HEPARIN A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES
J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS
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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1
Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Heparin: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00532-8 1. Heparin-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.
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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 heparin. 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 HEPARIN ................................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Heparin ......................................................................................... 4 E-Journals: PubMed Central ....................................................................................................... 60 The National Library of Medicine: PubMed ................................................................................ 67 CHAPTER 2. NUTRITION AND HEPARIN ....................................................................................... 115 Overview.................................................................................................................................... 115 Finding Nutrition Studies on Heparin ...................................................................................... 115 Federal Resources on Nutrition ................................................................................................. 117 Additional Web Resources ......................................................................................................... 118 CHAPTER 3. ALTERNATIVE MEDICINE AND HEPARIN ................................................................. 121 Overview.................................................................................................................................... 121 National Center for Complementary and Alternative Medicine................................................ 121 Additional Web Resources ......................................................................................................... 132 General References ..................................................................................................................... 135 CHAPTER 4. DISSERTATIONS ON HEPARIN ................................................................................... 137 Overview.................................................................................................................................... 137 Dissertations on Heparin ........................................................................................................... 137 Keeping Current ........................................................................................................................ 138 CHAPTER 5. PATENTS ON HEPARIN .............................................................................................. 139 Overview.................................................................................................................................... 139 Patents on Heparin .................................................................................................................... 139 Patent Applications on Heparin ................................................................................................ 160 Keeping Current ........................................................................................................................ 186 CHAPTER 6. BOOKS ON HEPARIN ................................................................................................. 187 Overview.................................................................................................................................... 187 Book Summaries: Federal Agencies............................................................................................ 187 Book Summaries: Online Booksellers......................................................................................... 188 Chapters on Heparin .................................................................................................................. 189 CHAPTER 7. PERIODICALS AND NEWS ON HEPARIN.................................................................... 191 Overview.................................................................................................................................... 191 News Services and Press Releases.............................................................................................. 191 Academic Periodicals covering Heparin .................................................................................... 193 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 195 Overview.................................................................................................................................... 195 U.S. Pharmacopeia..................................................................................................................... 195 Commercial Databases ............................................................................................................... 196 Researching Orphan Drugs ....................................................................................................... 197 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 201 Overview.................................................................................................................................... 201 NIH Guidelines.......................................................................................................................... 201 NIH Databases........................................................................................................................... 203 Other Commercial Databases..................................................................................................... 205 APPENDIX B. PATIENT RESOURCES ............................................................................................... 207 Overview.................................................................................................................................... 207 Patient Guideline Sources.......................................................................................................... 207 Finding Associations.................................................................................................................. 209 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 211 Overview.................................................................................................................................... 211
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Preparation................................................................................................................................. 211 Finding a Local Medical Library................................................................................................ 211 Medical Libraries in the U.S. and Canada ................................................................................. 211 ONLINE GLOSSARIES................................................................................................................ 217 Online Dictionary Directories ................................................................................................... 217 HEPARIN DICTIONARY ............................................................................................................ 219 INDEX .............................................................................................................................................. 303
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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 heparin 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 heparin, 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 heparin, 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 heparin. 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 heparin, 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 heparin. 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 HEPARIN Overview In this chapter, we will show you how to locate peer-reviewed references and studies on heparin.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and heparin, 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 “heparin” (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: •
Comparison of Carbogen Inhalation and Intravenous Heparin Infusion Therapies in Idiopathic Sudden Sensorineural Hearing Loss Source: Acta Otolaryngologica. Supplement 529: 86-87. 1997. Contact: Available from Scandinavian University Press North America. 875 Massachusetts Avenue, Suite 84, Cambridge, MA 02139. (800) 498-2877 or (617) 4976515. Fax (617) 354-6875. Summary: This article reports on a study which compares the effect of carbogen (5 percent carbon dioxide and 95 percent oxygen) inhalation and intravenous heparin (an anticoagulant) on sudden sensorineural hearing loss (SNHL). The patients were unselected patients with idiopathic sudden SNHL who were treated at a Department of Otolaryngology as inpatients: 44 patients were treated with carbogen inhalation and 43
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with heparin infusion. Conventional audiograms and speech audiometry were performed in the acute stage, after a treatment of 5 days, at a 1 month control, and at a 6 month control visit. The PTA (hearing threshold) at the pretreatment stage was 62 dB in the heparin and 55 dB in the carbogen group. One month later, the corresponding figures were 34 and 32 dB (the difference was not statistically significant). The authors conclude that neither treatment method proved superior in the treatment of sudden SNHL. The authors briefly discuss their findings. 2 figures. 10 references. •
Review Article: Potential Therapeutic Applications and Mechanisms of Action of Heparin in Inflammatory Bowel Disease Source: Alimentary Pharmacology and Therapeutics. 14(11): 1403-1409. November 2000. Contact: Available from Alimentary Pharmacology and Therapeutics. Blackwell Science Ltd., Osney Mead, Oxford OX2 OEL, UK. +44(0)1865 206206. Fax +44(0)1865 721205. Email:
[email protected]. Website: www.blackwell-science.com. Summary: Unfractioned heparin was recently reported to be beneficial in the treatment of inflammatory bowel disease (IBD). This article reviews the potential therapeutic applications and mechanisms of action of heparin in IBD. The available uncontrolled data show that the drug may be effective in steroid resistant ulcerative colitis (UC) with a percent of complete clinical remission of over 70 percent, after an average of 4 to 6 weeks of therapy. The administration of unfractioned heparin is not currently justified by the very limited available data. The worsening of rectal bleeding is infrequent in treated UC patients and only rarely does it require blood transfusion or a colectomy (removal of part of the colon). Low molecular weight heparin was used in a single trial in patients with steroid refractory UC, with results similar to those observed with unfractioned heparin. Since a prothrombotic state has been described in IBD, and microvascular intestinal occlusion (blockage of the smallest blood vessels in the intestine) seems to play a role in the pathogenesis of IBD, it is reasonable that part of the beneficial effects of unfractioned heparin in IBD may result from its anticoagulant properties. However, beyond its well known anticoagulant activity, unfractioned heparin also exhibits a broad spectrum of immunomodulating and anti inflammatory properties, by inhibiting the recruitment of neutrophils and reducing pro inflammatory cytokines. Moreover, heparin can restore the high affinity receptor binding of basic fibroblast growth factor; this would aid healing of the ulcerated mucosa. The authors conclude that unfractioned heparin may represent a safe therapeutic option for severe, steroid resistant UC, although randomized, controlled trials are needed to confirm this data. 1 figure. 2 tables. 71 references.
Federally Funded Research on Heparin The U.S. Government supports a variety of research studies relating to heparin. 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.
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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).
Studies
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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 heparin. 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 heparin. The following is typical of the type of information found when searching the CRISP database for heparin: •
Project Title: A PEPTIDE APPROACH TO IMPROVE VEIN GRAFT EFFICACY Principal Investigator & Institution: Panitch, Alyssa; Assistant Professor; Bioengineering; Arizona State University P.O. Box 873503 Tempe, Az 852873503 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2009 Summary: (provided by applicant): While much of the PI's previous research has been peripherally related to biomedicine, it was all done as an engineer's approach to solve biomedical problems. The materials were designed with only a basic understanding of the biological and medical needs. The proposed training opportunity would provide the PI with an in depth knowledge of some aspects of vascular medicine and physiology as well as added knowledge in mathematical modeling and peptide chemistry. The overall goal is to expand the PI's experience and training in biomedicine as well as in peptide chemistry and modeling to position her for a lifetime of research in biomedicine. Cardiovascular disease is the leading cause of death in the United States. The treatment of cardiovascular disease often involves surgically bypassing occluded segments of blood vessels with human saphenous vein grafts. The development of vein graft stenosis within 1 year after implantation occurs in up to 20-40% of grafts and frequently leads to end-organ failure, including myocardial infarction and extremity amputation. Shortterm graft failure is due to technical problems and vasospasm during harvest and preparation. Long-term graft failure is due to a hyperplastic wound healing response, intimal hyperplasia. The purpose of this proposal is to develop a protein/peptide based therapeutic agent to enhance graft patency. The hypotheses of this investigation is that synthetic phosphorylated heat shock related protein human (HSP20) analogues (pHSP20) can be optimized and delivered in a controlled manner that will prevent vein graft spasm and intimal hyperplasia. The specific aims are to: 1) Optimize TAT-pHSP20 as a functionally active biomolecule, la) Develop and synthesize a panel of analogues of the TAT-pHSP20 peptides, lb) Determine the bioactivity of the peptides ex vivo using strips of human saphenous vein grafts. 2) Develop and characterize controlled release systems for TAT-pHSP20 to ensure sustained delivery of the biomolecule in an effective therapeutic concentration. 2a) Determine the association and release of TAT from the heparin biogel. 2b) Determine the bioactivity of the biogel ex vivo in a muscle bath using strips of human saphenous vein grafts. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: A POXVIRAL PROTEIN THAT INHIBITS CHEMOKINE FUNCTION Principal Investigator & Institution: Krathwohl, Mitchell D.; Medicine; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 15-SEP-1999; Project End 31-MAY-2004 Summary: The candidate's long term goals are to become a fully independent investigator and join the faculty of an academic medical school. The short term goals are to gain superior skills and background understanding of molecular biology and receptor
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biology. The career development plan provides for intense mentoring, didactic instruction and close supervision by an advisory committee. The environment at this institution provides a number of individuals with superior skills in immunology, virology, molecular biology and chemokine biology. The broad, long term goals of this project are to understand the role of chemokines in viral infection and to develop novel compounds to inhibit the inflammatory response. The theoretical model to be used is that virus infection of cells results in a release of chemokines that attempt to recruit inflammatory cells. The molluscum contagiosum virus (MCV) is able to then make a protein that specifically blocks the effects of these released chemokines, thus preventing an inflammatory response and elimination of the virus itself. The specific hypotheses to be tested are: 1) the viral protein is made very early in the viral life cycle in order to effectively block the innate immune response. 2) The viral protein is able to block the action of multiple chemokines and block the chemotaxis of multiple inflammatory cell types. 3) The viral chemokine accomplishes it's effects by binding to but not activating chemokine receptors. 4) Structural features of the viral protein at the amino terminus and an internal site known as the heparin binding site are important for the function of this protein. The specific aims of this research are: 1) To characterize the time course of production after infection of the viral chemokine inhibitor protein, MC148R, by infecting keratinocytes with MCV and testing for mRNA production and protein production. 2) To identify the ability of MC148R to block chemotaxis induced by a panel of chemokines, and to identify which subsets of inflammatory cells are blocked by MC148R. 3) To characterize the ability of MC148R to bind to chemokine receptors and induce an intracellular signal. Binding will be assayed by radioactively labeling MC148R and demonstrating radioactivity on cells carrying cloned chemokine receptors. Intracellular signaling will be assayed using a calcium flux assay in cells with cloned chemokine receptors. 4) To determine the regions of MC148R that are important for blocking chemotaxis by constructing mutant proteins at both the amino terminus and the internal heparin binding site. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: A PUTATIVE HEPARIN RECEPTOR IN SMOOTH MUSCLE CELLS Principal Investigator & Institution: Lowe-Krentz, Linda J.; Associate Professor; Biological Sciences; Lehigh University Bethlehem, Pa 18015 Timing: Fiscal Year 2002; Project Start 01-JUN-1995; Project End 31-JUL-2005 Summary: (provided by applicant): The overgrowth of vascular smooth muscle cells is a hallmark of the late stages of vascular disease and contributes to the eventual blocking of affected arteries. Heparin has been shown to slow smooth muscle cell growth in vitro and in selected in vivo studies. Heparin effects on vascular smooth muscle cells have been explained by theories including heparin receptors, heparin interaction with growth factors and endocytosis of heparin. Data from the P.I.'s laboratory implicate a heparin receptor and signal transduction involving cGMP production and specific MAPK phosphatases. The proposed research aims to test the hypothesis that heparin treatment of cultured heparin-sensitive vascular smooth muscle cells will result in decreased activity of upstream signal steps in the MAPK pathway and decreased SAPK pathway activity through heparin's interaction with the heparin receptor previously identified in the P.l.'s laboratory. The proposed research will evaluate heparin and heparin receptor effects on upstream signaling from the PDGF receptor through SOS, Ras, and Raf using heparin, anti-heparin receptor antibodies, cGMP analogs, and PKG blockers. Studies of heparin effects on MAPK activity throughout the cell cycle will evaluate whether additional MAPK activity seen throughout the cycle is decreased, or
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whether the heparin effects are only at the Gi release from GO check point. The proposed research will evaluate signaling in response to Angiotensin II activation to determine whether the heparin effects on smooth muscle cell MAPK signal transduction are limited to MAPK activation in response to growth factors, or can modulate MAPK signaling regardless of activation system. These studies will also include evaluation of stress kinase activity in heparin treated smooth muscle cells to examine whether these parallel pathways are altered by heparin as might be expected based on our information about the mechanism by which MAPK activity is decreased. Finally, this study will continue work aimed at identifying a clone for the heparin receptor to enable further studies regarding the mechanism of heparin action. Together these studies will confirm the importance of the heparin receptor in heparin induced changes in vascular smooth muscle cells and will provide a significant advancement in understanding of how heparin alters sensitive vascular smooth muscle cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ACTIVATION OF HEMOSTASIS Principal Investigator & Institution: Bennett, Joel S.; Professor; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-MAR-1996; Project End 31-JAN-2006 Summary: Hemostatic and thrombotic disorders are among the leading causes of morbidity and mortality in the United States. Platelet activation and the subsequent binding of macromolecular ligands to the integrin alphaIIbbeta3 are critical events in the pathogenesis of these disorders. The objective of this SCOR Program is to further understanding of the mechanism and consequences of platelet activation, both at the laboratory and clinical levels, with the ultimate goal of providing a rational basis for new and novel therapies. The SCOR Program is composed of five projects and one core unit. Project 1 examines the structural features of alphaIIbbeta3 involved in its activation by platelet agonists. The structure of its ligand binding sites and its cytoplasmic and transmembrane domains will be studied, as well the interaction of the cytoplasmic domains with the platelet cytoskeleton. The latter studies are based on hypothesis that the platelet cytoskeleton regulates alphaIIbbeta3 function. Project 2 examines the biochemistry and cell biology of the platelet protein pleckstrin, asking how pleckstrin regulates cytoskeletal organization, how it affects megakaryocyte development, and what are its physiological ligands. Project 3 examines the consequences of eicosinoid receptor activation. Questions to be addressed include the role of thromboxane receptor activation in atherogenesis and plaque progression, and whether thromboxane receptor activation in atherogenesis and plaque progression, and Project 4 is to define the molecular basis of heparin- associated thrombocytopenia (HIT). The antigenic sites on PF4/heparin responsible for HIT will be characterized, the pathogenicity of various HIT antibodies for thrombosis will be studied, and two murine HIT models will be used to identify factors that predispose to thrombosis. Project 6 is based on the observation that most platelet agonists active platelets via one or more G protein coupled receptors on the platelet surface. Questions asked include whether simultaneous activation of multiple G proteins is required for platelet activation, what are the consequences in vivo of sustained signaling through G proteins, and do RGS proteins limit the duration of G protein signaling to prevent inappropriate platelet activation? The five projects will be supported by an Administrative Core that provides for the administrative and secretarial requires of the SCOR Program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: AIRWAY INFLAMMATION
