 217 Hyperplasia, 14, 36, 49, 129, 217 Hypersensitivity, 13, 33, 42, 181, 202, 217, 247 Hyperthyroidism, 82, 217 Hypertriglyceridemia, 93, 99, 118, 132, 204, 218 Hypertrophy, 105, 106, 132, 134, 217, 218 Hypesthesia, 218, 232 Hypodermic, 95, 218 Hypoglycemia, 121, 218 Hypotensive, 94, 218, 222 I Iatrogenic, 144, 218 Iatrogenic Disease, 144, 218 Id, 61, 64, 156, 160, 161, 162, 166, 172, 174, 218 Iliac Artery, 209, 218 Immune function, 218, 256 Immune response, 6, 15, 22, 31, 52, 180, 184, 186, 200, 214, 218, 219, 226, 253, 259 Immune system, 22, 35, 184, 187, 188, 205, 218, 219, 225, 230, 258, 260 Immunity, 12, 40, 41, 115, 218, 225, 234 Immunization, 180, 218, 219, 242 Immunodeficiency, 156, 218 Immunofluorescence, 13, 218 Immunogenic, 218, 224 Immunoglobulin, 184, 218, 229 Immunohistochemistry, 11, 17, 18, 49, 55, 218 Immunologic, 56, 180, 194, 218, 226, 245 Immunology, 19, 51, 131, 132, 134, 180, 210, 218 Immunosuppressant, 117, 134, 210, 219 Immunotherapy, 180, 188, 202, 219 Impairment, 7, 15, 77, 121, 186, 204, 209, 219, 227 Implant radiation, 219, 221, 222, 245, 260 Implantation, 5, 11, 198, 219 Impotence, 143, 165, 176, 208, 219 In situ, 14, 18, 46, 49, 52, 219 In Situ Hybridization, 14, 18, 46, 219 Incision, 219, 221 Incubated, 127, 219

Index 269

Incubation, 219, 223 Incubation period, 219, 223 Indicative, 111, 141, 219, 236, 258 Induction, 9, 13, 16, 35, 37, 47, 52, 54, 120, 143, 183, 219 Infantile, 219, 224 Infertility, 143, 219 Infiltration, 35, 110, 128, 212, 220 Infusion, 35, 220, 231 Ingestion, 213, 217, 220, 240 Inhalation, 180, 220, 240 Initiation, 11, 37, 51, 220, 256 Inlay, 220, 247 Insight, 27, 32, 35, 44, 45, 84, 220 Insulator, 220, 230 Insulin, 20, 24, 76, 81, 100, 103, 108, 109, 121, 123, 127, 132, 134, 213, 220, 222, 257 Insulin-dependent diabetes mellitus, 121, 124, 220 Integrins, 10, 32, 129, 130, 211, 220 Interferon, 13, 33, 146, 220 Interferon-alpha, 220 Interindividual, 74, 220 Intermediate Filaments, 220, 232 Intermittent, 14, 117, 165, 221 Internal radiation, 221, 222, 245, 260 Interstitial, 110, 190, 209, 221, 222, 231, 246, 260 Intervention Studies, 76, 221 Intestinal, 38, 94, 134, 192, 202, 207, 213, 221, 226, 260 Intestine, 188, 189, 207, 221, 223 Intoxication, 221, 260 Intracellular Membranes, 221, 227 Intracranial Pressure, 82, 221 Intrahepatic, 124, 221 Intramuscular, 136, 221 Intraocular, 82, 221 Intraocular pressure, 82, 221 Intravascular, 14, 84, 117, 221 Intravenous, 210, 220, 221 Intrinsic, 4, 180, 187, 221 Intubation, 192, 221 Invasive, 4, 14, 33, 102, 218, 221, 226 Involuntary, 187, 194, 199, 208, 210, 221, 231, 255 Ionization, 221 Ionizing, 47, 181, 207, 221, 245 Ions, 11, 187, 190, 204, 205, 217, 221, 229, 243 Iris, 199, 221, 244 Irradiation, 47, 221, 233, 260