EPITHELIAL
CONTROL
OF
ALLERGIC
LUNG
Principal Investigator & Institution: Corry, David B.; Assistant Professor of Medicine; Medicine; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2009 Summary: (provided by applicant): The long-term objectives of this laboratory are to elucidate the immunopathologic basis of airway obstruction in a murine model of asthma. This proposal will investigate the role the epithelium plays in allergic lung inflammation and focus specifically on two epithelium-derived immunoregulatory molecules, Clara cell secretory protein (CCSP) and syndecan-1. Clara cells are nonciliated respiratory epithelial cells that secrete one of the most abundant airway proteins, CCSP. The airway epithelium also sheds the heparin sulfate proteoglycan syndecan-1 into the airway. Although the biological functions of CCSP remain unclear, it is an antiprotease potentially capable of neutralizing exogenous proteases, which our laboratory has shown are critical to the induction of allergic airway disease. CCSP may also regulate adaptive immune responses of the airway by influencing epitheliumderived factors necessary for growth and survival of T cells. Our preliminary studies show that both CCSP and syndecan-1 down-regulate airway Th2 responses provoked by exogenous proteases. Thus, CCSP and syndecan-1 are immunosuppressive with regard to allergic lung inflammation, but their precise mechanisms of action remain uncertain. In Aim 1, we will dissect the major mechanism by which CCSP attenuates allergic inflammation. We will focus specifically on T cell-dependent effects and explore T helper effector differentiation in vitro and in vivo, Th2 homing to lung and Th2 activation and cytokine production in vitro. Where effects are observed, we will correlate immunosuppressive activities with the antiprotease potential of CCSP. For Aim 2, we will explore the potential of CCSP for prevention/amelioration of allergic lung disease. Mice will be challenged intranasally with CCSP during immune induction with protease-containing allergens and following established allergic lung inflammation to evaluate these two endpoints. Efficacy of CCSP will be compared to a specific protease inhibitor, streptomyces subtilisin inhibitor (SSI). Finally, Aim 3 will explore how syndecan-1 modulates allergic inflammation, either through effects of the core protein or the heparin sulfate side chains. We will extend these mechanistic studies to understand if either CCSP or syndecan-1 directly suppress Th2 function in vitro. Together, our findings will provide broad insight into how the epithelium modulates allergic inflammation, potentially identifying novel therapeutic targets. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ANTI ANGIOGENIC ACTIVITY OF CLEAVED HMW KININOGEN Principal Investigator & Institution: Mccrae, Keith R.; Associate Professor of Medicine; Medicine; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2005 Summary: (Applicant's Description) High molecular weight kininogen (HK) is an abundant plasma glycoprotein that plays a central role in contact activation. HK is cleaved to two-chain high molecular weight kininogen (HKa) on the endothelial cell surface. Cleavage of HK to HKa leads to the release of bradykinin, and is accompanied by a dramatic structural arrangement. Although binding of bradykinin to endothelial cells leads to well-defined responses, functional consequences that result from binding of HKa have not been reported. We have observed that HKa, but not HK, inhibits endothelial proliferation and induces endothelial apoptosis in a Zn2+-dependent
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manner. Proliferation is inhibited by 50% at an HKa concentration of 10 nM. In contrast, HKa does not inhibit the proliferation of aortic smooth muscle or trophoblast cells, or tumor-derived cell lines. In mice, HKa inhibits the neovascularization of basic FGFcontaining Matrigel plugs. Modeling of HKa domain 5 (D5), which also induces endothelial cell apoptosis in a Zn2+-dependent manner, reveals that the structure of the heparin and zinc-binding pharmacophores within this domain closely resemble those within the antiangiogenic polypeptide, endostatin. We have also identified peptides from the endothelial cell binding regions of HKa domains 3 and 5 that inhibit endothelial cell proliferation at low micromolar to nanomolar concentrations; D5, but not D3-derived peptide exhibit Zn2+ dependence. Further insight into the mechanism of HKa is provided by the observations that HKa causes apoptosis of only subconfluent, proliferative endothelial cells, and that culture of endothelial cells on collagen I, IV or a smooth muscle cell-derived matrix protects against HKa-induced apoptosis. In this application, we propose to further define the mechanism of Hka-induced endothelial cell apoptosis, and to use site-directed mutagenesis to determine whether the Zn2+binding pharmacophore(s) in domain 5 are important in antiangiogenic activity. We will also characterize the in viva antiangiogenic activity of HKa domains 3 and 5, as well as peptides derived from them. Finally, we propose to identify the endothelial cell receptor that mediate the antiangiogenic effects of Hka. These studies should provide new information concerning the physiologic regulation of angiogenesis, and may lead to identification of new antiangiogenic agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ANTIGENS OF KAPOSI'S SARCOMA ASSOCIATED HERPESVIRUS Principal Investigator & Institution: Chandran, Bala; Professor; Microbiology, Molecular Genetics, and Immunology; University of Kansas Medical Center Msn 1039 Kansas City, Ks 66160 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-JAN-2007 Summary: (Provided by the applicant): The AIDS-defining illness Kaposi's sarcoma (KS) and several lines of evidences suggest that Kaposi's sarcoma-associated herpesvirus (KSHV) or HHV-8 is vital for KS pathogenesis. The long-term objective of this research is to examine the role of HHV-8 in the pathogenesis of KS. Serological studies conducted in the last funding period suggest that HHV-8 lytic replication precedes AIDS-KS. To determine the role of lytic replication in KS pathogenesis, the focus of the present study is on HHV-8 binding and entry interactions with host cells, with a rationale that these interactions per se may have a role in the pathogenesis of KS. In vitro and in vivo, HHV8 has a broad tropism. Our studies show that this broad cellular tropism may be in part due to HHV-8's interaction with the ubiquitous host cell surface heparin sulfate (HS)like molecules. HHV-8 envelope glycoprotein gB interacts with HS and rabbit anti-gB antibodies neutralized HHV-8 infection. Sequence analyses show that among the HHV8 glycoproteins, and among all the gB of human and animal herpesviruses sequenced to date, only HHV-8 gB possesses the "RGD" (Arg-Gly-Asp) amino acids in the extracellular domain. The "RGD" amino acids is the minimal peptide region of many proteins known to interact with host cell integrins critical for the regulation of gene expression, cellular growth and differentiation. We hypothesize that HHV-8 envelope glycoprotein gB interaction with host cell surface integrins may play a vital role in the biology of HHV-8 infection and in the pathogenesis of HHV-8 associated KS. To examine this hypothesis, four major specific aims have been formulated: (1) To determine whether HHV-8 recognize host cell surface integrin molecules (2) To determine the role of integrins in HHV-8 interactions with host cells (3) To determine
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Heparin
the interactions between HHV-8 gB and the cell surface integrins. (4) To determine the morphological and molecular consequences of HHV-8 and HHV-8 gB interactions with cell surface integrins. These studies are significant since they will provide an insight into the biology of HHV-8 and it's role in the pathogenesis of KS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ANTITHROMBIN REGULATION OF COAGULATION PROTEASES Principal Investigator & Institution: Rezaie, Alireza R.; Associate Professor; Biochem and Molecular Biology; St. Louis University St. Louis, Mo 63103 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2003 Summary: Antithrombin (AT), a plasma serine protease inhibitor (serpin), inactivates factor Xa and thrombin by a branched pathway, suicide substrate inhibition mechanism in which an initial reversible Michaelis complex is converted into a tetrahedral or an acyl-enzyme intermediate similar to the normal reaction of these enzymes with their true substrates. In contrast to true substrates, however, a conformational change in the reactive site loop of the serpin leads to insertion of the loop into the A-beta-sheet of the molecule. This results in distortion of the catalytic machinery so that the intermediate is deacylated very slowly and, therefore, is trapped as a kinetically stable, irreversible complex. Unlike AT, binding of the non-serpin inhibitor, tissue factor pathway inhibitor, to factor Xa traps the protease as a reversible, high affinity Michaelis complex. AT is relatively inactive unless it binds to the heparin-like glycosaminoglycans, which are either present in the microvasculature or therapeutically administered for prophylaxis and treatment of venous thrombosis. The low inhibitory activity of AT is due to partial preinsertion of the reactive site loop of AT into the A-beta-sheet of the molecule. Heparin binding to AT induces a conformational change in the reactive site loop of the serpin that causes the expulsion of this inserted region thereby conferring a canonical conformation for the loop that is complimentary to the active site pocket of protease. We have prepared several serpin and protease mutants to investigate the following five Aims: 1) determine the contribution of the catalytic Ser195 of the proteases in binding to the serpin and non-serpin inhibitors; 2) determine whether the AT-protease complexes are trapped as tetrahedral or acyl-enzyme intermediates; 3) determine how heparin might catalyze the AT inactivation of factor Xa in the prothrombinase complex; 4) determine whether there is a heparin binding "exosite" on factor Xa, analogous to that in thrombin; and 5) determine the structural basis for the partial loon preinsertion and the resulting non-canonical conformation of the reactive site loop of the serpin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BARRIER FOR INTRAPORTAL ISLET TRANSPLANTATION Principal Investigator & Institution: Chaikof, Elliot L.; J.E. Skandalakis Professor; Surgery; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2004; Project Start 30-SEP-1999; Project End 31-JUL-2009 Summary: (provided by applicant): A significant obstacle in islet transplantation is the high rate of primary nonfunction and early islet destruction, which has been observed after intraportal islet infusion, both in animal models and in clinical trials. Substantial evidence now suggests that an acute blood mediated inflammatory injury is largely responsible for the observed functional stunning or destruction of islets and may well amplify subsequent immune reactions. In this proposal, we hypothesize that physiologically relevant anti-coagulant/anti-inflammatory processes establish an important paradigm for the design of a conformal islet encapsulation barrier that is
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"actively" anti-inflammatory. Specifically, we plan to fabricate an ultrathin film on the islet surface by a strategy of layer-by-layer (LbL) polymer assembly. Maladaptive inflammatory responses will be modulated by incorporating into the thin film, thrombomodulin (TM) and heparin, as inhibitors of thrombin dependent responses and CD39 as an inhibitor of purinergic mediated (i.e. ATP/ADP) procoagulant/proinflammatory pathways. In this manner, the islet cell mass required to achieve euglycemia will be reduced and long-term graft survival enhanced. Specifically, we intend to: (1) Fabricate a biocompatible conformal islet encapsulation barrier of deemed permeability by a strategy of layer-by-layer (LbL) polymer assembly. Porcine and mouse islets will be conformally coated with a polymer film and their short-term function and viability characterized. The ability of a conformal coating to prevent activation of the coagulation cascade and enhance islet engraftment will be defined using established allograft (B 10.BR -> C57/BL6) and xenograft (Porcine -> C57/BL6) models. (2) Determine the complementary effects of surface-bound heparin and thrombomodulin as interactive anti-inflammatory strategies designed to optimize islet engraftment and long-term islet survival. The ability of a TM and heparin containing conformal coating to prevent activation of the pro-inflammatory responses will be determined in vitro and in vivo and the capacity to enhance islet engraftment and long-term survival characterized. (3) Define the capacity of CD39 to abrogate prothrombotic and proinflammatory pathways that contribute to primary islet non-function and late islet destruction. CD39 will be incorporated onto conformally coated islets, either alone or as a component of TM and heparin containing films. The capacity of CD39 to potentiate the anticoagulant/anti-inflammatory properties of a protein C activating polymer coating will be determined. Enhancement of islet engraftment and long-term survival will be investigated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GROUPS
BIOMEDICAL POLYMERS WITH HEPARIN-BINDING END
Principal Investigator & Institution: Ward, Robert S.; President; Polymer Technology Group, Inc. 2810 7Th St Berkeley, Ca 94710 Timing: Fiscal Year 2004; Project Start 01-AUG-2004; Project End 31-JAN-2005 Summary: (provided by applicant): Endpoint immobilization of heparin on the surface of polymeric biomaterials is a well-established method for improving thromboresistance. The most effective currently-available heparinization methods are costly, multi-step procedures that may degrade the mechanical properties of the base polymer. This makes them impractical for both low-cost devices like IV catheters and for prosthetic implants in which retention of physical-mechanical properties is vital for assuring safety and efficacy, e.g., circulatory support devices and vascular grafts. The proposed study will determine the feasibility of synthesizing tough, thermoplastic polyurethane biomaterials with built-in covalently bonded end groups with binding sites for heparin. A novel diamine-diamide-alcohol (PIME-SME) synthesis procedure will be optimized for high yield and low cost. Several samples of Bionate (r), a biostable polycarbonate-urethane, will then be synthesized using the mono-functional PIME-SME in a range of bulk concentrations. The use of this new surface modifying end group will avoid the reduction of mechanical properties associated with modifications to the polymer backbone previously used for binding heparin. Heparinization will be performed by simply soaking the device or component made from the subject polymer in dilute heparin solution. Highly surface specific Sum Frequency Generation Vibrational Spectroscopy will be used to assure maximum concentration of heparin
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Heparin
binding groups at the surface of the polymer before exposure to heparin, and to measure the resulting surface heparin concentration following heparin binding. The activity of the adsorbed heparin will first be determined by a chromogenic anti-Xa heparin assay. A biological assay that measures the amount of antithrombin III (ATIII) that binds to the heparinized surface will also be used to determine if the adsorbed heparin maintains a conformation that binds ATIII. From the analytical characterization and the biological assays, the optimal bulk concentration of PIME-SME will be determined to provide maximum heparin binding on the surface of the modified polymers. During Phase II, scale up to manufacturing on our existing continuous reactor will be performed following extensive in vivo and in vitro testing. In Phase III The Polymer Technology Group will offer polyurethanes and device components with heparin binding capacity for sales or license, as part of its existing catalog of biomaterials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BIOMIMETIC SCAFFOLDS FOR MULTIPLE GROWTH FACTOR DELIVERY Principal Investigator & Institution: Andreopoulos, Fotios M.; Surgery; University of Miami-Medical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2004; Project Start 12-JUL-2004; Project End 31-MAR-2007 Summary: (provided by applicant): Chronic, non-healing wounds are a major health problem with more than 10 million Americans per annum receiving treatment, at a cost of greater than 10 billion dollars. Exogenous growth factor therapy for the treatment of chronic and acute wounds has shown promising results in accelerating the rate of healing in in-vitro and in vivo models. Unfortunately, inadequate methods of locally delivering active growth factors in a timely order limit the widespread utilization of growth factor therapy in a clinical wound management setting. A major challenge lies in the development of sophisticated peptide delivery systems that mimic the endogenous release profiles of growth factor production during the natural tissue repair process. We hypothesize that bioactive scaffolds impregnated with multiple growth factors that are released at controlled rates, offer the possibility of augmenting the rate of healing to a greater extent than a single growth factor therapy. This study is sought to a) understand how we can predictably modulate the sequential delivery of multiple growth factors from a single polymeric scaffold by manipulating the scaffold's properties and b) evaluate the synergistic effects of dual controlled growth factor delivery in cutaneous repair. We propose two Specific Aims. In AIM 1a we will synthesize biodegradable, polyethylene glycol-heparin (PEG-heparin) hydrogel scaffolds with tunable physical properties that release at controlled rates two well-known tissue repair factors, namely epidermal growth factor (EGF) and basic fibroblast growth factor (b-FGF). In AIM 1b we will determine the significance of controlled delivery on peptide bioactivity in an in vitro milieu and in AIM 2 we will assess the ability of the growth factor releasing scaffolds to promote cutaneous regeneration in a partial thickness wound model. The sequential delivery of these factors will be programmed by: a) controlling the physical properties of the scaffold (e.g. light exposure, gel composition), b) altering the growth factor loading capacity and c) pre-encapsulating each one of these factors (i.e. depending upon the preferred order of release) within biodegradable poly (lactide-co-glycolide) (PLG) microspheres before they are loaded into the gel scaffold. The heparin content of the gel scaffold will stabilize EGF and b-FGF and serve as a docking station for the prolonged release of the peptides to the wound area. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CARCINOGENESIS AND DRUG DEVELOPMENT Principal Investigator & Institution: Lippard, Stephen J.; Professor of Chemistry; Chemistry; Massachusetts Institute of Technology Room E19-750 Cambridge, Ma 02139 Timing: Fiscal Year 2002; Project Start 01-JUL-1980; Project End 31-JAN-2006 Summary: (Applicant's Description): The objective of this training program i s to produce young scientists qualified to make original research contributions in the chemical sciences related to cancer, both its prevention and treatment by chemotherapy. Ten faculty members of the Chemistry Department constitute the core research team around which the educational offerings of the program are built. Predoctoral candidates admitted to the program first complete a rigorous selection of courses and examinations after which they concentrate in one of several available research areas, also available to postdoctoral trainees, for their Ph.D. dissertation. Included in this offering are projects in the molecular basis of carcinogenesis, mechanistic studies of anticancer drugs, the synthesis of new antitumor agents including combinatorial chemistry, and new approaches to chemotherapeutic intervention through the study of cell surfaces and signal transduction. A new requirement has been introduced that postdoctoral associates take one course of direct relevance to cancer biology. Specific projects include cellular responses to DNA damage; mechanistic and synthetic studies of platinum anticancer drugs; chemical methods for the analysis of carcinogen metabolism; DNA damage, carcinogenesis and molecular biomarkers for cancer epidemiology; purine biosynthesis as an appropriate target for new antitumor agents; inhibitors of ribonucleotide reductases; bleomycins and enediynes as antitumor antibiotics; synthetic and biochemical studies of heparin-like glycosaminoglycans; the use of the fumagillin family of natural products as probes; the development of general synthetic methodology appropriate for combinatorial chemistry and rapid throughput screening; and strategies to prepare anticancer agents. In addition to their research, graduate and postdoctoral students in the program are required to expand their knowledge through participation in a regularly scheduled seminar program and by travel to key scientific meetings. At MIT, trainees present their research results, listen to presentations by their colleagues, and hear a variety of lectures by c a n c er researchers in the greater Boston community. Included are epidemiologists and clinical oncologists as well as basic scientists, to give the trainees a comprehensive picture of the roles of environmental factors in the etiology of cancer and of chemotherapy in the prevention and clinical management of the disease. At national and international meetings, members of the training grant give papers and attend sessions on work related to their own project as well as the projects of others on the training grant. Their experiences are then related to other trainees in the program upon returning to MIT. Education in the proper conduct of science and in scientific ethics is required through assigned readings and participation in regularly scheduled sessions with the faculty in which case studies are presented and discussed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CATABOLISM OF COAGULATION FACTOR VIII Principal Investigator & Institution: Saenko, Evgueni L.; American National Red Cross Washington, Dc 20037 Timing: Fiscal Year 2002; Project Start 01-FEB-2001; Project End 31-JAN-2005 Summary: (Investigator's abstract) Factor VIII (fVIII) is an important plasma component required for haemostasis, since genetic defects in this molecule cause a life-threatening coagulation disorder known as Hemophilia A. This genetic disease is treated by repeated infusions of expensive fVIII products. A more effective therapy can be
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provided if the molecular basis of fVIII clearance is understood and a novel recombinant fVIII protein with a prolonged lifetime in circulation is developed. We have previously found that the low density lipoprotein receptor-related protein (LRP), the main endocytic liver receptor, and cell surface heparan sulfate proteoglycans (HSPGs) cooperate in the clearance of fVIII, since simultaneous blocking of these two receptor systems dramatically prolonged the lifetime of fVIII in mice. While in purified system both LRP and HSPGs were shown to interact with fVIII via the sites located within the A2 domain, the precise molecular events responsible for fVIII catabolism are currently not well characterized. We propose to identify the amino acid residues critical for fVIII interaction with LRP and HSPGs by mutational analysis of the regions previously identified as LRP and HSPGs binding sites of fVIII. The mutations will be introduced into B-domain depleted recombinant fVIII, which is functionally identical to plasmaderived fVIII and is presently used for Hemophilia A therapy. We will express these fVIII mutants in mammalian cells and test them for binding to LRP and heparin, used as model of HSPGs, in purified systems. The catabolism of the mutants will be examined in vitro using LRP-expressing cells and in vivo in a murine model of Hemophilia A. These experiments will identify fVIII mutants with reduced binding to LRP and HSPGs and will clarify the role of these two receptor systems in fVIIII clearance. The proposed studies should develop an insight into the mechanism of fVIII regulation in circulation and will provide a basis for generation of a novel type of recombinant fVIII products, having a prolonged lifetime in circulation. Development of such fVIII derivatives, which may be prospective for less expensive Hemophilia A therapy, is the long-term goal of our studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RESPONSES
CEREBELLAR
PROTEOGLYCANS
IN
SONIC
HEDGEHOG
Principal Investigator & Institution: Rubin, Joshua B.; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2005 Summary: This proposal examines the regulation of sonic hedgehog (Shh) response in developing cerebellum. Sonic hedgehog produces multiple morphogenetic and mitogenic effects during development including cerebellar granule cell proliferation. Dysregulation of Shh has profound developmental consequences and is implicated in several cancers. The mechanism of Shh signaling is poorly understood and lags far behind our knowledge of several other growth factors. In Drosophila, Tout-velu, a putative glycosyltransferase involved in the synthesis of heparin sulfate proteoglycans (HSPG) is necessary for Hh response. There are multiple examples of HSPG modulation of growth factor signaling and several diseases of HSPG synthesis with significant developmental abnormalities and increased cancer risks. We have focused on the effects of HSPGs on Shh receptor binding and signaling in the developing mouse cerebellum. In preliminary studies we have demonstrated direct interaction of Shh with heparin, and shown that reduction of cell surface HSPGs results in decreased Shh induced proliferation consistent with the effect of the Tout-velu mutation. Surprisingly, these same treatments result in increased Shh binding. Further, we have found that cerebellar expression of EXT2, a vertebrate Tout-velu homolog, increases with age and is more abundant in post-mitotic granule cells. We hypothesize that the synthesis of HSPGs is regulated during cerebellar development and is a determinant of Shh binding and Shh responses. We will test our hypotheses by determining the pattern of expression of EXT family members (EXT1-3, L1-3) in developing cerebellum. We will measure Shh
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pathway activation in primary cultures of cerebellum from Ptc-LacZ (plus/minus) mouse and Shh receptor binding after genetic and biochemical manipulation of HSPG synthesis. The necessity for direct HSPG-Shh interactions will be determined by sitedirected mutagenesis of the putative Shh heparin binding domain. Taken together these experiments will generate novel information regarding HSPG modulation of the relationship between Shh binding and signaling and may shed new light on the mechanisms by which dysfunction of Shh and HSPG produce disease. In addition, these studies will provide me with the opportunity to learn the techniques of modern cell and molecular biology and establish the skills with which to study neural developmental. Dr. Rosalind Segal's laboratory in the Department of Pediatric Oncology at the DanaFarber Cancer Institute provides an excellent environment for me to develop as an independent investigator. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONTROL OF GROWTH OF VASCULAR WALL CELLS 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-JUL-1985; Project End 31-JUL-2003 Summary: (Adapted from Applicant's Abstract): The investigators will test four hypotheses regarding positive and negative growth control and cytokine- inducible functions of vascular smooth muscle cells (SMC) and endothelial cells (EC): 1. Heparin binding growth factors (HBGFs) contribute to SMC growth during atherogenesis. a) They will monitor expression of FGF family members and heparin binding epidermal growth factor like molecule (HB-EGF) in normal and atheromatous arteries from humans and rabbits. b) They will test whether cytokines regulate HBGF expression by cells found in human atheroma. c) They will study whether membrane bound forms of HB-EGF participate in "juxtacrine" signaling (stimulation requiring cell-cell contact), and whether proteolysis regulates HB-EGF action by release of surface-bound precursors. 2. Certain inflammatory stimuli can mobilize active IL-1beta from a preformed precursor pool in vascular EC. EC in vitro and in vivo contain immunoreactive IL-1beta. They hypothesize that this is inactive 33 kD pro-IL-1beta that requires proteolytic processing for biological activity. They will study the control by inflammatory mediators of IL1beta processing in EC and SMC which may represent an additional level of local regulation of this multipotent cytokine. 3. Monocyte- colony stimulating factor (M-CSF) promotes SMC growth during atherogenesis. a) They will determine whether human SMC transfected with c-fms, the M-CSF receptor, respond mitogenically to M-CSF. b) They will test whether SMC express membrane bound forms of M-CSF that may participate in "juxtacrine" signaling. c) They will localize c-fms expression in experimental and human atheroma to determine if SMC express this receptor in vivo during atherogenesis. 4. They will test whether local activity of a cytokine inducible nitric oxide synthase (iNOS) in SMC modulates the growth and other non-contractile functions of SMC and other cells. a) They will characterize cDNAs encoding iNOS in SMC. b) They will raise antibodies against SMC iNOS and probe its expression in vivo. c) They will test whether NO or NOS activity modulates the proliferative and matrix stimulatory effects of mediators such as PDGF, TGFs, and HBGFs on SMC. d) They will test whether NO or NOS expression by SMC inhibit mitogenic responses of Tlymphocytes, and might thus modulate local immune responses during vascular diseases. The results of this study should help unravel mechanisms of arterial pathology, to understand normal vascular homeostasis, and to aid the rational design of therapies for prevalent vascular diseases.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORE--VECTOR Principal Investigator & Institution: Snyder, Richard O.; Assistant Professor; University of Florida Gainesville Gainesville, Fl 32611 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2009 Summary: It is essential that investigators affiliated with this program be provided with consistently high titer, pure rAAV preparations. Therefore, the Vector Core Laboratory at the University of Florida has three objectives. The first objective of the Vector Core Laboratory is to make the highest quality preclinical vector for the investigators affiliated with this program conducting pre-clinical gene transfer experiments, as well as, safety and toxicology studies to support the AAV platform. Each virus preparation is now produced using a mini-Ad plasmid DNA system to eliminate Ad contamination. Small-scale preparations of rAAV 1, 2, and 5 vectors are purified by iodixanol gradient centrifugation followed by heparin affinity or anion exchange chromatography. Largescale preparations of rAAV2 are purified by a newly developed method that uses FPLC chromatography on heparin sulfate, phenyl Sepharose, and cation exchange columns. All virus stocks are subjected to stringent quality control assays to assess purity, particle titer, infectious titer, particle to infectivity ratio and potential contamination by rcAAV. The second objective of the vector core is the routine and large-scale production and purification of other AAV serotypes, including AAV1, AAV5, AAV7, and AAV8 vectors, and capsid mutants of AAV serotypes 2, 1, and 5. Assays and specific reagents will be developed to accurately determine the titers of the different serotype vectors and the capsid mutants. The third objective of this proposal is to develop viral vectors targeted to bronchial epithelial cells in order to provide a highly specific delivery of the cystic fibrosis (CF) gene, as well as to diminish the transduction of collateral tissues thereby reducing the required dose of vector to the patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DECIDUAL SIGNALS IN THE ESTABLISHMENT OF PREGNANCY Principal Investigator & Institution: Soares, Michael J.; Professor; University of Kansas Medical Center Msn 1039 Kansas City, Ks 66160 Timing: Fiscal Year 2002; Project Start 02-MAY-2002; Project End 31-MAR-2007 Summary: The establishment and maintenance of pregnancy require the appropriate development of a specialized maternal tissue, referred to as decidua. Decidual cells arise from uterine stroma via the actions of progesterone, form intimate relationships with placental structures, and facilitate the development of the embryo. Among the important functions of decidual cells are their hormone/cytokine producing capabilities. Hormone/cytokines related to prolactin (PRL) are prominent decidual cell secretory proteins and include, decidual/trophoblast prolactin-related protein (d/tPRP). The uteroplacental PRL family contributes to the regulation of uterine inflammatory cell responses accompanying pregnancy. D/tPRP has been shown to associate with heparin containing molecules in the extracellular matrix and specifically interact with eosinophils. Eosinophils are a part of the maternal inflammatory response and must be controlled in order to ensure the establishment of pregnancy. We hypothesize that the decidual cell product, d/tPRP, participate in the modulation of maternal adaptations to pregnancy, including mediation of the anti-inflammatory actions of progesterone. In this research project, we propose to investigate decidual cell signaling. In Aim 1 we propose to identify cellular responses to d/tPRP. Aim 2 focuses on determining mechanisms
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underlying the interactions of d/tPRP with heparin and eosinophils. Under Aim 3 we examine d/tPRP- eosinophil interaction in vivo. The planned research utilizes cellular and molecular and in vitro and in vivo strategies. Data derived from the proposed experimentation will improve our understanding of the nature of decidua cell signaling and the role of the decidual PRL family in the regulation of viviparity. These findings will provide considerable insight into the etiology of developmental disorders associated with pregnancy failure and will also have important ramification on our understanding of the control of eosinophil functions in aberrant processes such as immune disease and cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DESIGNING MECHANISM-BASED ANTICOAGULANTS Principal Investigator & Institution: Desai, Umesh R.; Associate Professor; Medicinal Chemistry; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2007 Summary: (provided by applicant): Thrombotic and vascular disorders are among the leading cause of deaths in the US annually. Unfractionated heparin and low-molecularweight heparins have become major anticoagulant drugs for use in these hematological disorders with combined annual sales of more than $ 3 billion. Unfortunately heparin and low molecular weight-based anticoagulation therapy is beset with several problems including bleeding complications. Heparin anticoagulation therapy is primarily based on the ability to accelerate the inhibition of factor Xa and thrombin by antithrombin, a plasma serine proteinase inhibitor. At the molecular level, heparin binding induces a conformational change in antithrombin ('activation') to greatly enhance its ability to inhibit factor Xa. However, the polyanionic nature of heparin also results in non-specific interactions leading to the numerous undesirable side effects. Alternative approaches based on rationally designed small non-sugar heparin-mimics that eliminate these side effects and possibly possess advantages, such as oral activity, are therefore highly desirable. Our central hypothesis is that efficient activation of antithrombin leading to specific inhibition of factor Xa can be achieved with small non-sugar molecules. We propose to synthesize and study rationally designed small organic molecules as conformational activators of antithrombin. Towards this end we will I) synthesize and characterize rationally designed bicyclic-unicyclic, bicyclic-linker-unicyclic and bicyclicbicyclic activators of antithrombin, II) investigate the molecular interaction of antithrombin with designed, small heparin mimetics using biochemical and biophysical techniques, and III) design rational advanced organic, non-sugar activators based on initial promising leads. Detailed investigation of the rationally designed molecules will provide the knowledge to deduce quantitative structure-function relationship critical for the design of an effective non-sugar heparin-mimic. These aims will be investigated utilizing computerized molecular modeling; fluorescence spectroscopic study of interactions; rapid kinetic determination mechanism of interaction; enzyme kinetics; and synthetic organic chemistry. This fundamental research will establish the principles of effective conformational activation of antithrombin by small nonheparin molecules for accelerated inhibition of factor Xa. Successful completion of this research will contribute fundamental knowledge for the design of an effective anticoagulant I) with reduced non-specific adverse effects normally associated with heparin therapy and II) with better oral activity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: RECEPTORS
DIFFERENCES
IN
SYNAPTIC
VS
NONSYNAPTIC
AMPA
Principal Investigator & Institution: Arai, Amy C.; Pharmacology; Southern Illinois University Carbondale 900 S. Normal Carbondale, Il 629014709 Timing: Fiscal Year 2002; Project Start 09-FEB-2001; Project End 31-JAN-2005 Summary: AMPA-type glutamate receptors mediate most excitatory synaptic transmission in the brain. Receptor binding studies have shown that AMPA receptors exist in two distinct states with 20-fold different affinities. It is suggested that the two forms are differentially localized with synaptic receptors being of the low-affinity type and non-synaptic receptors of the high-affinity type. Thus, AMPA receptors in patches excised from the soma (and hence of non-synaptic origin) may have different kinetic properties than those in synapses. This would entail that somatic and synaptic receptors contribute differentially to neurological disorders involving excitotoxic damage to neurons. This proposition will be tested by examining if differences between synaptic and non-synaptic AMPA receptors are also detected with physiological measures and if they correspond to the high-low affinity distinction seen in binding. To facilitate this comparison, both physiological data and binding data will be collected under equivalent conditions. Aim One will determine 'physiological KD' values for equilibrium currents in patches excised from hippocampal pyramidal cells and compare them with binding affinities obtained in the same buffer and at the same temperature. The results will then be compared with similar measures from recombinant AMPA receptors stably expressed in HEK293 cells that appear to be entirely of high affinity (Aim Two) and with data from synaptic receptors in autapses of cultured neurons, which presumably are of low affinity (Aim Three). It is further known that binding to the low-affinity receptors can be modulated about two-fold by biochemical manipulations such as treatment with concanavalin A, phospholipase A2 or neuroaminidase. The consequences of some of these treatments for AMPA receptor kinetics will be examined in Aim Four using the same approach. It was also observed that high affinity receptors, unlike their lowaffinity counterpart, are highly unstable at 37 degrees C and it seems likely that this is related to the fast 'run-down' of AMPA receptor currents in patch experiments. Determining which cellular factor stabilizes the low-affinity receptors will constitute the Fifth Aim of this application. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DRUG ELUTING STENT GRAFT FOR TREATMENT OF AAA Principal Investigator & Institution: Bajgar, Clara; Implant Sciences Corporation 107 Audubon Rd, #5 Wakefield, Ma 01880 Timing: Fiscal Year 2002; Project Start 11-FEB-2002; Project End 31-JUL-2002 Summary: (provided by applicant): Abdominal aortic aneurysms (AAA) affect approximately two percent of women and five percent of men over age sixty five, and are almost certainly fatal if allowed to rupture. Although surgery involving vascular grafts or endovascular graft systems is widely accepted as a standard treatment for AAA, new, minimally invasive stent grafting technologies are rapidly entering the market. Stented aneurysms are, however, like stented postangioplasty arteries, subject to thrombolysis and restenosis. Heparin and Heparin derivatives are commonly used to treat thrombolysis; several pharmacotherapeutic agents are claimed to control restenosis. Implant Sciences proposes to improve drug delivery to AAA sites by incorporating Heparin and a restenosis-inhibiting drug into a non-erodable, biodurablepolyurethane graft-coating. Rapamycin, based on its success in recently completed and