Irritable Bowel Syndrome, 94, 144, 222 Islet, 19, 100, 222 Isoflavones, 41, 222 Isoprenoid, 26, 222 J Joint, 176, 186, 222, 235, 254 K Kallidin, 190, 222 Kallikrein-Kinin System, 36, 222 Kb, 44, 152, 222 Keratolytic, 202, 222 Kidney Disease, 87, 131, 152, 157, 163, 222 Kidney Failure, 207, 212, 222 Kinetic, 19, 25, 29, 221, 222 L Labile, 197, 222 Lag, 102, 222 Laminin, 110, 187, 209, 222 Large Intestine, 203, 221, 223, 245, 251 Laser therapy, 165, 223 Latency, 31, 223 Latent, 46, 51, 223, 241 Lectin, 223, 227 Legal blindness, 165, 223 Lens, 192, 223, 259 Lentivirus, 5, 36, 223 Leptin, 136, 223 Lesion, 13, 27, 42, 48, 54, 64, 81, 100, 111, 117, 127, 135, 199, 223, 224, 254, 258 Lethal, 9, 223 Leukapheresis, 185, 223 Leukemia, 156, 223 Leukocytes, 12, 21, 33, 100, 110, 187, 189, 194, 207, 214, 220, 223, 238 Libido, 183, 223 Library Services, 172, 223 Ligament, 223, 243 Ligands, 28, 31, 32, 34, 50, 54, 99, 100, 192, 220, 223, 253 Ligation, 143, 223 Linkage, 79, 223 Lipid A, 16, 23, 57, 81, 128, 224 Lipid Peroxidation, 102, 224, 236 Lipid Peroxides, 103, 224 Lipodystrophy, 20, 224 Lipopolysaccharides, 224 Liposomes, 92, 106, 224 Lipoxygenase, 109, 185, 224 Lithotripsy, 91, 224 Lobe, 184, 193, 224 Localization, 13, 23, 51, 218, 224

270

Arteriosclerosis

Localized, 4, 92, 106, 179, 202, 219, 222, 224, 239, 249, 258 Locomotion, 224, 239 Longitudinal study, 52, 81, 224 Loop, 29, 225 Lovastatin, 80, 225 Low-density lipoprotein, 53, 57, 97, 103, 123, 124, 204, 224, 225 Lubricants, 225, 231, 238 Lucida, 222, 225 Lumen, 186, 192, 207, 225 Lupus, 27, 53, 225 Lycopene, 74, 225 Lymph, 187, 195, 206, 217, 225 Lymph node, 187, 225 Lymphatic, 125, 206, 219, 225, 251, 252, 255 Lymphatic system, 125, 225, 251, 252, 255 Lymphocyte, 27, 40, 184, 225, 226 Lymphoid, 184, 225 Lymphokines, 225, 226 Lymphoma, 156, 225 Lysine, 217, 225, 240, 257 Lytic, 46, 225 M Macrophage, 6, 26, 35, 197, 225, 226 Macrophage Activation, 6, 35, 226 Macula, 211, 226 Magnetic Resonance Imaging, 14, 84, 226 Major Histocompatibility Complex, 40, 226 Malabsorption, 156, 192, 226 Malignant, 156, 184, 185, 226, 231, 235, 245, 248 Malnutrition, 181, 186, 190, 226, 230 Mammary, 199, 226 Mammogram, 191, 226, 228 Mandible, 181, 226, 247 Mania, 94, 226 Manifest, 73, 226 Matrix metalloproteinase, 11, 57, 110, 226 Mean blood pressure, 116, 226 Meat, 226, 248 Medial, 37, 186, 226 Mediate, 8, 12, 13, 129, 192, 226, 229 Mediator, 16, 226, 250 Medicament, 93, 109, 120, 126, 227, 253 MEDLINE, 153, 155, 157, 227 Megakaryocytes, 189, 227 Meiosis, 227, 228, 254 Melanin, 221, 227, 238, 257 Melanocytes, 227