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highly publicized clinical trials when delivered from an eluting stent directly to percutaneous coronary revascularization sites, is the inhibitor of choice. To sequester the drugs, an eluting polymer currently marketed in Europe as VascuLink will be employed. By substituting for systemic drug administration localized, time-release, multi-drug delivery via a coated-stent, the proposed device not only affects a lifesaving repair but also, by minimizing Heparin and Rapamycin doses, reduces the potential for adverse side effects. PROPOSED COMMERCIAL APPLICATION: Although endovascular repair of AAA is not likely to replace surery, it can be extended to many patients who were previously considered poor surgical candidates. Compared to open surgery the hospital stay and the recovery times are shorter, both perceived positively by the patient (improved quality of life) and by the healthcare system (cost effectiveness). With the population aging and approximately 100,000 new AAA cases diagnosed every year, the commercial potential is significant, and, with the newer, improved devices, will become even more so. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EFFECTIVE AND NON-TOXIC ANTAGONIST TO HEPARIN AND LMWH Principal Investigator & Institution: Park, Yoon-Jeong J.; Industrail Science & Technology Network 2101 Pennsylvania Ave York, Pa 17404 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-JAN-2004 Summary: To prevent heparin-induced bleeding, protamine is used in nearly 2,000,000 cardiac/vascular operations to reverse the anticoagulant effects of heparin. Intravenous use of protamine, however, can cause life-threatening adverse reactions. In fact, the combined use of heparin and protamine was suggested as the major cause of morbidity and mortality for patients undergoing such surgeries. Although many attempts have been made, to date, protamine remains as the sole clinical heparin antidote; due to its unmatched reliability, efficacy, and low costs. A recent authoritative review by clinicians concluded that the ideal heparin-neutralizing agent should be a compound that provided all advantages and yet lacked anaphylactic potential of protamine. An explicit examination of the mechanism of heparin neutralization and protamine toxicity by us suggests that complete heparin neutralization may require only a small arginine-rich fragment in protamine, whereas the toxicity of protamine is attributed primarily to its polycationic and polymeric nature. Thus, a chain-shortened low molecular weight protamine (LMWP), if it can be derived from protamine to contain only the heparinneutralizing domain, could be this ideal heparin- neutralizing agent. Further, this LMWP may also be devoid of antigenicity and immunogenicity; both are known to contribute significantly to protamine toxicity. The ultimate goal of this SBIR project is therefore to develop LMWP to be a non-toxic, wholesale protamine substitute. During the Phase I work, the feasibility of this approach was successfully demonstrated. In this Phase II application, the focus is to demonstrate the utility of the approach in aborting all patients, either diabetic or non-diabetic, with or without pre- development of antiprotamine antibodies in their system, from possible attack of protamine allergy. In Phase III, ISTN will team up with identified industrial partners to proceed FDAapproved clinical trials, standarization of the compound under GMP, and commercialization of the final LMWP products. PROPOSED COMMERCIAL APPLICATION: Our assessment made in Section 3.5.3.3 indicates that the annual protamine production totals 1 metric ton in the US and 10 metric tons worldwide. The main objective of this SBIR project is to develop LMWP as a non-toxic protamine substitute without the risk of protamine allergy. If proves successful, it is expected that
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Heparin
LMWP would become a wholesale replacement of protamine in all its pharmacological and clinical uses. The commencial potential of this project is therefore enormous. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EFFECTS OF STRETCH ON IC AND NORMAL UROTHELIA Principal Investigator & Institution: Chai, Toby C.; Associate Professor; Surgery; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2002; Project Start 15-JUN-2001; Project End 31-MAY-2006 Summary: (Adapted from the Applicant's Abstract): Interstitial cystitis (IC) patients typically present with extreme urinary frequency, urgency and pelvic pain. It has a 10:1 female:male predominance. Since the pathophysiologic picture of IC is unclear, cure remains elusive and treatment options are largely ineffectual. Even the diagnosis of IC is controversial. An objective diagnostic criterion is the cystoscopic appearance of glomerulations after bladder hydrodistention (stretch) under anesthesia. Recent data disputed the diagnostic specificity of this procedure because hydrodistention of control bladders resulted in glomerulations. Based on the investigators' preliminary data which showed that IC urothelia responded to stretch significantly differently than controls in cystoscopic appearance, levels of urinary heparin binding epidermal growth factor-like growth factor (HB-EGF), antiproliferative activity (APF), and adenosine triphosphate (ATP), they propose to test these hypotheses: 1. Bladder glomerulations, which appear after hydrodistention, are specific for NIH-IC symptoms criteria (NISC). 2. Male patients with chronic non-bacterial prostatitis (prostatitis class III or chronic pelvic pain syndrome, CPPS) and NISC have post-hydrodistention glomerulations whereas males with CPPS and no NISC do not. This observation would further strengthen the association of glomerulations with NISC. 3. Some NISC patients improve symptomatically after hydrodistention and degree of improvement correlates with changes in urinary markers (APF, HB-EGF and ATP). 4. In vitro stretch of IC urothelial cells results in increased ATP, HBEGF and decreased APF activity compared to stretch of control cells. 5. There is increased expression of P2X1 and P2X3 ATP receptors in IC compared to control bladder urothelium and suburothelium. This project is unique because it links clinical and laboratory data to test the central hypothesis that IC urothelia respond differently to stretch. Only human samples will be used to provide optimal clinical relevance. Findings from this study will clarify the current diagnostic dilemma regarding specificity of glomerulations for diagnosing IC and determine the therapeutic efficacy of hydrodistention. Furthermore, this study will explore the exciting new discovery that ATP released by stretched IC cells is significantly higher compared to controls. ATP may mediate nociception in the bladder. Urothelial stretch thus appears to be an important consideration in diagnosis, treatment and pathophysiology of IC. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ENGINEERING FGF-1 FOR INCREASED ANGIOGENICITY Principal Investigator & Institution: Brey, Eric M.; Surgery; Loyola University Chicago Lewis Towers, 13Th Fl Chicago, Il 60611 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2006 Summary: (provided by applicant): Critical limb ischemia results in 150,000 nontraumatic lower limb amputations annually, with over half occurring in diabetic patients. The long-term goal of this research is to design a growth factor that can be used to increase blood flow in ischemic limbs of diabetic patients. This proposal is driven by the hypothesis that fibroblast growth factor-one (FGF-1) can be engineered for increased
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angiogenicity by creating chimeras with vascular targeting sequences and using site directed mutagenesis to modify specific amino acids sequences involved in thrombin degradation and heparin dependence. A chimera of FGF-1 fused with a peptide sequence that binds angiogenic endothelial cells (NGR) will be synthesized and characterized. The in vitro mitogenicity of this chimera (NGR/FGF-1) for endothelial, smooth muscle, and mural precursor cells will be determined, as will its susceptibility to thrombin degradation and heparin dependence. A fibrin gel model will be used to quantify the in vitro angiogenicity of NGR/FGF-1 and determine its 3D spatial localization in relation to vessel sprouts. The in vivo angiogenicity of NGR/FGF-1 and other previously designed FGF-1 mutants will then be quantified using a novel 3D technique and a simple collagen gel model. This gel, implanted in a mouse model of diabetes will be used to identify the growth factors with the strongest angiogenicity. The two most angiogenic growth factors will then be assessed for their ability to promote angiogenesis and increase blood flow in a diabetic mouse model of critical limb ischemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ESTROGENS AND INSULIN RESISTANCE IN WOMEN Principal Investigator & Institution: Olefsky, Jerrold M.; Professor; Medicine; University of California San Diego La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-MAY-2007 Summary: (provided by applicant): There are genetic and environmental causes of insulin resistance, and clearly these two inputs can be additive and interactive. A high fat intake is an important environmental factor which can cause, or exacerbate, insulin resistance and enhance the risk for the development of Type II diabetes. Our recent studies have shown that lipid/heparin infusions lead to insulin resistance in men, but not in pre-menopausal women. We also have preliminary data showing that postmenopausal women are fully susceptible to fat-induced insulin resistance and that estrogen replacement therapy re-establishes the protective state. In addition, we have conducted a series of studies in rats, demonstrating that estrogenization (endogenous or exogenous) will protect females from fat -induced insulin resistance. Based on these findings, we propose that men and non-replaced post-menopausal women will exhibit fat-induced insulin resistance, whereas, adequately estrogenized women will be protected. We will test these ideas, not only by employing the lipid/heparin infusion glucose clamp technique, but also by placing experimental subjects on control and high fat diets. It is also possible that adequate estrogen can ameliorate the effects of other physiologic causes of insulin resistance. Thus, we also will conduct studies to determine whether estrogenization can protect women from the insulin resistance induced by obesity and aging. Using muscle biopsy samples collected during the glucose clamp studies, we will conduct experiments aimed at identifying cellular mechanisms for these protective effects of estrogens. We also propose an extensive series of animal studies, in which we will explore in more detail the mechanisms of estrogen protection from fatinduced insulin resistance. We will conduct studies in normal male and female rats, ovariectomized rats, and old estrogen deficient female rats+/- treatment with estradiol, an estrogen antagonist, or estrogen receptor isoform specific agonists. Studies in mice with deletion of the alpha or beta forms of the estrogen receptor, as well as muscle specific estrogen receptor specific knockout animals are also proposed. We will also determine whether the fat cell secreted protein ACRP3O is modulated by estrogen status, and whether the insulin sensitizing effects of ACRP3O are responsible for the estrogen induced protection from insulin resistance. If the concepts contained in this
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Heparin
application prove correct, then these findings could have significant implications concerning the mechanisms of insulin resistance as well as the treatment and possibly prevention of this disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EXTRAVASCULAR THROMBIN REGULATION BY HEPARIN COFACTOR II Principal Investigator & Institution: Church, Frank C.; Professor; Pathology and Lab Medicine; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 01-JUL-1984; Project End 31-JUL-2005 Summary: (provided by applicant): Thrombosis is a major cause of morbidity and mortality in Western man. It is important to understand how the body regulates both thrombin activity and production. Our long-term goal is to understand the interactions between the "glycosaminoglycan (GAG)-dependent" serine protease inhibitor (serpin) heparin cofactor II (HCII), GAGs and thrombin and attempt to define how these interactions regulate the "cytokine-like" effects of thrombin on thrombin responsive cells. The serine protease thrombin has a key role in blood coagulation and other host defense mechanisms. Thrombin has two distinct types of activities: (i) those related to hemostasis, which are primarily manifest at sites of intravascular injury; and (ii) cytokine-like activities, which are primarily manifest in the extravascular stroma. There is much clinical evidence to suggest that antithrombin (AT) controls the first type of thrombin activity. We have a theory that HCII in the presence of extravascular proteoglycans regulates the second type of thrombin activity. We also hypothesize that thrombin dysregulation in atherosclerotic vessels is partly due to the loss of HCII-GAG interactions because of changes to proteoglycans with the progression of disease. Finally, we have a hypothesis that HCII activity is dependent upon unique protein-GAG interactions to displace its acidic domain for thrombin inhibition. To test these hypotheses, we propose to one, examine the mechanism of HCII-thrombin inhibition in the presence of GAGs, and to "transfer" the HCII structural elements for GAGdependent activity to a non-GAG-dependent serpin (alpha1-protease inhibitor) by sitedirected mutagenesis; two. crystallize HCII and crystallize thrombin-HCII acidic domain peptides, and to study structure-function relationships of the acidic domain; and three, characterize the ability of HCII to regulate thrombin's cytokine-like activity for mononuclear leukocytes and endothelial cells exposed to pro- and antiatherogenic substances, and to study the in vivo localization of HCII, AT, and thrombin antigen in normal and atherosclerotic vessel wall. While it is evident that inhibition of plasmaderived proteases is achieved by specific interactions, there are many essential molecular and cellular details that remain to be described. The information provided by the experiments outlined in this grant proposal will further define the mechanism of how HCII functions in thrombosis, especially related to atherosclerosis. Understanding the molecular and cellular properties of HCII may lead to new insight into the pathophysiology and therapies of cardiovascular diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FATTY ACIDS, ANGIOTENSIN AND OXIDATIVE STRESS Principal Investigator & Institution: Egan, Brent M.; Associate Professor; Pharmacology; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 15-AUG-1997; Project End 31-MAR-2005
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Summary: (provided by applicant): BACKGROUND: Obese hypertensives have elevated plasma non-esterified fatty acids (NEFAs) including oleic acid. Oleic acid induces a PKC-dependent increase of reactive oxygen species in vascular smooth muscle cells. In volunteers consuming diets low in anti-oxidants for 3 weeks, raising plasma NEFAs with an infusion of Intralipid and heparin increased blood pressure (BP) about l4/8 mmHg and elevated plasma F2-isoprostanes, an index of oxidative stress, p
Project Title: INTERACTION
FLOW
EFFECTS
ON
ENDOTHELIAL/TROPHOBLAST
Principal Investigator & Institution: Douglas, Gordon C.; Associate Professor; Cell Biology & Human Anatomy; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 956165200 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2007 Summary: (provided by applicant): In humans and higher primates, fetal trophoblasts gain access to the lumens of dilated uterine capillaries and migrate along endothelium against the flow of blood eventually remodeling spiral arteries. Our general hypothesis is that migration of trophoblasts within uterine blood vessels is regulated by blood flowderived shear stress. New data now show that trophoblasts migrate against flow when
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Heparin
cultured on top of confluent uterine endothelial cells. To account for these observations, two, not mutually exclusive, mechanisms are proposed. First, we suggest that shear stress causes an asymmetric distribution of immobilized chemokines or adhesion molecules on endothelial cells that generates a haptotactic gradient directing trophoblast migration against flow. Second, we suggest that interaction of trophoblasts with immobilized chemokines and/or adhesion molecules on endothelial cells results in trophoblast activation causing trophoblasts to respond to shear stress by migrating against flow. Four aims will allow us to distinguish these mechanisms and characterize the features that define the shear stress-dependent migratory phenotype. First we will use videomicroscopy to characterize the effect of different levels of shear stress on the directional migration of trophoblasts on uterine endothelial cells. Aim 2 uses confocal microscopy to study the role of chemokines and endothelial adhesion molecules in shear stress-mediated trophoblast migration. We will also use migration checkerboard assays to determine whether chemokine- or adhesion molecule-induced trophoblast migration is haptotactic, chemotactic or chemokinetic. Aim 3 determines the effect of shear stress and trophoblast-endothelial interaction on induction of a migratory trophoblast phenotype. We will use confocal microscopy to characterize the leading edge/trailing edge distribution of CCR5, beta1 integrin, and cytoskeletal elements in trophoblasts exposed to different levels of shear stress in the presence of endothelial cells. Expression of these proteins will be quantiated by laser scanning cytometry, immunoblotting, and quantitative RT-PCR analysis. Function-blocking antibodies will identify the role of trophoblast adhesion molecules and chemokine receptors in flow-induced migration on endothelium. Aim 4 will use quantitative laser scanning cytometry to examine the expression of chemokine receptors, chemokines, and adhesion molecules in intravascular trophoblasts and endothelial cells in serial sections of uterine tissue. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GLYCOSYLATED NANOPARTICLES TO INHIBIT RECEPTOR CLUSTERI Principal Investigator & Institution: Wei, Alexander; Associate Professor; Chemistry; Purdue University West Lafayette West Lafayette, in 479072040 Timing: Fiscal Year 2004; Project Start 01-JUN-2004; Project End 31-MAY-2009 Summary: (provided by applicant): Receptor tyrosine kinases and other cell-surface receptors are known to activate signal transduction pathways by ligand-induced dimerization or clustering, resulting in a range of important health-related consequences such as cell proliferation, inflammatory response, and angiogenesis. Receptor clustering is often promoted by heparin-binding proteins complexed onto nearby proteoglycans. This proposal will develop a new class of receptor inhibitors based on a novel concept called anti-clustering, in which nanometer-sized complexes will bind to multiple receptors but retain them in arrested states. Sulfated oligosaccharide ligands will be grafted onto colloidal gold nanoparticles, which will serve as multivalent scaffolds for the selective recruitment and orientation of heparin-binding signaling proteins such as growth factors or chemokines. Synthetic strategies will be developed for functionalizing nanoparticles with orthogonally protected oligosaccharides, which will be deprotected and sulfated in variable order to generate libraries of glycosylated nanoparticles (GNs) with variable sulfation patterns. Specific Aims include: (1) a robust method for encapsulating nanoparticles in nondesorptive coatings and functionalizing them with orthogonally protected oligosaccharides at low surface densities; (2) orthogonal protecting-group strategies for synthesizing disaccharides with up to 32 different sulfation patterns; (3) generation and characterization of sulfated GN libraries; (4)
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screening of GNs for highaffinity binding to fibroblast growth factors (FGFs), and their subsequent evaluation as inhibitors (anticlustering agents) against FGF receptormediated signal transduction using a cell proliferation assay. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HB-EGF AND INTESTINAL ISCHEMIA/REPERFUSION Principal Investigator & Institution: Besner, Gail E.; Professor; Children's Research Institute 700 Children's Dr Columbus, Oh 432052664 Timing: Fiscal Year 2002; Project Start 15-JAN-2002; Project End 31-DEC-2005 Summary: The broad, long term objectives are to utilize the cytoprotective abilities of heparin-binding EGF-like growth factor (HB-EGF) in the treatment of intestinal ischemia/reperfusion (I/R) injury. The goal of the present study is to determine the means by which HB-EGF decreases expression of inducible nitric oxide synthase (iNOS) and production of reactive oxygen species (ROS) within the intestine following I/R injury. We have shown that administration of HB-EGF during the ischemic phase of an I/R episode in rats substantially attenuates the extent of intestinal tissue damage and decreases mortality; as well, the post-I/R expression of iNOS, systemic appearance of nitric oxide, and generation of ROS within the affected intestine are significantly decreased. Using in vitro studies, we have demonstrated that treatment with HB-EGF decreases cytokine- induced upregulation of iNOS in human intestinal epithelial (DLD1) cells, and reduces generation of ROS by leukocytes and rat intestinal epithelial cells. Our hypothesis is that HB-EGF decreases tissue injury following I/R by limiting the increased expression of iNOS and ROS that occur in this setting. To test this hypothesis, the application has two specific aims: (I) To delineate the protective effects of HB-EGF in an in vivo model of intestinal I/R injury, and (II) To elucidate the mechanisms by which HB-EGF attenuates the post-I/R increase in iNOS and ROS. The research design and methods are to clarify issues regarding the dose, route, and timing of HB-EGF administration in vivo, and to use our animal model of intestinal I/R to characterize the effects of HB-EGF on expression of iNOS, ROS, antioxidant enzymes and proinflammatory cytokines by the intestine post-I/R. In Aim II, DLD-1 cells will be used to determine if HB-EGF alters the rate of iNOS mRNA transcription or its stability, and if NF- kappaB activation occurs following HB-EGF administration. Human umbilical vein endothelial cells will be used to determine if HB- EGF affects the conversion of xanthine dehydrogenase to the oxidase form, and human leukocytes will be used to determine the effects of the peptide on NAPDH oxidase expression and function. The health relatedness of this work is to eventually perform clinical trials of the use of HB-EGF in patients with intestinal I/R injury, and the data generated in this proposal will allow us to obtain important information regarding the mechanisms of HB- EGF intestinal cytoprotection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HEPARAN SULFATE PROTEOGLYCAN /PROSTATE CANCER METASTASIS Principal Investigator & Institution: Farach-Carson, Mary C.; Professor; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2003; Project Start 17-SEP-2003; Project End 31-JUL-2008 Summary: The interactions between prostate cancer cells and the bone stroma facilitate the progression of metastases growing in bone and bone marrow. Understanding the bone stromal microenvironment and its postive impact on growth of prostate cancer
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Heparin
cells at both cellular and molecular levels will allow us to develop novel therapeutic strategies specifically targeted to bone metastases. Heparin/heparan sulfate binding growth factors (HBGF) produced by bone marrow, by prostate cancer cells themselves, and sequestered in the bone matrix stimulate growth of metastatic prostate cancer cells. Agents that disrupt interactions between prostate cancer cells and the bone environment are expected to reduce the growth of metastatic prostate cancer cells at bony sites. Our hypothesis is that heparan sulfate proteoglycans in the stromal extracellular matrix, the most abundant of which is perlecan, function as co-receptors to deliver heparin binding growth factors to prostate cancer cell HB growth factor receptors. Three overall specific aims are proposed to test this hypothesis and to dissect the complex HBGF-mediated paracrine actions occurring between marrow stromal cells and prostate cancer cells. These studies will take advantage of prior work in our laboratory that has generated powerful reagents for disrupting HBGF-dependent signaling. Specifically, two types of interventions, a heparin binding protein (HIP) and related bioactive peptide and a perlecan ribozyme that we have generated will be tested for the ability to interfere with HBGF stimulation of prostate cancer cell growth. Strong preliminary studies indicate that PIn knockdown by an active ribozyme inhibits growth of prostate cancer cells in a mouse model. Together, our studies will complement other projects in the program project focusing on the important role of the stromal-epithelial interactions supporting prostate cancer progression. Finally, this project will support the training of a ribozyme core technician who will work with us in Delaware but who will be responsible for production of functional ribozymes as needed for other projects in the program. 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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Project Title: HEPARIN ON HYPOXIC PULMONARY HYPERTENSION AND REMODELING Principal Investigator & Institution: Hales, Charles A.; Professor of Medicine; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-JUL-1987; Project End 31-MAY-2005 Summary: Thickening of the media with intrusion on the vascular lumen contributes substantially to the pulmonary hypertension seen in primary or secondary pulmonary hypertension. Heparin has been shown to be antiproliferative and antihypertrophic for systemic and pulmonary artery smooth muscle cells (PASMC) in vitro and has been variably effective at inhibiting in vivo remodeling in several systemic and pulmonary models. We have found that commercial heparin lots vary widely in their antiproliferative activity. However, an effective antiproliferative heparin in vitro for PASMC proliferation can prevent hypoxic pulmonary hypertension in mice, rats and guinea pigs and can reverse it in guinea pigs even in the presence of continued hypoxia. We have also shown that heparin's ability to inhibit PASMC proliferation and in vivo pulmonary hypertension correlates with its ability to prevent mitogen stimulation of the Na+/H+ antiporter. We have found that highly specific antagonists of the Na+/H+ antiporter such as dimethyl amiloride (DMA) can inhibit PASMC proliferation in response to growth factors in vitro and can substantially prevent hypoxic pulmonary hypertension and remodeling in rats. As we dissect the chemistry of antiproliferative heparins we have shown, among other things, that the protein core is unimportant and that 3-0-sulfate is not an important feature in full-length heparin. We have made new heparin derivatives by O-acetylating heparin with butanoyl and hexanoyl which are more potent antiproliferative agents on PASMC than native heparins and are nonanticoagulant. We have found that in PASMC heparin stimulates the production of the cell cyclin kinase inhibitors p21 and p27 which are inhibitors of cell proliferation in other cells. With this progress we hope to continue our pursuit of an effective treatment for pulmonary hypertension with the following specific aims: 1) Continue examining strongly versus weakly antiproliferative heparins in order to discover the reasons for the differences with a goal of amplifying the antiproliferative potency and perhaps divorcing it from the anticoagulative and osteopenic properties. 2) Determine in the pig, as a preclinical trial in a large mammal, if heparin or heparin fragments or the Na+/H+ inhibitor DMA are effective at preventing hypoxic pulmonary hypertension and 3) Determine if heparin's mechanism of action in preventing SMC proliferation is via stimulation of the cyclin kinase inhibitors p21 and p27. Thus, this proposal may lead to new therapeutic agents for humans with pulmonary hypertension and may elucidate a new understanding of how heparin prevents PASMC growth. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HEPARIN SEQUENCES FOR APPLICATIONS TO HEMOSTASIS Principal Investigator & Institution: Seeberger, Peter H.; Firmenich Assistant Professor; Chemistry; Massachusetts Institute of Technology Room E19-750 Cambridge, Ma 02139 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: Heparin-like glycosaminoglycans (HLGAGs) are the most acidic naturally occurring biopolymers, found in the extracellular matrices. These complex polysaccharides play a key role in regulating the biological activity of several proteins in the coagulation cascade and in hemostasis. The relationship between structure and activity of HLGAGs is still very poorly understood due to the complexity and heterogeneity of these polymers. It has become increasingly evident that defined lengths
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Heparin
and sequences of HLGAGs are responsible for binding to a particular protein and modulating its biological activity. Detailed structure-activity studies on HLGAG oligosaccharides have suffered from the lack of pure material. Due to the complexity and heterogeneity of these polysaccharides there are, at the present time, no feasible approaches for the preparation of defined HLGAG oligosaccharides. Determination of structure-activity relationships of HLGAGs creates an opportunity for the discovery of novel therapeutic interventions for a variety of disease states. The principal investigator's present an entirely novel approach to the generation of defined HLGAG oligosaccharides by combining the enzymatic degradation of natural heparin with chemical synthesis. The program will draw from extensive expertise in enzymatic degradation of HLGAGs using heparinases, chemical synthesis of complex oligosaccharides and an understanding of the biological activities of HLGAGs. This relatively simple synthetic strategy would particularly lend itself to the solid support synthesis of defined HLGAG sequences, much like peptides and oligonucleotides are currently assembled. This novel and interdisciplinary program initially will be aimed at providing a proof-of-principle for the strategy to assemble HLGAG sequences involved in coagulation and hemostasis processes. However, areas of clinical opportunities of HLGAGs go beyond hemostasis, and can include angiogenesis and growth factor mediated signal transduction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMMUNE THROMBOCYTOPENIA/T*
MECHANISMS
IN
HEPARIN-INDUCED
Principal Investigator & Institution: Reilly, Michael P.; Medicine; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2005 Summary: (provided by applicant): Heparin-induced thrombocytopenia/thrombosis (HIT/T) is the most frequent cause of drug-induced antibody-mediated thrombocytopenia, a common cause of life-and limb-threatening platelet activation and thrombosis, and a model to study how an exogenous molecule (heparin) induces antibody formation against a self protein (platelet factor 4; PF4). Although antibodies to heparin/PF4 complexes are found in essentially all patients with HIT/T, it is unclear how antibody formation is initiated, why only a small subset of these antibodies cause disease or the mechanism by which they initiate thrombosis. We have recently developed a double transgenic mouse model and showed in vivo that heparin, PF4, antibodies to the heparin/PF4 complex, and the platelet Fc receptor for IgG, FcgammaRIIA are both necessary and sufficient to recapitulate the severe thrombocytopenia and thrombosis seen in patients with HITT. We have also found that PF4 and heparin form large oligomeric complexes that are immunogenic in vitro and are recognized by HIT antibodies. We will use these new findings to explore the immune mechanisms of antibody development, antigen recognition and pathogenesis of thrombosis in HIT through three interrelated aims. In Specific Aim 1 we will determine the heparin:PF4 ratio that supports the development of thrombocytopenia and thrombosis in vivo using mice in which the endogenous mouse PF4 has been knocked out. In Specific Aim 2 we will examine the structure of heparin/PF4 oligomers, their recognition by HIT antibodies, molecular composition, capacity to promote antibodymediated platelet activation through FcgRIIA, and uptake and processing by dendritic cells. We will develop a library of human IgG1 and IgG2 antibodies to these complexes in XenoMouseII mice. In Specific Aim 3 we will systematically vary four host factors important to HIT/T development in vivo, in order to determine their contribution to the
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spectrum of human disease. The antibody source and titer, the heparin:PF4 structure, Fcg receptor variants that influence the balance of platelet activation and splenic clearance, and atherosclerotic vasculature will be examined in genetically-defined mouse models. Taken together these studies will provide insight into the development of self-reactive antibodies and thrombosis in patients with HIT/T, facilitate development of new diagnostic tests to identify patients at risk, provide a platform to design rational inhibitors of antibody development and provide a model to test new therapies for this serious disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INHIBITOR-RESISTANT THERMOSTABLE DNA POLYMERASES FOR PCR Principal Investigator & Institution: Coleman, William J.; Group Leader; Kairos Scientific, Inc. 10225 Barnes Canyon Rd, #a110 San Diego, Ca 92121 Timing: Fiscal Year 2004; Project Start 01-MAY-2004; Project End 31-JAN-2005 Summary: (provided by applicant): DNA-based analytical and diagnostic procedures are increasingly exploiting the ability of PCR amplification technology to rapidly and accurately provide information about biological samples, often in a high-throughput format. Several key methods also rely on quantitative analysis of the amplification reactions. However, many types of tissue, blood and other clinical samples which can be used to generate template DNA for PCR amplification contain endogenous inhibitors of DNA polymerases. These inhibitors can seriously interfere with the analysis by creating false negative results. Such inhibitors include heparin and heine in blood, and bile salts in feces. In addition, a number of reagents used for DNA extraction or detection inhibit PCR reactions. We propose to use a combination of directed evolution and patented screening technology to create thermostable DNA polymerase variants that are resistant to common PCR inhibitors. Our sotid-phase MicroColonylmager (MCI) Technology is superior to conventional liquid-phase methods for analyzing mutagenized libraries of enzymes because it enables screening of 3,000-10,000 variants per assay while at the same time minimizing the amount of substrate required. By creating application-specific polymerase variants engineered to resist inhibitors, this technology will provide PCR users with cost-effective and time-saving reagents that will improve the reliability of their assays. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: INITIATION AND REGULATION OF BLOOD COAGULATION Principal Investigator & Institution: Lella, Vijaya Mohan Rao.; Professor; Biochemistry; University of Texas Hlth Ctr at Tyler 11937 Us Highway 271 Tyler, Tx 75708 Timing: Fiscal Year 2001; Project Start 01-APR-1998; Project End 31-MAR-2005 Summary: Tissue factor (TF)-dependent blood coagulation plays a primary role in hemostasis after tissue injury and also in pathogenesis. Binding of factor VII to TF is the initial step in TF-dependent blood coagulation. A key reaction must then follow: activation of the bound factor VII to give rise to catalytically active VIIa/TF complexes. Little is known about how the activation of factor VII and the subsequent VIIa/TFcatalytic activity are regulated in vivo and to what extent anti-coagulantly active cell surface heparin sulfate proteoglycans play a role in the regulation of these critical steps in TF-induced coagulation. Further, which specific amino acid side chains in VIIa and TF are involved in the recognition of tissue factor pathway inhibitor (TFPI) and the cell biology of VIIa/TF remain unknown. The primary focus of the present proposal is to
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Heparin
obtain important information on these unanswered questions. The specific goals are: (1) Test a hypothesis, both in vitro and in vivo, that cell surface heparin sulfate proteoglycans limit activation of factor VII bound to TF expressed on cell surfaces and thereby regulated TF-induced coagulation (2) Test a hypothesis that recognition structures for substrate factor X presents in VIIa/TF complex contribute to the enhancing effect of Xa during the quaternary complex formation of VIIa/TF/TFPI/Xa (3) Test a hypothesis that cell surface TF redistributes upon complex formation with VIIa, Xa and TFPI and define the role of TFPI in this process (4) Test a hypothesis that the binding of TFPI/Xa to cell surface VIIa/TF affects internalization of cell surface VIIa/TF complexes and elucidate the intracellular trafficking of internalized VIIa and TF. In the proposed studies, various well established techniques, such as radioligand binding, coagulation assays, electron microscopy, and a rabbit intravascular coagulation model system will be used. Information obtained from these studies will aid in understanding important clinical issues, such as why infused factor VIIa is effective in controlling the bleeding in hemophiliacs. The above studies will further our understanding of the structural mechanism of macromolecular assembly of VIIa/TF/TFPI/Xa. Such an understanding may lead to the design and application of therapeutic measures aimed at the treatment of hemorrhagic disease and thrombotic complications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INTERLEUKIN-6 EXPRESSION AND FUNCTION IN ADIPOSE CELLS Principal Investigator & Institution: Harp, Joyce B.; Associate Professor; Nutrition; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: Elevated interleukin-6 (IL-6) is associated with fat wasting in systemic infection and cancer cachexia. However, important new data indicates that circulating IL-6 is also elevated in human obesity, and adipose tissue is the principal source of this elevation. Because obesity is among the most prevalent public health challenges in the United States, it is important to understand IL-6 expression and function in adipose tissue, and to determine whether dysregulated expression of adipose tissue IL-6 is involved in the development of obesity and obesity-related co-morbidities. IL-6 traditionally signals through STAT3 activation, but in differentiating preadipocytes, IL-6 inhibits and STAT3 appears to be necessary for adipocyte formation. In this proposal we propose the following Specific Aims. Aim 1: To determine mechanisms involved in IL-6induced inhibition of adipogenesis. We hypothesize that greater than or equal to 10 ng/ml IL-6 inhibits the preadipocyte to adipocyte conversion by altering normal cell cycle progression and subsequent adipogenic transcription factor expression. We will determine in 3T3-L1 preadipocytes the effect of IL-6 on cell cycle progression and differentiation. Using chimeric GM-CSF- gp130 receptor transfections, the signaling mechanisms involved to transduce IL-6 effects will be explored. To explore the physiological relevance of IL-6 in adipose tissue, we will determine whether IL-6 knockout mice have altered adipose tissue growth, glucose, and lipid metabolism on normal and high fat diets. Aim 2: To characterize adipose tissue IL-6 expression in animal models of obesity. We find IL-6 mRNA is expressed in adipose tissue of lean mice, but it has been reported that obese db/db mice do not express IL-6 mRNA in adipose tissue. Since glucocorticoids repress IL-6 expression, we hypothesize that IL-6 expression is depressed in adipose tissue of ob/ob and db/db mice by high systemic
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corticosterone levels that are characteristic of these models of obesity. We also predict that IL-6 expression is elevated in adipose tissue of diet-induced obese (DIO) mice, similarly to obese humans. DIO mice retain normal corticosterone levels with the development of obesity. We will characterize IL- 6 expression in adipose tissue of lean control, DIO, ob/ob, and db/db all on a C57BL/6J background at baseline and in response to glucocorticoid agonists and antagonists, and thiazolidinediones. Aim 3: To identify the differentiation-induced STAT3 activating ligand. Our new pilot data indicate that IL-6 is not the autocrine factor responsible for MDI-induced STAT3 activation, but that the heparin binding ligand midkine (MK) is. In this Aim, we will confirm our preliminary studies, and determine whether midkine is the sole STAT3 activating ligand released upon MDI stimulation of 3T3-LI cells. Aim 4: To determine the role of STAT3 activation in adipogenesis. We hypothesize that activation of STAT3 is necessary for adipogenesis. We will block MDI-induced STAT3 activation by overexpression of PIAS3. Alternately, we will mimic STAT3 activation by overexpression of a constitutively active STAT3 to determine whether STAT3 activation alone is necessary and sufficient to induce adipogenesis. The role of STAT3 in fat pad formation will be investigated by implantation into the subcutaneous space of nude mice human preadipocytes that express vector, PIAS3, or constitutively active STAT3. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LIGAND-BINDING IN THE REACTION MECHANISM OF DAO Principal Investigator & Institution: Gassner, George T.; Chemistry and Biochemistry; San Francisco State University 1600 Holloway Ave San Francisco, Ca 941321722 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2005 Summary: (provided by applicant): Diamine oxidase (DAO) activities are elevated in boundaries separating quiescent and rapidly dividing cells where the transformation of molecular oxygen and biogenic amines to aminoaldehydes and hydrogen peroxide by these enzymes may play a significant role in the regulation of cell division in normal and cancerous tissues. Biochemical studies of this enzyme will help to elucidate the molecular mechanism of cellular response to changes in polyamine concentration in normal and disease states. Here we propose to 1) develop and optimize purification schemes for diamine oxidase from bovine liver and kidney and evaluate the substrate specificities of these isoforms 2) identify the role of manganese in ligand-binding and the catalytic mechanism, 3) characterize the heparin, and nucleic acid-binding interactions of DAO and the modulation of its catalytic activity associated with these biopolymers. The primary structure, glycosylation, cofactor content, specific activity, and substrate specificities of the purified isozymes will be compared. Catalytic reaction mechanisms of the purified enzymes will be studied through a combination of ligand binding, steady state, and pre-steady state kinetic measurements. DNA, RNA, heparin, and metal binding mechanisms, as well as the polynucleotide sequence binding specificity of these isozymes will be investigated by using a combination of titrametric, stopped-flow and continuous flow measurements. The role of polynucleotide, metal, and heparin-binding in catalysis will be established through the measurement of ligandspecific effects on steady-state kinetic parameters and reaction product distributions. The influence of nucleic acid binding on individual reaction steps will be established by observing changes in the kinetics of the oxidative and reductive half reactions by stopped-flow spectroscopy. The role of polyamines in the DAO-nucleic acid binding interaction and the kinetics of oxidation of DAO with polyamines will be investigated. Elevated concentrations of diamines and increased diamine oxidase activity generates significant concentrations of hydrogen peroxide and aminoaldehydes, which may lead
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to oxidative damage and the formation of inter- and intramolecular cross-links between reactive groups of susceptible proteins and nucleic acids. Products recovered from in vitro reactions of defined composition will be screened for DAO-induced molecular modifications by capillary electrophoresis and mass spectrometry. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MACROPHAGE MECHANISMS
CHYLOMICRON/B48
RECEPTOR,
BINDING