Melanoma, 105, 106, 156, 227 Membrane Proteins, 98, 224, 227 Memory, 22, 31, 51, 202, 227 Meninges, 193, 200, 204, 227 Meningitis, 138, 227 Menopause, 77, 227, 241 Menstrual Cycle, 227, 242 Menstruation, 125, 182, 227, 234 Mental Disorders, 87, 194, 227, 242, 244 Mental Health, iv, 4, 72, 87, 152, 154, 227, 242 Mentors, 19, 30, 43, 227 Mercury, 210, 227 Mesoderm, 227, 260 Meta-Analysis, 97, 228 Metabolic disorder, 100, 121, 124, 228 Metabolite, 19, 225, 228, 241 Metastasis, 110, 117, 121, 192, 226, 228 Metastatic, 101, 105, 106, 228, 249 Metastatic cancer, 101, 105, 228 Methionine, 228, 253 Methyltransferase, 31, 228 MI, 178, 228 Microbe, 228, 256 Microcalcifications, 191, 228 Microcirculation, 125, 228, 239 Microfibrils, 47, 228 Microfilaments, 211, 220, 228 Micronuclei, 10, 228 Microorganism, 104, 196, 228, 260 Micro-organism, 202, 228 Microscopy, 8, 14, 18, 49, 50, 187, 228 Microtubule-Associated Proteins, 228, 232 Microtubules, 220, 228, 229, 232 Migration, 40, 49, 52, 54, 129, 130, 226, 229 Mineralocorticoids, 180, 200, 229 Mitochondrial Swelling, 229, 231 Mitosis, 185, 228, 229 Mobility, 29, 229 Modeling, 21, 25, 229 Modification, 5, 7, 19, 47, 53, 85, 229 Molecular Chaperones, 98, 194, 215, 229 Molecular Conformation, 37, 229 Molecular Probes, 205, 229 Molecular Structure, 49, 229 Monitor, 38, 46, 229, 233 Monoclonal, 8, 16, 217, 222, 229, 245, 260 Monocyte, 27, 229 Mononuclear, 6, 15, 34, 40, 42, 46, 229 Morphogenesis, 4, 129, 230 Morphological, 16, 127, 206, 227, 230 Morphology, 13, 14, 226, 230

Index 271

Motility, 49, 132, 134, 230, 250 Mucosa, 94, 192, 207, 225, 230, 252, 260 Mucositis, 230, 255 Mucus, 230, 258 Multiple sclerosis, 110, 138, 230 Muscle Contraction, 49, 182, 230 Muscle Fibers, 230, 231 Muscular Atrophy, 156, 230 Muscular Dystrophies, 205, 230 Mutagenesis, 29, 230 Mutagenicity, 10, 230 Mutagens, 230 Mutate, 10, 230 Mydriatic, 203, 230 Myelin, 230 Myocardial Ischemia, 69, 79, 81, 83, 84, 85, 86, 183, 199, 230 Myocardial Reperfusion, 231, 246 Myocardial Reperfusion Injury, 231, 246 Myocardium, 5, 17, 46, 183, 228, 230, 231 Myosin, 5, 49, 104, 230, 231 Myotonic Dystrophy, 156, 231 N Naphthalenes, 105, 231 NCI, 1, 86, 151, 195, 231 Necrosis, 100, 128, 185, 193, 219, 228, 230, 231, 246, 250 Need, 3, 5, 7, 10, 14, 100, 103, 138, 142, 167, 180, 195, 213, 226, 231, 256 Neocortex, 231, 232 Neoplasia, 156, 231 Neoplasm, 231, 248, 257 Neoplastic, 108, 217, 225, 231 Nephritis, 110, 231 Nephron, 212, 222, 231 Nephropathy, 18, 109, 121, 126, 127, 133, 164, 222, 232 Nerve, 132, 186, 202, 226, 230, 232, 234, 237, 241, 248, 249, 251, 252, 257 Networks, 42, 74, 232, 254 Neural, 180, 182, 216, 232 Neuritis, 6, 232 Neuroendocrinology, 143, 232 Neurofibrillary Tangles, 123, 232 Neurofilaments, 232 Neuronal, 120, 232, 249 Neurons, 202, 211, 231, 232, 253, 254 Neuropathy, 18, 126, 127, 164, 232, 237 Neuropeptide, 132, 133, 232 Neuroses, 109, 232 Neurosis, 109, 232 Neurotransmitters, 232, 258