Principal Investigator & Institution: Bradley, William A.; Professor of Medicine; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2005 Summary: ApoB is essential to life yet excess apoB100 or apoB48 is atherogenic and associated with increased risk of cardiovascular disease. We identified and cloned a new, unique receptor (R) for dietary triglyceride-rich lipoproteins (TGRLP), the apoB48 R. It is constitutively expressed on monocyte-macrophages (MM), including human atherosclerotic foam cells and bone marrow precursors, and endothelial cells (ECs), cells intimately involved in hemostasis and atherothrombogenesis as well as hemopoiesis, immune function and tissue nutrition. Although we have documented that the apoB48 R binds to apoB48, major questions remain on the precise mechanism(s) of binding and why normal VLDL and LDL have low affinity for this R--which microdomain of apoB48 is necessary for R binding and how the other apoB regions, apoproteins, and lipid constituents modulate binding of lipoproteins to this R. Our published and preliminary data support the hypotheses that (1) an apoB48 microdomain that is required for binding is at or near the lipoprotein lipase binding site, is not releaseable by trypsin, is not in a heparin binding domain, and is masked in normal VLDL and LDL; (2) apoB48 R binding affinity is greater in large particles (Sf greater than 100) than in small particles (Sf less than 100); and (3) apoE inhibits binding to the apoB48 R. This ensures sufficient uptake of larger nutrient-rich (lipids and lipid-soluble vitamins) dietary particles by cells responsible for tissue nutrition, immune function and hemopoiesis, cells with high nutritional requirements, and directs smaller apoB lipoproteins to the liver, as observed in vivo. We propose multiple approaches to define the R-binding apoB48 microdomain (Aim 1) and to define modulators of this interaction (Aim 2), using native, modified, and model lipoproteins, monoclonal antibodies, C-terminal truncated apoB, molecularly engineered apoB mutant constructs, and cell and ligand blotting studies. Knowledge of the basic biochemical determinants and molecular mechanisms that govern the interactions of TGRLP with the apoB48 R are crucial to meaningful intervention to prevent excess, atherothrombogenic uptake by this route while preserving sufficient nutrient uptake or, conversely, to enhance uptake in subjects with multiple pathologies due to defective or deficient apoB. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISM OF FIBRINOGEN ASSEMBLY IN EXTRACELLULAR MATRIX Principal Investigator & Institution: Simpson-Haidaris, Patricia J.; Associate Professor; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2003 Summary: The process of blood vessel repair following injury is carried out in a temporal and spatial manner by the dynamic interaction of fibrinogen (FBG), fibrin and the extracellular matrix (ECM) with cells of the vessel walls. The long term objectives of
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this proposal are to characterize the cellular and molecular mechanisms by which vessel repair occurs. Proteoglycans are essential components of the receptor- growth factor interactions, cell-cell recognition systems, and cell-ECM adhesion processes that interact coordinately to stimulate cell proliferation and migration required for cellular repair. Because cell surface heparan sulfate proteoglycans perform essential functions in these processes, and with the extensive clinical application of heparin in the prevention in the prevention of thrombosis, the potential for heparin binding to fibrin(ogen) has important implications in understanding the mechanisms of heparin modulation of hemostasis, fibrinolysis, angiogenesis and tissue remodeling. Preliminary studies demonstrate that FBG, not fibrin, is incorporated into ECM, resulting in exposure of a cryptic heparin binding domain (HBD). We will test the hypothesis that FBG, through its HBD, plays an active role in heparin and heparin sulfate modulation of cell-cell and cell-matrix interactions involved in vessel repair. The proposed experiments will elucidate the mechanisms by which FBG is assembled into preformed, mature matrices of polarized and interstitial cell types to determine the functional role of matrix-FBG in mediating signal transduction to bring about the ordered process of cell repair and tissue remodeling. Specific Aim 1 of this proposal will be to define the essential structural domains of matrix FBG, and to determine the reciprocal cell-surface receptors and matrix constituents that support assembly of FBG into ECM. The techniques of cell biology, protein biochemistry, confocal scanning laser cytometry, fluorescence microscopy, and immunodetection will be used to characterize the ligands and receptors critical for the assembly of FBG into ECM. Specific Aim 2 will be to examine the cellular responses to FBG deposited and assembled into mature ECM. Modulation of cell proliferation and migration by FBG deposited into ECM, including the signal transduction pathways involved, will be examined using cell and molecular biology techniques. Defining the structure/function relationships involved in FBG, fibrin and the ECM interaction with cells of the vessel wall will provide a new understanding of the host response to injury with implications for treatment of thrombosis and therapeutic manipulation of angiogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISM OF HUMAN MAST CELL TRYPTASE REGULATION Principal Investigator & Institution: Schechter, Norman M.; Research Professor; Dermatology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: The goal of this work is to describe the biochemical mechanism for the functional instability of the serine protease human tryptase and to define the relevance of this mechanism to the regulation of tryptase in vivo. Serine proteases in blood and inflammatory cells play important roles in host defense. The enzymatic activity of these proteases is tightly regulated by other proteins which act as physiological inhibitors; the absence of such regulation can have serious pathological consequences. Enzymatically active tryptase is stored in large amounts within the secretory granules of mast cells, and is released upon stimulation of these cells. However, regulation of tryptase is a mystery because no physiological inhibitor has been identified. Tryptase exhibits many features not seen in other serine protease, namely i) a tetrameric structure composed of four catalytic subunits, ii) rapid and spontaneous activity loss under physiological conditions, and iii) stabilization by interactions with heparin, a highly sulfated glycosaminoglycan also stored in mast cell granules. These features may function in an integrated manner to regulate the activity of the protease. Studies of the properties associated with activity loss suggest that it is a reversible process involving limited
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conformation changes important to the active site structure of all serine proteases, Physical, kinetic and spectral studies of native tryptase and newly produced recombinant/mutant tryptases are proposed to identify more completely the structural changes production the functional instability of tryptase and to establish the contribution of tetramer dissociation to activity loss. Physical studies will be utilized to establish the affinity and rate constraints for the interaction of tryptase with heparin, and mutational studies will be used to identify the heparin binding site. These studies will establish the structural basis for the intrinsic instability of tryptase and the mechanism by which heparin exerts its stabilizing effects. The rate and affinity constants for the interaction with heparin will define the functional life-time of tryptase after secretion from the mast cell. Understanding the structural properties responsible for the functional instability may provide new targets for therapeutic inhibitors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MICROMECHANICS OF THE EXTRACELLULAR MATRIX Principal Investigator & Institution: Fernandez, Julio M.; Professor; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-JAN-2001; Project End 31-JUL-2002 Summary: (From the applicant's abstract) The extracellular matrix (ECM) is the mechanical scaffold that determines the elasticity and tensile strength of organs and tissues and finely regulates their development by controlling cell adhesion and migration. The ECM is formed by modular proteins and polysaccharides knitted together by self-assembly and through interactions with the cell adhesion receptors of a variety of cell types. Mechanical forces play important roles in ECM assembly and function. ECM fibrils are pre-stretched up to four times their resting length and are thought to translate mechanical forces into biological signals through cryptic binding sites that are exposed by mechanical unfolding. However, nothing is known about the molecular basis of the mechanical extensibility and mechanical signaling of the molecules composing the ECM. The long term aim of this proposal is to determine the force driven conformational changes that allow the ECM molecules to extend under an applied force and turn this force into a cellular signal. Towards this aim we will combine cellular and molecular biological techniques together with state of the art force spectroscopy (AFM) techniques and GFP based fluorescence imaging techniques, capable of observing force driven conformational changes in single molecules. During our first grant period we propose to focus on fibronectin and heparin, abundant molecules which are thought to play crucial mechanical roles in the ECM and have a central function in general animal physiology and pathology. We will use force spectroscopy to examine the mechanical unfolding of native fibronectin and of selected fibronectin modules that are known to play important mechanical roles in matrix assembly. We will engineer recombinant fibronectin proteins designed with specific mechanical properties that then will be transfected into CHO cells for fibronectin secretion and matrix assembly. We will use novel GFP based energy transfer probes in order to measure the resting force per molecule and to determine if unfolding occurs in vivo. We will also use force spectroscopy to detect force driven conformations in matrix glycosaminoglycans, in particular of heparin. We will use GFP probes to examine the binding of fibronectin modules to heparin under a stretching force. Mechanical forces play a critical role in ECM assembly and function. The proposed experiments will investigate, for the first time, the molecular basis of matrix mechanics. The findings may be of great importance for organ and tissue engineering and wound repair. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MINORITY PREDOCTORAL FELLOWSHIP PROGRAM Principal Investigator & Institution: Garner, Omai B.; Cellular & Molecular Medicine; University of California San Diego La Jolla, Ca 920930934 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): Heparan sulfate is a type of glycosaminoglycan (GAG) characterized by alternating uronic acid and D-glucosamine units (Esko and Lindahl, 2001). Heparan sulfate can be found on a number of cell types in a wide range of species from early metazoans to human cells. The chains are assembled while attached to a core protein, and the composite structure is called a proteoglycan. Heparan sulfate proteoglycans can be membrane-intercalated or GPI anchored, secreted, or stored in granules along with other secretory products (Bernfield et al., 1999). Proteoglycans function in a wide array of cellular activities including signaling, cell adhesion, and migration. T cells produce heparan sulfate(Wilson and Rider, 1991) and it is likely that heparan sulfate plays a critical role in their development and activation. This proposal contains a series of experiments that will examine the structure, assembly, and function of heparan sulfate proteoglycans in T cells. One set of experiments examines the composition of heparan sulfate proteoglycans in different T-cell subsets. A second aim focuses on the effect of inactivating a key heparan sulfate biosynthetic enzyme, GIcNAc N-deacetylase/N-sulfotransferase (NDST) on T cell development and activation. The long range goals of this study are to better understand the function of heparan sulfate in cell biology, which may provide novel targets for pharmacologic intervention in T cell mediated immunity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MIP-1B STRUCTURAL FEATURES RESPONSIBLE FOR FUNCTION Principal Investigator & Institution: Liwang, Patricia J.; Associate Professor; Biochemistry and Biophysics; Texas A&M University System College Station, Tx 778433578 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2006 Summary: (provided by applicant):Long-term objective of this proposal is to understand the structural details of the interaction between the chemokine MIP-Ia and its binding partners, particularly CCR5, its natural receptor. CCR5 is a 7- transmembrane helix receptor that is also used as a co-receptor by HIV in order to gain entry to the cell. I MIP1beta has been shown to block HIV entry to the cell by binding to CCR5, thereby suppressing HIV infection. In Specific Aim 1 a binding surface used by MIP-1beta to interact with CCR5 is hypothesized, and experiments to define the details of MIP-IbetaCCR5 interaction are proposed. In order to elucidate specific properties required for inhibition of HIV, MIP-1beta variants with differing quatemary structure and receptor binding capability will be tested as HIV inhibitors. In Specific Aim 2 NMR structural studies of the interaction between MIP- 113and heparin will be carried out to define the glycosaminoglycan binding surface of MIP- 1131 and to define the quaternary arrangement of MIP-1beta as it binds these sugars. In Specific Aim 3, two strategies will be pursued to investigate possible soluble proxies for the CCR5 receptor. First, X-ray crystallography and NMR spectroscopy will be used to determine the structure of the complex between MIP-1beta. and the virally encoded chemokine binding protein, p35. This will allow both an understanding of this particular complex and may also provide insight on modes of chemokine binding used by the natural receptor CCR5. Second, a novel strategy to investigate the structure of CCR5 is proposed, in which portions of CCR5 are grafted onto a stable scaffold. These three Specific Aims will delineate the
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molecular details of MIP-1beta binding to its biological partners, and will allow the design of specific, tight-binding anti-HIV therapeutics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MODULATION GLYCOSAMINOGLYCANS
OF
INTEGRIN
FUNCTION
BY
Principal Investigator & Institution: Strand, Kurt B.; Surgery; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2007 Summary: (provided by applicant): In this three-year fellowship, I plan to define the role of heparin in the modulation of the human platelet integrin. Our principal hypothesis is that heparin binds to the platelet integrin receptor GplIblIIa ((IIb(3), and alters its function. Using recombinant protein expression and functional assays with human platelets, as well as the model system of K562 cells expressing that integrin, I propose to define which integrin subunits are modulated by heparin and whether heparin's action depends exclusively on either subunit. Secondly, I plan to define the mechanisms by which heparin modulates integrin function, by examining receptor conformation and signaling. The laboratories of Dr. Sobel and the Vascular Biology Group at the University of Washington will provide excellent resources and environment to accomplish these goals. My mentoring committee includes leaders in each of the specific scientific fields where I will be acquiring new scientific skills. The experiments in the Aims should clearly show if our hypothesis is correct, and will define the precise structure-function relations and signaling pathways of heparin's interactions with the platelet integrin alphaIIb/beta3. Additional experiments are also anticipated to point to alternative hypotheses if our initial ones are not borne out. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR BASIS OF BLOOD COAGULATION REGULATION Principal Investigator & Institution: Olson, Steven T.; Professor; Molecular Biol/Oral Diseases; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 01-JAN-1994; Project End 31-MAR-2006 Summary: (provided by applicant): The plasma protein, antithrombin, and its glycosaminoglycan activator, heparin, act as essential anticoagulant regulators of blood clotting proteinases. Inherited mutations which cause a loss of antithrombin inhibitory function or which block heparin activation of this function are thus associated with an increased risk of thrombosis. Moreover, complete antithrombin deficiency in man is unknown and produces embryonic lethality in mice. The long term goal of this proposal is to provide a complete understanding of the anticoagulant function of antithrombin and heparin at the molecular level and elucidate their contribution to hemostasis. Our hypotheses are: i) antithrombin's specificity for inhibiting multiple procoagulant proteinases with different substrate specificities arises from secondary interaction sites or exosites outside of the main reactive loop region of the inhibitor used for binding proteinases; ii) three basic residues of antithrombin are principally responsible for binding heparin at an allosteric site through an induced-fit mechanism and the action of these residues is coupled to global conformational changes leading to inhibitor activation; iii) limited conformational changes in or near the 325-375 region which are not essential for inhibitor function are responsible for the expression of the antiangiogenic activity of antithrombin. These hypotheses will be tested by the following specific aims: l) We will elucidate the structural determinants of antithrombin's
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specificity for different clotting proteinases and assess how these determinants are expressed upon heparin activation; 2) We will determine the relative importance of antithrombin residues responsible for binding heparin and how they cooperate to induce antithrombin into an activated state with high heparin affinity and rapid reactivity with clotting proteinases; and 3) We will characterize the conformational differences between antithrombin forms with and without anti-angiogenic activity and localize the serpin structure which mediates this activity. These studies will utilize sitedirected mutagenesis together with thermodynamic and kinetic characterization of variant antithrombins to elucidate the relationship between antithrombin structure and function. These studies are expected to increase understanding of natural molecular defects in antithrombin and to provide a rational basis for the design of novel antithrombotic and antiangiogenic agents through the engineering of modified antithrombins or heparin mimetics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR THROMBOCYTOPENIA
BIOLOGY
OF
HEPARIN
ASSOCIATED
Principal Investigator & Institution: Poncz, Mortimer; Professor; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 15-MAR-2002; Project End 31-JAN-2003 Summary: Heparin-induced thrombocytopenia (HIT) is a life-threatening complication of heparin therapy that involves thromboctyopenia and thrombosis. Platelet Factor 4 (PF4)/heparin complexes are involved in the development of HIT. The studies proposed below will further define the molecular basis of the development of HIT. In addition, we believe that these studies may provide insights into other related disorders, such as the Anti-phospholipid Syndrome, which are also immune-based disorders combining thrombocytopenia and a high risk of developing thrombosis. There are 3 specific aims to this application: I. Characterize the antigenic sites on PF4/heparin involved in HIT. We have clearly shown that there are at least two antigenic sites recognized by HIT antibodies. Using mutant forms of PF4, we have defined one as being immediately adjacent to PF4's Cys36. We have also developed a HIT-like murine (m) monoclonal antibody (MoAb) KKO that recognizes a second site and have used a random peptide phage-display library to define a mimetope for KKO. By using mutant PF4/heparin complexes, HIT-like moAbs, further studies with the random peptide phage-display and NMR studies, we plan to fully characterize the antigenic sites on PF4/heparin. We also plan to determine whether either HIT antigenic sites is linked to the clinical course in HIT. II. Define the immune response in HIT patients. We plan to isolate additional MoAbs and characterize them as described above for KKO. We will also have established a phage-display library from a patient with HIT and thrombosis. HIT-like phage-display clones will be isolated from this library and from libraries to be established from HIT patients without thrombosis and from patients with antiPF4/heparin antibodies who do not develop HIT. The hypervariable regions, isotype utilization and antigen affinity and specificity will be compared to each other. Such studies should provide additional insights into how HIT antibodies develop and lead to disease. III. Use a murine HIT model to characterize risk factors and treatment strategies. We have developed a murine passive immunization HIT model in which we have documented thrombocytopenia, but no obvious thrombosis. We plan on maximizing this system, and then test variables, such as the specific nature of the MoAb, the nature of the platelet Fc receptor and the presence of pre- existing vascular disease, on the development of thrombosis. The model may also allow us to test strategies to