Neutron Capture Therapy, 107, 108, 232 Neutrons, 181, 221, 233, 245 Neutrophil, 27, 110, 233 Niacin, 81, 233, 257 Nitrates, 70, 233 Nitric acid, 233 Nitric Oxide, 5, 16, 29, 36, 40, 43, 52, 70, 233 Nitrogen, 130, 131, 133, 181, 182, 183, 209, 213, 233, 257 Nitroglycerin, 71, 72, 82, 233 Norepinephrine, 132, 134, 233 Nuclear, 16, 23, 34, 38, 90, 99, 122, 160, 187, 198, 205, 208, 211, 231, 233, 242 Nuclei, 181, 184, 198, 205, 226, 228, 229, 233, 234, 243, 254 Nucleic acid, 38, 98, 101, 212, 217, 219, 230, 233, 244 Nucleic Acid Hybridization, 217, 233 Nutritional Status, 41, 234 O Observational study, 76, 234 Ocular, 105, 234 Odds Ratio, 234, 246 Odour, 185, 234, 258 Ointments, 234, 236 Oligomenorrhea, 234, 240 Omega-3 fatty acid, 41, 80, 234 Oncogene, 156, 216, 234 Oncogenic, 220, 223, 234 Opacity, 192, 202, 234 Open Reading Frames, 223, 234 Operon, 39, 234, 247 Ophthalmic, 130, 234 Opsin, 234, 247 Optic Disk, 203, 234 Optic Nerve, 204, 234, 235, 236, 247, 248 Optic nerve head, 204, 235 Organ Culture, 13, 17, 18, 33, 34, 235 Organ Transplantation, 6, 42, 52, 56, 235 Osmotic, 181, 229, 235 Osteoarthritis, 110, 235 Osteoblasts, 235 Osteocalcin, 105, 106, 235 Osteogenic sarcoma, 235 Osteolytic, 96, 130, 235 Osteoporosis, 20, 96, 109, 110, 119, 130, 134, 208, 235 Osteosarcoma, 105, 235 Ovaries, 235, 240, 250 Ovary, 101, 200, 235, 240, 252 Overexpress, 11, 35, 235

272

Arteriosclerosis

Overweight, 4, 24, 60, 102, 235 Ovum, 200, 235, 242, 260 Oxamic Acid, 90, 122, 235 Oxidation, 103, 129, 137, 179, 184, 185, 201, 213, 224, 235, 236 Oxidative Stress, 15, 20, 32, 52, 60, 74, 235 Oxides, 107, 236 Oxygen Consumption, 8, 208, 236, 247 Oxygenase, 129, 236 P P53 gene, 46, 236 Pachymeningitis, 227, 236 Palliative, 236, 255 Pancreas, 6, 179, 188, 203, 220, 222, 236, 257 Pancreatic, 100, 121, 156, 236 Pancreatic cancer, 156, 236 Pancreatitis, 108, 109, 236 Panic, 94, 236 Paraffin, 17, 236 Parenchyma, 106, 236 Paresis, 232, 236 Paresthesia, 109, 236 Paroxysmal, 156, 183, 215, 236 Particle, 39, 54, 94, 236, 251, 256 Pathogenesis, 6, 15, 17, 22, 27, 33, 35, 36, 43, 47, 49, 51, 144, 236 Pathologic, 11, 17, 18, 34, 40, 185, 188, 199, 217, 236, 237, 244, 247 Pathologic Processes, 185, 237 Pathologies, 19, 42, 126, 237 Pathophysiology, 7, 10, 49, 237 Patient Education, 164, 170, 172, 178, 237 Peau d'orange, 165, 237 Pelvic, 206, 237, 243 Penis, 143, 237 Peptide, 13, 14, 18, 25, 31, 34, 94, 96, 99, 132, 134, 210, 223, 237, 240, 241, 243 Peptide T, 13, 31, 237 Percutaneous, 85, 130, 131, 224, 237 Perfusion, 5, 34, 77, 84, 237, 256 Periodontitis, 110, 237 Perioperative, 15, 237 Peripheral blood, 51, 220, 237 Peripheral Nervous System, 132, 134, 237, 253 Peripheral Neuropathy, 121, 165, 237 Peripheral Vascular Disease, 48, 75, 82, 102, 237 Perivascular, 6, 237 Peroxidase, 185, 224, 238 Peroxide, 109, 238

Personality Disorders, 238 Petroleum, 211, 236, 238 PH, 23, 94, 238 Phagocytosis, 129, 238 Pharmaceutical Preparations, 193, 211, 238 Pharmacologic, 34, 238, 256 Pharmacotherapy, 8, 136, 238 Phenotype, 19, 20, 32, 45, 47, 48, 165, 238 Phenyl, 107, 131, 238 Phenylalanine, 238, 257 Phospholipases, 238, 250 Phospholipids, 39, 94, 209, 224, 238 Phosphorus, 191, 238 Phosphorylated, 23, 196, 238 Phosphorylation, 8, 51, 130, 131, 238 Photocoagulation, 196, 238 Photodynamic therapy, 135, 238 Physical Examination, 70, 71, 82, 239 Physiologic, 23, 49, 181, 188, 227, 239, 245, 247 Physiology, 18, 28, 30, 32, 38, 50, 191, 239 Pigment, 95, 188, 225, 227, 239 Pilot study, 53, 239 Pituitary Gland, 200, 210, 239 Placenta, 239, 242, 244 Plants, 126, 181, 191, 192, 194, 213, 223, 230, 233, 239, 240, 248, 256, 257 Plaque, 14, 21, 80, 91, 108, 137, 162, 183, 186, 239 Plasma, 28, 29, 36, 50, 52, 57, 81, 90, 97, 99, 122, 124, 133, 181, 184, 193, 194, 197, 206, 210, 211, 213, 215, 217, 222, 223, 229, 239, 240, 241, 243, 246, 249, 256, 259 Plasma cells, 184, 239 Plasma protein, 181, 206, 239, 241, 243 Plasmapheresis, 185, 239 Plasmid, 44, 239, 259 Plasmin, 96, 239, 241 Plasminogen, 96, 239 Plasminogen Activators, 239 Platelet Activation, 240, 250 Platelet Aggregation, 182, 233, 240 Platelet-Derived Growth Factor, 33, 131, 240 Plateletpheresis, 185, 240 Platelets, 23, 71, 185, 233, 240, 255 Platinum, 225, 240 Pleated, 240 Poisoning, 194, 221, 227, 240, 249 Pollen, 125, 240, 244 Polyarteritis Nodosa, 27, 240

Index 273

Polycystic, 72, 108, 109, 157, 240 Polycystic Ovary Syndrome, 72, 108, 109, 240 Polylysine, 101, 240 Polymerase, 14, 240, 247 Polymerase Chain Reaction, 14, 240 Polymorphic, 74, 240 Polymorphism, 25, 79, 241 Polypeptide, 182, 196, 198, 210, 217, 239, 241, 243, 260 Polysaccharide, 184, 193, 214, 241, 243 Posterior, 182, 186, 193, 195, 221, 236, 241, 248 Postmenopausal, 78, 83, 208, 235, 241 Postnatal, 241, 252 Postsynaptic, 241, 250 Potassium, 125, 181, 229, 241 Potentiate, 91, 92, 241 Potentiation, 241, 250 Practice Guidelines, 24, 154, 241 Pravastatin, 104, 241 Precipitation, 101, 241 Precursor, 94, 99, 132, 133, 183, 194, 205, 207, 209, 214, 233, 238, 239, 241, 243, 257 Predisposition, 28, 241 Prekallikrein, 36, 241 Premedication, 144, 241 Prenatal, 206, 212, 241 Prevalence, 52, 74, 77, 79, 80, 83, 234, 241 Primary endpoint, 15, 242 Primary Prevention, 53, 79, 242 Primary tumor, 106, 242 Probe, 10, 242 Progeny, 101, 198, 242 Progesterone, 83, 242, 252 Progressive disease, 13, 242 Projection, 201, 233, 234, 242, 246 Prokaryotic Cells, 98, 242 Proliferative Retinopathy, 82, 242 Proline, 196, 217, 242 Promoter, 12, 38, 44, 47, 105, 106, 242 Prone, 11, 242 Prophylaxis, 97, 98, 103, 126, 127, 130, 242, 260 Proportional, 71, 97, 242, 253 Prospective Studies, 85, 242 Prospective study, 224, 242 Prostaglandins, 222, 242 Prostate, 105, 156, 188, 242, 257 Prosthodontics, 143, 243 Protein C, 6, 21, 93, 104, 181, 182, 185, 187, 210, 224, 235, 243

Protein Conformation, 182, 243 Protein S, 20, 40, 157, 189, 198, 212, 235, 243, 247 Proteinuria, 212, 243 Proteoglycan, 19, 243 Proteolytic, 35, 197, 210, 239, 243 Prothrombin, 243, 255 Protons, 181, 217, 221, 243, 245 Protozoa, 198, 228, 243 Pruritic, 205, 243 Pseudoxanthoma, 164, 243 Pseudoxanthoma Elasticum, 164, 243 Psoriasis, 109, 123, 131, 196, 243 Psychiatry, 244 Psychic, 223, 232, 244, 249 Psychogenic, 143, 244 Psychosexual, 143, 244 Puberty, 243, 244 Public Policy, 153, 244 Publishing, 55, 143, 244 Puerperium, 125, 244 Pulmonary, 20, 104, 106, 110, 189, 199, 208, 215, 222, 244, 259, 260 Pulmonary Artery, 189, 244, 259 Pulmonary Embolism, 244, 260 Pulmonary Emphysema, 20, 110, 244 Pulse, 110, 111, 112, 113, 114, 115, 116, 175, 176, 229, 244 Pupil, 199, 203, 230, 244 Purines, 244, 250 Putrefaction, 211, 244 Pyrexia, 109, 244 Q Quercetin, 125, 244 Quiescent, 45, 46, 51, 244 Quinolones, 107, 244 R Race, 14, 229, 245 Radiation, 47, 108, 137, 183, 187, 207, 209, 210, 221, 245, 253, 260 Radiation therapy, 209, 221, 222, 245, 260 Radioactive, 187, 217, 219, 221, 222, 229, 233, 234, 245, 260 Radiolabeled, 26, 222, 245, 260 Radiological, 237, 245 Radiotherapy, 190, 222, 245, 260 Randomized, 7, 14, 24, 205, 245 Reactivation, 22, 31, 46, 51, 245 Reactive Oxygen Species, 20, 137, 245 Reading Frames, 245 Reagent, 99, 133, 134, 245 Receptors, Serotonin, 245, 250