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prevent HIT. Thus, we believe that our proposed studies will not only provide insights into the etiology and progression of HIT, but may provide novel new approaches for its prevention and/or its treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR MECHANISM OF THROMBIN INHIBITION Principal Investigator & Institution: Cooper, Scott T.; Biology; University of Wisconsin La Crosse 1725 State St La Crosse, Wi 54601 Timing: Fiscal Year 2003; Project Start 01-JUN-1997; Project End 31-JUL-2006 Summary: (provided by applicant): The regulation of coagulation is central to many diseases, including heart disease and stroke. The objective of this research is to better understand the different mechanisms by which the serpins antithrombin (AT) and protein C inhibitor (PCI) inhibit free thrombin and thrombin bound to thrombomodulin (TM). Specifically the role of the H-helix, and other predicted contact points between the serpin and TM will be investigated. Previously we made the observation that, unlike AT, PCI is a potent inhibitor of thrombin bound to TM. The heparin binding domains of PCI and AT also differ; in AT the D-helix is a major part of the heparin-binding domain, while the H-helix is the heparin-binding domain in PCI. Alignment of the sequences of PCI, AT and heparin cofactor II (HCII) suggests that AT is unique in having a negatively charged H-helix, while the other serpins have positively charged helices. In recent work we demonstrated that changing the charge of the H-helix of AT makes it behave more like PCI in inhibiting thrombin bound to either heparin or thrombomodulin. The crystal structure of thrombin complexed with TM has recently been solved. This structure was used to generate a molecular model of AT complexed with thrombin and TM to explain kinetic data design new experiments. The first aim of this proposal is to continue to explore the roles of the D and H helices of AT in the inhibition of thrombin in the presence and absence of TM or heparin. The molecular model of a complex between thrombin, TM and AT revealed several other potential contact points between AT and TM, which would not be present between PCI and TM. In addition, the amino terminus of AT contains several more amino acids than does PCI, forming a loop which appears to sterically interfere with TM bound to thrombin. The second aim is to explore the importance of this loop by removing amino acid residues from the center of the loop and assaying the ability of these mutants to inhibit thrombin bound to TM. Another contact point in the complex is between AT residues R259 to R262 and three negatively charged amino acids on TM (E357, D398 and EH00). The third aim is to change these residues and measure the impact on inhibition of thrombin bound to TM The outcome of these experiments will provide a clearer understanding of the different mechanisms by which PCI and AT inhibit thrombin complexed with TM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MOLECULAR REGULATION OF CORNEAL WOUND HEALING Principal Investigator & Institution: Yu, Fu-Shin X.; Associate Professor; Cellular Biology and Anatomy; Medical College of Georgia 1120 15Th St Augusta, Ga 30912 Timing: Fiscal Year 2003; Project Start 01-AUG-1995; Project End 31-JUL-2008 Summary: (provided by applicant): Proper healing of corneal wounds is vital to maintaining a clear, healthy cornea and for preserving vision. The long-term goal of the laboratory has been to obtain basic information about the molecular and cellular biology of corneal wound healing. Recent data demonstrated that epithelial injury induces ectodomain shedding of heparin-binding epidermal growth factor (EGF)-like growth
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factor (HB-EGF). Shed HB-EGF, in turn, acts as an autocrine ligand to activate EGFreceptor (EGFR) and subsequent intracellular signaling pathways necessary for regulating corneal epithelial wound healing. The current proposal will test the hypothesis that EGFR ligand shedding is catalyzed by an ADAM (a disintegrin and metalloprotease) in a tightly regulated manner and that EGFR activation by shed HBEGF elicits several intracellular signaling pathways that work in concert to regulate corneal epithelial migration and proliferation. (i) The ADAM that is involved in HB-EGF shedding and EGFR activation in corneal epithelial cells in response to wounding will be identified by antisense oligonucleotide inhibition and by expression of dominant negative (dn) and constitutively active (ca) mutants of four ADAMs. (ii) The mechanisms by which wound-induced HB-EGF shedding and sub-sequent EGFR activation is regulated will be elucidated. The protein kinase (PKC) isozyme involved in the PKC-Raf1-MEK-ERK signaling cascade will be identified using enzymatic assays. Its role in EGFR activation and corneal wound healing will be assessed by expression of dn and ca mutants. (iii) The mechanisms by which each EGFR-elicited signaling pathway participates in the regulation of corneal epithelial wound healing will be investigated. Activation of four such pathways, mitogen activated protein kinase, phosphatidylinositol 3-kinase, phospholipase Cg-protein kinase C, as well as focal adhesion kinase, will be determined using biochemical kinase assays; their cross-talk and contribution to regulation of corneal epithelial migration and proliferation will be assessed using pharmacological kinase inhibitors and ca- and dn-mutant expression. An understanding of the molecular events from signal generation to signal transduction during corneal epithelial wound healing should help in the identification of targets for therapeutic interventions of corneal diseases like recurrent erosions and persistent defects of the epithelium. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOUSE MODELS FOR INTERSTITIAL CYSTITIS Principal Investigator & Institution: Schwarz, Edward M.; Associate Professor; Medicine; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 21-SEP-2001; Project End 31-JUL-2005 Summary: Interstitial Cystitis (IC) is a chronic irritable voiding syndrome of unknown etiology. Urinary frequency, urgency, nocturia, suprapubic pressure, and bladder/pelvic pain characterize this condition and there are no predictably effective treatments. Thus, many suffer with incapacitating symptoms for the rest of their lives. We believe that a small animal model will greatly enhance progress since pathophysiologic mechanisms can be dissected and therapeutic strategies developed in a far more controlled environment than the clinic. A model of IC must display features common to the clinical conditions, including chronicity, key elements of the symptom complex, and common pathophysiologic alterations. One etiologic hypothesis is that an urothelial barrier defect exists permitting urinary constituents unusual access to the tissues of the bladder wall. Whether this is an initiating event or the result of other perturbations is controversial, but most lines of evidence support the existence of a barrier deficiency in the clinical syndrome. To generate a small animal model to test the hypothesis that there is a relationship between a barrier defect and irritable voiding patterns, we have developed quantitative methods to evaluate the interplay of bladder permeability with void volume and frequency in mice. We will monitor plasma fluorescein following intravesical administration to assess the integrity of the bladder permeability barrier. We will use computerized balances to measure void volume and frequency within and across days. We will induce chronic cystitis by continuous
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exposure of the urothelium to agents that disrupt the bladder lining by implanting indwelling bladder catheter in each mouse. This will allow us to determine the relationship between altered bladder permeability and micturition frequency and volume. We will attempt to prevent and/or reverse these chronic barrier defects with several drugs (heparin, pentosan polysulfate and hyaluronic acid) and see what effect they have on permeability and voiding patterns. Finally, we will attempt to generate a transgenic mouse model of IC by targeting the expression of a secreted form of mouse protamine-1 (sMP1) to the transitional epithelium and evaluate these animals in our system. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NANOPARTICLE TARGETING TO CONTROL ANGIOGENESIS Principal Investigator & Institution: Davidson, Jeffrey M.; Professor of Pathology; Pathology; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2003; Project Start 22-SEP-2003; Project End 31-JUL-2007 Summary: (provided by applicant): The goal of this project is to achieve targeted delivery of angiostatic agents to sites of neovascularization. This is a widely accepted strategy that is limited in part by technologies of delivery and validation. The proposed studies center around a novel, biocompatible delivery device, the nanoparticle (NP), as a means to provide sustained, targeted delivery of angiostatic agents to sites of angiogenesis: wounds and tumors. The key elements of the delivery system are low toxicity and compositional flexibility, based interactions of charged polymer pairs. As a model system, we have utilized novel peptide analogs of thrombospondin-l (TSP-1) previously shown to have angiostatic properties. To provide retention within NP, these peptides have been prepared as polyethylene glycol conjugates that retain both heparin binding and biological activity. NP prepared with TSP-1 peptide conjugates show a markedly different biodistribution than empty NP and localization to sites of neovascularization. This proposal sets out to accomplish three goals: (1) optimization of the NP formulation, including dose-setting and incorporation of other targeting agents; (2) use of imaging and tracer technologies to ascertain biodistribution of targeted NP in mice; (3) validation of the efficacy of targeted delivery of NP containing angiostatic agents to wounds and tumors. In further studies, a peptide sequence derived from apolipoprotein E will be incorporated into the nanoparticle to enhance selective targeting of endothelial cells. Tumor delivery and targeting will be tested by noninvasive imaging using luciferase bioluminescence, 123I-scintigraphic imaging, and magnetic resonance imaging with gadolinium contrast. Conventional tracer technologies and microscopic localization of fluorescently labeled NP will be applied as well. In vivo, real-time image analysis of tumor vascularity will be determined by power Doppler ultrasound, and tumor mass will be determined by magnetic resonance imaging. In addition, conventional morphometric and histological techniques will be used to quantify the efficacy of this novel drug delivery system. The objective is to design drug delivery systems that will specifically target pathological angiogenesis with minimal effects on the normal vasculature. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NANOSCALE ENGINEERING OF ERODIBLE DRUG DELIVERY MATRICES Principal Investigator & Institution: Furst, Eric M.; Chemical Engineering; University of Delaware Newark, De 19716
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Timing: Fiscal Year 2003; Project Start 19-SEP-2003; Project End 31-JUL-2007 Summary: (provided by applicant): The paradigm of modern biomaterials research is the design of materials that can respond to specific stimuli and elicit a desired biological response. The revolution in structural biology toward quantitative understanding of biomacromolecular and cellular behavior offers important information for the rational design of materials with desirable bioactivity. One of the primary goals of this proposal is the assembly of novel, noncovalently crosslinked hydrogel matrices via the interaction between biologically important proteins (such as growth factors) and polysaccharides; the thermodynamics and kinetics of the association will be manipulated to control materials properties and release profiles. The interactions used to control assembly will also permit delivery of the proteins by ligand exchange with cell surface receptors. Exploiting ligand exchange mechanisms as a strategy for delivery and erosion will be relevant to many in vivo processes in which cells overexpress certain receptors, and by this unique coordination of activities, the matrices will find application in the targeted delivery of growth factors for chemotherapeutic, tissue engineering, and wound healing applications. In addition to producing novel materials for macromolecular delivery, this work will also utilize new quantitative approaches for characterizing the mechanical response of these biomaterials on length and timescales that are relevant to cells. New quantitative approaches such as tracer particle microrheology and micromanipulation with laser tweezers will be applied to directly measure microscopic mechanics and relaxation timescales of these hydrogels. When coupled with the synthetic strategies above, these investigations will allow us to understand the specific impact of noncovalent molecular interactions on the structure and rheological properties of hydrogel matrices. This will permit the rational design of microscopic mechanical responses, molecular delivery kinetics, and functionality on length and timescales of cellular processes. The proposed strategies will therefore result in materials in which cellular and polymer responses are coupled, and will broadly impact the development of new biomaterials targeted to specific cellular events. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEW BIOMEDICAL INTERFACE MATERIALS Principal Investigator & Institution: Marchant, Roger E.; Professor of Biomedical Engineering; Biomedical Engineering; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-MAR-1988; Project End 31-MAR-2004 Summary: Cardiovascular biomaterials suffer from well-known problems associated with thrombosis and infection. The surface, or interface, of a biomaterial is one of the most important factors that determines its blood compatibility, or its ability to support growth and normal function of endothelial cells (EC). The proposed studies will focus on new interface materials designed to improve the host response to biomaterials. The objectives are to develop new biomimetic materials based on the central hypothesis that non-covalent physical forces created by a cell's glycocalyx provides the major determining factor in the adsorption and functional state of adsorbed proteins, that controls subsequent cell and molecular interactions. To test this hypothesis, we propose to investigate: (1) Biomimetic materials that mimick non- adhesive properties and anticoagulant functions of EC glycocalyx designed to achieve blood compatibility; and (2) biomimetic materials that mimick adhesive glycoproteins in the extracellular matrix (ECM) designed to facilitate endothelization. The biomimetic materials are designed to undergo irreversible assembly on a range of clinically- relevant biomaterials, and consist of surfactant polymers with pendant oligosaccharides, oligopeptides, and hydrophobic
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ligands. Surface modifications will be characterized by spectroscopic and physical methods, and atomic force microscopy that will permit nanoscale imaging and examination of intermolecular forces. EC-like anticoagulant functions will be achieved through pendant heparin oligosaccharides and bioactive oligopeptides derived from thrombomodulin. The effect of biomimetic modifications on interfacial properties and blood compatibility will be determined from spectroscopic, microscopic, and labeling measurements of protein and platelet-surface interactions under well-defined dynamic flow conditions. ECM-like biomimetic materials will incorporate bioactive oligopeptides derived from EC binding proteins and heparin binding oligopeptides from fibronectin. The adhesion, growth, migration, and shear stability of human ECs will be determined using a laminar flow system at physiologic shear stresses. Cell-surface interactions will be studied by analysis of actin stress fibers and focal adhesion proteins using confocal microscopy. From these studies, we shall determine the mechanisms by which alteration in interfacial properties affects adhesive plasma protein and platelet interactions, and how this correlates to blood compatibility or endothelization. If successful, this research will lead to highly effective biomimetic materials that combine protein resistance and anticoagulant functions; or facilitate stable endothelization. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NON-ANTICOAGULANT ODS HEPARIN IN MYOCARDIAL INFARCTION Principal Investigator & Institution: Cardin, Alan D.; Celsus Laboratories, Inc. 12150 Best Place Cincinnati, Oh 45241 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-JAN-2004 Summary: Restoration of blood flow to the ischemic coronary bed initiates the inflammatory process of reperfusion injury, progressive necrosis and apoptosis of myocytes, clinically known as myocardial infarction (MI). Although heparin has broad anti-inflammatory properties, its use as a cardioprotectant is limited by its potent anticoagulant action. A simple process has now been devised employing reductive alkalinization during lyophilization that selectively and quantitatively removes the 2-O and 3- O sulfates necessary for binding antithrombin III, critical for heparin's anticoagulant effect. When given at the time of coronary reperfusion, this novel, nonanticoagulant O-desulfated (ODS) heparin prevents neutrophil influx into the ischemicperfused myocardium, blocks myocyte apoptosis and dramatically reduces infarct size. The ultimate objective is to develop ODS heparin for clinical use to prevent myocyte injury and death in MI. The specific aims of Phase I SBIR will focus on the feasibility of producing GMP quality-drug substance. Pending the successful outcome of these studies, a Phase II SBIR will focus on the scale up of 10 kilos of GMP quality ODS heparin to satisfy the toxicology and PK requirements of an IND submission for its use as a cardioprotectant in MI through Phase II clinical trials. PROPOSED COMMERCIAL APPLICATIONS: Intellectual property: USPTO/EPO with claims to composition, methods of production and use to treat/prevent ischemic reperfusion injury in myocardial infarction (AMI), lung injury & stroke. O-DS heparin is non- anticoagulant, broad-acting anti-inflammatory drug shown to be highly effective in protecting against the irreparable tissue damage caused by reperfusion injury. Use in AMI & stroke alone could exceed $4 billion a year annually worldwide. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NON-IMMUNOGENIC PEPTIDE ANTICOAGULANT Principal Investigator & Institution: Farrell, David H.; Professor; Barlow Scientific, Inc. 6307 Tamoshan Dr Nw Olympia, Wa 98502 Timing: Fiscal Year 2003; Project Start 20-AUG-2003; Project End 31-JUL-2004 Summary: We have identified a novel heparin-like peptidyl coagulation inhibitor that is a peptide fragment of a naturally-occurring human fibrinogen isoform, gammaA/gamma' fibrinogen. The peptide is active as an anticoagulant in whole plasma, and is unlikely to elicit an immune response, since it is a normal fibrinolytic cleavage product of this fibrinogen isoform. This application focuses on the development of this peptide as a potential pharmacologic anticoagulant. This peptide anticoagulant would have significant advantages over heparin, and could be used as a general replacement for heparin, particularly when heparin is clinically contraindicated, as in cases of heparin-induced thrombocytopenia. The specific aims are therefore to: I) Express the gamma' chain peptide in a recombinant expression system. II) Assay the recombinant gamma1,' peptide for anticoagulant and anti-platelet activities. At the conclusion of these studies, essential milestones will be achieved for Phase II development of the gamma' peptide as a pharmacologic anticoagulant. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PATHOGENESIS OF THROMBOSIS IN HIT Principal Investigator & Institution: Arepally, Gowthami M.; Medicine; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: In applying for the mentored clinician scientist development award, the principal investigator is requesting support for an intensive program of laboratory training under the supervision of Dr. Walter Kisiel, Professor of Pathology at the University of New Mexico Health Sciences Center. The objectives of this proposal are designed to strengthen the applicant's scientific background in the biochemical basis of coagulation and endothelial cell biology, areas essential for an understanding of human thrombotic disorders. The award, if funded, will facilitate the long-term goals of the applicant in developing an independent scientific career in the field of hemostasis and thrombosis medicine. The Candidate and her mentor have developed a career development plan which includes a) assurance of protected research time of 80-90 percent b) a training program exposing the Candidate to new areas of scientific investigation in biochemistry, vascular biology, adhesion receptors, and vertebrate biology c) graduate level studies to reinforce the laboratory experience and d) an advisory panel of established investigators with expertise in disciplines related to the proposal. The studies proposed in this application will extend the applicant's previous work on Heparin-induced Thrombocytopenia (HIT) and Thrombosis (HITT). Lifethreatening thromboses occurs in 10-20 percent of patients who develop HIT. The pathogenesis of thrombosis in HIT remains uncertain. Unlike most other immune mediated thrombocytopenic disorders, antibodies to endothelial cells can be demonstrated in HIT/HITT. It is hypothesized that concurrent platelet and endothelial cell activation is critical for the development of thromboses in susceptible individuals. To study the biological basis by which thrombosis develops in HIT, the following specific aims will be studied: 1) Characterizing the interactions of HITT antibodies with endothelial cells. 2) Defining the biological basis of thrombosis in HITT using murine models. 3) Generation of monoclonal antibodies (MoAbs) to PF4/heparin and functional characterization of PF4/heparin MoAbs with respect to thrombosis. It is expected that