274

Arteriosclerosis

Recombinant, 44, 49, 54, 99, 104, 105, 106, 120, 132, 245, 259 Recombination, 45, 198, 212, 245 Rectum, 189, 203, 211, 223, 243, 245, 253 Recurrence, 53, 90, 128, 195, 246 Red blood cells, 71, 208, 236, 246, 248 Red Nucleus, 186, 246 Reductase, 100, 104, 109, 124, 129, 225, 241, 246 Refer, 1, 190, 197, 211, 212, 224, 226, 233, 246 Reference point, 102, 246 Refraction, 246, 251 Regeneration, 210, 246 Regimen, 29, 205, 238, 246 Regurgitation, 215, 246 Relative risk, 79, 80, 246 Relaxation Techniques, 72, 246 Remission, 246 Renal failure, 246 Renin, 30, 183, 222, 246 Reperfusion, 22, 23, 28, 231, 246 Reperfusion Injury, 23, 246 Repressor, 234, 246 Reproductive cells, 101, 212, 247 Resorption, 143, 247 Respiration, 191, 229, 247 Restoration, 23, 200, 231, 243, 245, 246, 247, 260 Retina, 165, 183, 195, 198, 203, 204, 223, 234, 235, 242, 243, 247, 248, 259 Retinal, 76, 203, 210, 234, 247, 259 Retinoblastoma, 156, 247 Retinoid, 99, 100, 247 Retinol, 247 Retinopathy, 18, 109, 121, 134, 164, 203, 247 Retrovirus, 31, 106, 247 Rheumatism, 121, 131, 137, 247 Rheumatoid, 100, 110, 117, 130, 247 Rheumatoid arthritis, 100, 130, 247 Ribosome, 247, 257 Rigidity, 221, 239, 247 Risk patient, 70, 248 Rods, 211, 247, 248 Rubber, 71, 179, 248 Rutin, 244, 248 S Saline, 71, 248 Salivary, 201, 203, 236, 248 Salivary glands, 201, 203, 248 Saphenous, 199, 248

Saphenous Vein, 199, 248 Saponins, 248, 252 Sarcoma, 248 Saturated fat, 41, 90, 96, 248 Schizoid, 248, 260 Schizophrenia, 109, 132, 134, 248, 260 Schizotypal Personality Disorder, 248, 260 Sclera, 195, 248, 249 Scleroderma, 185, 249 Sclerosis, 28, 37, 52, 54, 100, 111, 156, 185, 186, 230, 249 Sclerotic, 29, 249 Screening, 10, 51, 76, 99, 127, 133, 162, 195, 212, 249 Secondary tumor, 228, 249 Secretion, 26, 31, 33, 132, 134, 195, 200, 212, 216, 217, 220, 229, 230, 249, 256 Secretory, 98, 132, 134, 136, 249 Sedentary, 24, 249 Segmental, 212, 249 Segregation, 245, 249 Seizures, 236, 249 Selenium, 74, 126, 249 Self Care, 179, 249 Semen, 243, 249 Senile, 123, 235, 249 Senile Plaques, 123, 249 Septic, 138, 186, 249 Septicemia, 120, 249 Sequence Homology, 26, 237, 249 Sequencing, 240, 249 Sequester, 194, 249 Serine, 51, 200, 250, 257 Serotonin, 56, 238, 245, 250, 257 Serous, 206, 250 Sex Characteristics, 180, 183, 244, 250, 254 Sex Determination, 157, 250 Shock, 16, 40, 94, 98, 138, 144, 194, 224, 250, 257 Side effect, 92, 99, 118, 122, 180, 188, 250, 256 Signal Transduction, 8, 21, 32, 215, 250 Signs and Symptoms, 14, 76, 240, 246, 250, 258 Skeletal, 7, 183, 230, 250 Skeleton, 179, 209, 222, 250 Skull, 200, 221, 250, 254 Small intestine, 94, 188, 195, 204, 207, 216, 221, 251, 257 Social Support, 251, 252 Sodium, 125, 181, 222, 229, 251 Soft tissue, 189, 250, 251

Index 275

Solid tumor, 183, 251 Solvent, 25, 188, 213, 235, 251 Somatic, 180, 216, 227, 229, 237, 251 Sound wave, 251, 258 Spastic, 222, 251 Specialist, 166, 203, 251 Specificity, 8, 12, 25, 29, 31, 40, 44, 106, 180, 185, 190, 251, 256 Spectrum, 22, 34, 251 Sperm, 101, 183, 195, 240, 247, 251 Spinal cord, 186, 190, 193, 194, 204, 227, 232, 236, 237, 251, 254 Spinal Nerves, 237, 251 Spiro Compounds, 133, 252 Spleen, 201, 225, 252 Sporadic, 247, 252 Stabilization, 14, 69, 128, 252 Standard therapy, 70, 252 Standardize, 10, 252 Steatosis, 209, 252 Stem Cells, 6, 71, 252 Stent, 44, 177, 252 Sterility, 219, 252 Steroid, 78, 99, 133, 188, 200, 215, 248, 252 Stimulus, 199, 204, 205, 208, 222, 223, 252, 255 Stomach, 179, 186, 203, 208, 211, 213, 216, 251, 252 Stool, 222, 223, 252 Strand, 98, 240, 252 Stress management, 72, 252 Stroke, 14, 25, 30, 38, 48, 63, 70, 87, 102, 128, 142, 152, 160, 162, 163, 191, 252 Stroma, 221, 236, 252 Stromal, 189, 206, 252 Stromal Cells, 189, 252 Styrene, 248, 253 Subacute, 219, 253 Subarachnoid, 214, 253 Subclinical, 72, 74, 76, 77, 78, 83, 219, 249, 253 Subcutaneous, 179, 205, 224, 253, 259 Subspecies, 75, 251, 253 Substance P, 228, 249, 253 Substrate, 10, 25, 207, 211, 253 Substrate Specificity, 25, 253 Sudden death, 128, 253 Sulfur, 108, 131, 209, 228, 253 Sunburn, 109, 253 Superoxide, 15, 29, 52, 253 Supplementation, 55, 60, 63, 79, 103, 253 Suppositories, 211, 253

Suppression, 36, 39, 104, 137, 200, 253 Suppressive, 98, 121, 134, 253 Surface Plasmon Resonance, 11, 253 Sympathetic Nervous System, 132, 134, 187, 253, 254 Sympathomimetic, 207, 233, 254 Symphysis, 243, 254 Symptomatic, 184, 236, 254 Synaptic, 250, 254 Syncope, 144, 254 Synergistic, 28, 97, 137, 254, 255 Systemic, 7, 27, 31, 53, 105, 106, 185, 189, 207, 215, 219, 222, 232, 245, 249, 254, 260 Systolic, 8, 112, 115, 217, 226, 254 Systolic blood pressure, 8, 112, 115, 254 Systolic pressure, 226, 254 T Tardive, 94, 254 Taurine, 188, 194, 202, 254 Telangiectasia, 157, 254 Telophase, 228, 254 Temporal, 49, 215, 216, 254 Testosterone, 246, 254 Thalamic, 186, 254 Thalamic Diseases, 186, 254 Therapeutics, 28, 52, 255 Thermal, 91, 204, 215, 233, 240, 255 Thigh, 209, 214, 255 Threonine, 51, 237, 250, 255 Threshold, 24, 217, 255 Thrombin, 23, 25, 29, 210, 240, 243, 255 Thrombocytes, 138, 240, 255 Thrombolytic, 239, 255 Thrombomodulin, 243, 255 Thromboplastin, 241, 255 Thromboses, 107, 119, 255 Thrombus, 47, 94, 96, 199, 219, 230, 231, 240, 255, 259 Thymidine, 105, 106, 255 Thymidine Kinase, 105, 106, 255 Thymus, 196, 218, 225, 255 Thyroid, 90, 122, 217, 255, 257 Thyroid Gland, 217, 255 Thyroxine, 181, 238, 255 Tic, 255 Time Management, 252, 255 Tin, 236, 237, 240, 256 Tissue Distribution, 190, 256 Tolerance, 34, 125, 179, 213, 215, 256 Tomography, 78, 256 Tonicity, 132, 134, 256 Topical, 143, 196, 217, 231, 236, 256

276

Arteriosclerosis

Torsion, 219, 256 Toxic, iv, 21, 54, 92, 106, 110, 188, 198, 201, 207, 218, 224, 232, 233, 249, 253, 256 Toxicity, 22, 36, 92, 204, 227, 256 Toxicology, 154, 256 Toxins, 184, 207, 213, 219, 249, 256 Trachea, 190, 255, 256 Transcriptase, 247, 256 Transcription Factors, 45, 47, 256 Transduction, 5, 6, 11, 250, 256 Transfection, 10, 189, 205, 256 Transforming Growth Factor beta, 40, 256 Transgenes, 44, 257 Translation, 11, 245, 257 Translocation, 8, 257 Transmitter, 179, 186, 226, 233, 257 Trauma, 231, 236, 257 Trees, 248, 257 Triglyceride, 50, 93, 97, 118, 123, 196, 217, 218, 257 Troglitazone, 104, 257 Trypsin, 257, 260 Tryptophan, 196, 250, 257 Tuberculosis, 199, 225, 257 Tuberous Sclerosis, 157, 257 Tumor marker, 188, 257 Tumor suppressor gene, 40, 236, 257 Tumour, 107, 135, 257 Type 2 diabetes, 4, 19, 24, 60, 120, 257 Tyrosine, 8, 23, 51, 257 U Ubiquitin, 232, 258 Ulcer, 94, 110, 128, 258 Ulceration, 121, 258 Ulcerative colitis, 144, 258 Ultrasound test, 70, 258 Unconscious, 201, 218, 258 Uraemia, 236, 258 Ureter, 224, 258 Urethra, 237, 242, 258 Urine, 189, 197, 215, 243, 258 Uterus, 200, 206, 227, 235, 242, 258 V Vaccine, 180, 191, 258 Vagina, 202, 227, 258 Vascular Surgical Procedures, 49, 258 Vasculitis, 27, 236, 240, 258 Vasoconstriction, 132, 134, 207, 258 Vasodilation, 22, 94, 258 Vasodilator, 190, 231, 258

Vasomotor, 18, 32, 208, 258 Vasopressins, 222, 258 Vector, 5, 28, 36, 99, 104, 120, 132, 256, 259 Vein, 71, 72, 85, 183, 186, 221, 233, 248, 259 Venom, 94, 259 Venous, 45, 52, 128, 143, 144, 186, 193, 201, 233, 243, 259, 260 Venous blood, 193, 259 Venous Thrombosis, 259, 260 Ventricle, 216, 244, 254, 259 Ventricular, 36, 78, 231, 259 Venules, 189, 191, 206, 228, 259 Veterinary Medicine, 117, 153, 259 Villous, 192, 259 Viral, 15, 31, 36, 40, 43, 46, 51, 52, 54, 117, 121, 234, 247, 256, 259 Viral Load, 15, 31, 259 Viral vector, 36, 259 Virulence, 256, 259 Virus, 28, 31, 36, 52, 54, 187, 193, 207, 214, 220, 239, 256, 259 Visceral, 24, 187, 259 Visceral fat, 24, 259 Visual Acuity, 223, 259 Visual field, 223, 259 Vitelline Membrane, 259, 260 Vitreous Body, 247, 259, 260 Vitreous Hemorrhage, 203, 260 Vivo, 5, 6, 9, 12, 21, 23, 26, 27, 28, 33, 34, 35, 36, 40, 41, 44, 45, 48, 49, 51, 53, 54, 91, 99, 101, 115, 117, 135, 137, 216, 219, 224, 260 W Warfarin, 80, 260 White blood cell, 71, 179, 184, 219, 223, 225, 229, 230, 233, 239, 260 Windpipe, 190, 255, 260 Withdrawal, 132, 133, 260 Wound Healing, 91, 192, 210, 220, 226, 260 X Xenograft, 183, 260 X-ray, 50, 84, 165, 183, 185, 198, 210, 221, 226, 233, 245, 260 X-ray therapy, 222, 260 Y Yeasts, 211, 238, 260 Yolk Sac, 27, 260 Z Zygote, 198, 260 Zymogen, 117, 243, 260

Index 277

278

Arteriosclerosis

Index 279

280

Arteriosclerosis

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