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these proposed studies will contribute to a fundamental understanding of pathogenetic mechanisms for thrombosis in HITT, and lead to future investigations addressing therapeutic interventions in HITT. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC PHARMACOLOGY RESEARCH UNIT NETWORK Principal Investigator & Institution: Adamson, Peter C.; Division Chief; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 191044399 Timing: Fiscal Year 2004; Project Start 07-JAN-1999; Project End 31-DEC-2008 Summary: (provided by applicant): The recent advances in our understanding of the molecular basis for a broad range of pediatric diseases, coupled with the legislative changes culminating in the Best Pharmaceuticals for Children Act, has dramatically increased the potential for defining novel therapeutic approaches for a spectrum of childhood diseases. Further, it provides an important opportunity for improving our understanding of how best to utilize medications currently available for children. The Children's Hospital of Philadelphia (CHOP) has the necessary research infrastructure, patient population, and clinical and laboratory expertise to continue its participation and leadership in the Pediatric Pharmacology Research Unit (PPRU) Network. Under the PI leadership of a Board-certified clinical pharmacologist over the past 4 years, the CHOP PPRU experienced impressive growth both in patient accrual to studies and in the development of industry sponsored trials for Network participation. The CHOP PPRU's recruitment of an internationally renowned population pharmacokinetic modeler further increases the depth and strength of this program. The core laboratory has an in depth experience with state-of-the-art analytical techniques allowing for analysis of a broad spectrum of drugs in biologic matrices, each performed according to FDA's Good Laboratory Practices (GLP) specifications. Novel analytical methodologies developed by the CHOP PPRU will allow for ongoing genotype-phenotype correlative studies. The recent establishment of a proteomics core further expands upon these research capabilities. The CHOP PPRU will continue to emphasize clinical pharmacologic trials in the immunocompromised host, the critically ill infant and child, and in pediatric pain management. Two protocols developed for the PPRU Network, "A Pediatric Phase 1 Trial, and Pharmacokinetic, Pharmacogenetic and Pharmacodynamic Study of Dexmedetomidine" and "A Pediatric Population Pharmacokinetic Study of Heparin: Clinical Utility of Exposure and Biomarkers of Anticoagulation" are proposed and highlight CHOP's PPRU scientific focus. Our expertise in drug analytical methods, pharmacokinetic modeling, pharmacogenomics and proteomics, combined with unparalleled pediatric clinical expertise and access to a diverse pediatric population, assure the continued successful participation of the CHOP PPRU in collaborative Network research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FRONTIERS
POLYMER
MEMBRANE
ION/POLYION
SENSORS:
NEW
Principal Investigator & Institution: Meyerhoff, Mark E.; Professor; Chemistry; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-APR-1981; Project End 31-MAR-2006 Summary: (provided by applicant): The continued development, study, and bioanalytical applications of novel polyion and anion selective polymer
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membrane/film-based electrochemical and optical sensors are proposed. Research during the next phase of this long-term project will build upon several significant discoveries/advances made during the most recent project period relating to potentiometric polyion sensing and new chemistries for anion-selective sensors. These include dramatically lowering the detection limits toward biomedically important polyions (e.g., heparin, protamine, etc.) via use of a novel rotating potentiometric membrane electrode configuration, and 2) uncovering a unique hydroxide ion bridged dimer/monomer equilibrium that can exist for certain metalloporphyrins when used as ionophores in organic polymer films for devising anion sensing electrodes. Future efforts will include both fundamental and applied studies in both the polyion and anion sensing areas. Specific goals for the polyion sensor efforts include: a) better understanding the nature (size, stoichiometry, etc.) of the ion-exchanger/polyion complexes that form within the polymer membranes used to fabricate such devices; b) demonstrating broader bioanalytical applications of the new, more sensitive rotating polyion sensing membrane electrode configuration; c) investigating the use of polyion sensors (including rotating arrangement) to detect polycationic dendrimers and their interaction with DNA; and d) further development of a completely new and rapid homogeneous immunoassay method for detecting of small, clinically and environmentally important analytes using polyions as labels. In the area of anion sensors, efforts will focus on establishing which metalloporphyrins can spontaneously form hydroxide ion bridged dimer structures within polymeric films, and determining how these reactions affect the response properties of anion selective electrodes formulated with such ionophores. In addition, studies will be undertaken to utilize this novel chemistry to devise completely new polymer film-based optical sensors for anions and neutral species (amines, gases, etc.) based on the ability of such ligating species to break metalloporphyrins dimers into monomers within the organic films, yielding a large shift in the lambdamax of the Soret band. Investigations of electrochemical anion sensors based on a new type of lipophilic dendntic anion-exchanger structure are also proposed. It is anticipated that this research will continue to provide the analytical community with a wide array of new and/or improved chemical sensors as well as novel sensor-based methods that will have immediate applications as tools for basic research and within modem clinical and environmental test instrumentation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INHIBITION
POLYURETHANE
CALCIFICATION:MECHANISM
AND
Principal Investigator & Institution: Levy, Robert J.; Professor; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 191044399 Timing: Fiscal Year 2002; Project Start 01-AUG-1997; Project End 31-JUL-2005 Summary: Polyurethane calcification and associated thrombosis remain major obstacles hindering the long term use of polyurethanes in prosthetic valves and ventricular assist systems. Progress in the past three years of this Program has successfully addressed the initial goals of this Program by elucidating the mechanisms of polyurethane calcification and creating synthetic methodology involving hard segment activation to modify (either in bulk or on the surface) already polymerized polyurethanes. Thus, we have created polyurethanes with covalently attached bisphosphonates as effective anticalcification agents. In the Program Continuation, we will address inhibiting thrombus deposition on polyurethane, and thrombus related calcification Aim 1. To derivatize polyurethane with heparin in order to confer relative thrombo-resistance. It is hypothesized that this modification will both reduce platelet-fibrin thrombus build up and retard the
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development of thrombus associated calcification. Aim 2. Polyurethanes modified with tethered gene vectors to provide local fibrinolysis. This aim will be concerned with modifying the polyurethane surfaces to enable gene transfer of an antibody immobilize gene vector encoding for tissue plasminogen activator (tPA), in order to bring about local fibrinolysis. It is hypothesized that fibrinolysis will help to reduce thrombus buildup. Aim 3. Semilunar cusp replacements combining bisphosphonate, heparin, and local gene therapy to over-express tPA. It is hypothesized that our combined therapeutic modifications to prevent polyurethane cuspal calcification and retard thrombosis, will provide optimal pharmacologic synergy in a sheep pulmonary cusp implant model of polyurethane calcification. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PROSTATE CANCER BONE METASTASIS: BIOLOGY AND TARGETING Principal Investigator & Institution: Chung, Leland W.; Professor and Director; Urology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2003; Project Start 17-SEP-2003; Project End 31-JUL-2008 Summary: (provided by applicant): This multi-institutional Program Project from the Emory University School of Medicine focuses on the elucidation of the biology and molecular pathways involved in the interaction between stromal cells of the bone or the prostate and malignant prostate cancer cells. The overarching theme of this Program Project is that prostate cancer cell interaction with its microenvironment determine tumor growth, invasion, and metastasis in an organ-specific manner. This is manifested in clinical prostate cancer bone metastasis where the proliferation of both tumor epithelium and surrounding bone osteoblasts are accelerated. By understanding the molecular basis of this interaction, novel therapeutic targeting strategies can be developed to treat prostate cancer bone metastasis. This Program Project comprises of 3 Projects and 3 Cores and is organized to achieve synergy among the individual scientists who already have an established track record of prior research collaborations. Specific areas of investigation are: Project 1-Chung: the analysis of extracellular matrix (ECM) and integrin interaction in prostate cancer growth and metastasis; Project 2-FarachCarson: the assessment of the roles of heparan sulfate proteoglycan (HSPG), heparin binding (HB) growth factors and their receptors in prostate cancer bone metastasis; Project 3-Petros: the determination of the effect of mitochondrial DNA (mtDNA) mutations on prostate cancer growth and metastasis, with specific focus on the antiapoptotic function of mtDNA mutations in prostate cancer cells. Each of the projects has its own targeting theme and collaboratively will interact and achieve the goal of developing mechanism-based rational therapeutic approaches for the treatment of prostate cancer bone metastasis. This Program Project is supported by three Cores: the Administrative and Biostatistical Core A-Chung, the Animal and Tissue Culture Core BMartin and the Pathology and Laboratory Support Core C-Amin. The ultimate goal of this Program Project is to develop novel diagnostic, prognostic and treatment modalities based on a mechanistic understanding of prostate tumor and prostate and bone stroma interaction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PROSTATE CANCER-BONE INTERACTION--SECRETION OF EGFR Principal Investigator & Institution: Freeman, Michael R.; Director; Children's Hospital (Boston) Boston, Ma 021155737
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Timing: Fiscal Year 2002; Project Start 05-JUN-1998; Project End 31-MAR-2004 Summary: A common feature of advanced prostate cancer is metastasis to vertebral bone. Once metastasis to bone is evident, disease progresses rapidly and is almost uniformly fatal. Dissemination of malignant cells frequently occurs prior to diagnosis, and up to 25% of patients have bone metastases at the time of presentation. The mechanisms of tumor cell arrest in bone, proliferation at bony sites, and bone tissue destruction in prostate cancer ar poorly understood. In the proposed experiments, the principal investigator wil use a novel and highly sensitive bioassay, along with other methods, to determine to role of FGF-2 (basic fibroblast growth factor), and possibly othe bone-derived factors, in regulated cleavage-secretion from prostate carcinoma cells of the epidermal growth factor receptor (EGF-R) ligands, heparin-binding EGF-like growth factor (HB-EGF) amphiregulin and transforming growth factor-alpha (TGFalpha). Dr. Freeman presents preliminary data that FGF-2 activation of the extracellular signal-regulated kinase/mitogen activated protein kinase (ERK-MAPK) pathway mediates cleavage-secretion of HB-EGF from prostatic tumor cells. The specific aims are: Specific Aim 1: Determine if FGF-2 increases HB-EGF synthesis and secretion in human prostate adenocarcinoma cells by an extracellular signal-regulated kinase(ERK-MAPK-) dependent mechanism. Specifi Aim 2: Determine if FGF-2 isolated from extracellular bone matrix mediates cleavage-secretion of HB-EFG by an ERK-MAPKdependent mechanism. Determine if FGF-2 is the only heparin-binding factor in bone matrix capable of regulating cleavage-secretion of HB-EGF. Determine if osteoblasts secrete an activity capable of mediating secretion of HB-EGF. Specific Aim 3: Determine if cleavage-secretion of the EGF-R ligands, TGFalpha and amphiregulin, is regulated by FGF-2, factors derived from extracellular bone matrix, and osteoblast secretions in a similar fashion to cleavage-secretion of HB-EGF. Specific Aim 4: Determine the effect of endogenous proHB-EGF, proamphiregulin and proTGFalpha synthesis by Pca cells on metastasis to bone. These studies will expand our understanding of the pathways regulating activation of the EGF-R in prostate adenocarcinoma cells generally, and specifically within the bone microenvironment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PROTEINS AS SIGNALS IN UROTHELIAL CELL PROLIFERATION Principal Investigator & Institution: Bassuk, James A.; Research Scientist; Children's Hospital and Reg Medical Ctr Box 5371, 4800 Sand Point Way Ne, Ms 6D-1 Seattle, Wa 98105 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 31-DEC-2007 Summary: (provided by applicant): Understanding how the urothelium grows and differentiates is central to understanding a number of bladder diseases. Being able to modulate these processes would allow us to improve treatment of urinary tract abnormalities in children and adults. Preliminary evidence in our laboratory suggests that Fibroblast Growth Factor (FGF)-10 plays an important role in regulating DNA synthesis of urothelial cells, a crucial process involved in control of growth, differentiation, and repair of the urothelium. This process is described by a complex network of paracrine action that originates in the mesenchyme but acts on the urothelium. Disruption of this process in FGF10-null mice alters the differentiation of bladder urothelial cells and results in an abnormal transitional epithelium typified by incomplete stratification. Other processes involved in the control of growth and differentiation of the urothelium include cytokines and growth factors of various types. We propose to attack the FGF-10 part of these processes because a) nothing is known about the biology of FGF-10 in the bladder and b) an understanding of how FGF-10
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works in conjunction with these other processes will allow us to develop new and innovative methods to strengthen our translational approach to the problem of bladder and urinary tract disease. In order to achieve these goals, we have established specific aims for this period of support to better understand how FGF-10 functions in the context of a dynamic steady-state interrelationship that stimulates the progression of the urothelial cell cycle. Two mechanisms for how FGF-10 triggers proliferation are hypothesized: 1) the translocation of FGF-10 into urothelial cell nuclei and 2) a signalling cascade that begins with the heparin-dependent phosphorylation of tyrosine residues of surface receptors. We propose that negligible levels of FGF-10 define the normal urothelial phenotype -that of quiescence. During proliferative phases, levels of FGF-10 rise at the urothelial cell surface and/or within urothelial cell nuclei. Since our preparations of recombinant FGF-10 induce urothelial cell proliferation in animals, we eventually plan to evaluate the feasiblity of FGF-10 therapy in repairing the urothelium in clinical settings such as urethral trauma stricture disease and trauma. This study of the basic mechanisms of action will set the stage for later clinical use. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF SEQUENTIAL PROTEIN KINASE PATHWAYS Principal Investigator & Institution: Johnson, Gary L.; Professor and Chair; Pharmacology; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-SEP-1988; Project End 31-MAY-2003 Summary: (provided by applicant): Mitogen-activated protein kinases (MAPKs) are serine-threonine protein kinases that are activated by diverse stimuli ranging from cytokines, neurotransmitters, hormones, cellular stress and cell adherence. The basic assembly of MAPK pathways is a three-component module conserved from yeast to humans. The MAPK module includes three kinases that establish a sequential activation pathway comprising MAPK kinase kinase (MKKK), MAPK kinase (MKK), and MAPK. Currently, the mammalian MAPKs can be subdivided into five families: ERK1/2, p38alpha, Beta, Gamma, delta, JNK1 ,2,3, ERK3/4 and ERK5. Each family of MAPKs has distinct biological regulatory functions. The number of different MKKKs in MAPK modules allows for a diversity of inputs capable of activating specific MAPK pathways. The hypothesis that is the foundation of the research described in this proposal is that multiple MKKKs regulate common MKK/MAPK modules. MKKKs are differentially regulated by upstream signals allowing common MAPK pathways to be selectively regulated by the specific MKKK within the MAPK module. The composition of MAPK modules involves scaffolding proteins and interaction domains encoded in each MKKK, MKK and MAPK. The targeted gene disruption of each MKKK will therefore have a selective loss in the regulation of MAPK pathways in response to a set of specific stimuli. The phenotypic consequence of specific MKKK gene disruptions will therefore have unique defects in cellular regulation. My laboratory first cloned four of the MKKKs referred to as MEKK1, 2, 3 & 4. MEKKs regulate the JNK pathway. MEKK2 and 3 also regulate the ERK5 pathway. Targeted gene disruption of MEKK1, 2, 3 & 4 by homologous recombination has been completed. The MEKK1, 2 and 3 knockouts have unique phenotypes, signaling defects and pathologies. MEKK4 knockout is being characterized. MEKK1-/- animals have defects in cytokine expression, protease regulation and organ homeostasis. MEKK2-/- animals have immune defects with loss of cytokine expression and deficient T cell migration to lymph nodes. MEKK3-/- embryos die at day E4-7 and are postulated to have defects in trophoblast signaling in response to FGF4 or HB-EGF (heparin-binding EGF). Specific aims include: define the
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pathophysiology of mice having the targeted disruption of MEKK genes, define the signaling and functional abnormalities in cells deficient for each MEKK, and characterize the function of scaffold proteins we cloned that bind MEKK2 & 3. Cumulatively, the studies are defining the role of MEKKs in the control of physiological processes including wound healing, cardiac hypertrophy, lung inflammation, immune response and signaling controlling embryo development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF SMOOTH MUSCLE PROLIFERATION Principal Investigator & Institution: Patel, Rekha C.; Biological Sciences; University of South Carolina at Columbia Byrnes Bldg., Room 501 Columbia, Sc 29208 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: (Adapted from Investigator's Abstract): Vascular disease, which is the principal cause of heart attack, stroke and circulatory deficit disorders, is responsible for 50 percent of all mortality in the western world. Proliferation of vascular smooth muscle cells (VSMCs) is a key step in the pathogenesis of atherosclerosis and restenosis after vascular interventions such as angioplasty. Much attention has been focused on the search for an antiproliferative agent to regulate smooth muscle proliferation. Interferons (IFNs), which are cytokines secreted by the immune cells present in the atherosclerotic lesion, have been show to be antiproliferative towards VSMCs. Natural glycosaminoglycans such as heparin are also known to inhibit smooth muscles. Heparin is used widely as one of the local-delivery drugs after invasive procedures. In spite of the well-documented antiproliferative effects of IFNs and heparin on VSMCs, the molecular mechanisms that are involved have not yet been identified. PKR (protein kinase, RNA activated) is an IFN induced, growth inhibitory protein kinase, which is activated by double stranded (ds) RNA in virus-infected cells. PKR's role in regulation of cell proliferation has become clear in recent years. It's over expression or activation has been shown to be growth inhibitory. PKR is also activated by heparin in vitro and our results indicate that treatment of VSMCs with heparin results in activation of PKR. PKR is also induced at the transcriptional level by IFN treatment of VSMCs We hypothesize that, PKR is involved in mediation both heparin and IFN's antiproliferative effect towards VSMCs. We propose to test this with the following specific aims: 1. To investigate the role of PKR in the antiproliferative action of heparin and IFN on VSMCs. 2. To characterize the functional domains of PKR involved in mediating heparin's antiproliferative effect. The long-term goal of this proposal is to elucidate the molecular mechanisms involved in the inhibition of VSMC grown by heparin and IFN thereby offering on opportunity to design better ways of controlling the vascular diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REGULATORY ROLES OF LACTOFERRIN IN HEMOSTASIS Principal Investigator & Institution: Wu, Haifeng M.; Pathology; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2002; Project Start 01-APR-1995; Project End 31-MAR-2004 Summary: Lactoferrin is a prominent component of neutrophil secondary granules and can be released when neutrophils are activated. The concentration of lactoferrin in blood has been demonstrated to be increased in certain inflammatory diseases. In contrast to a well described biochemical characterization of lactoferrin as an iron-binding protein, its physiological role in the regulation of inflammation and other host defense mechanisms is unclear. The current proposed study will test three hypotheses: (i) lactoferrin derived
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from neutrophils is an important physiological mediator in the down-regulation of blood anticoagulation; (ii) the significant elevation of lactoferrin in blood, or at sites of inflammation can contribute significantly to the development of prothrombotic sequelae as seen in the disseminated intravascular coagulation (DIC) associated with bacterial infections; and (iii) the structural determinant(s) of lactoferrin involved in heparin binding is located within a specific sequence (residues 25-31) of the N-terminus. Thus, specific aims of this proposal are: (1) to determine the relationship between the elevation of plasma lactoferrin and the development of prothrombotic complications in patients with bacterial infections. The plasma lactoferrin concentration in patients with DIC resulting from different underlying diseases or with different inflammatory diseases will be examined; (2) to define the structural determinant(s) of lactoferrin involved in heparin binding. Both site- specific and domain-replacement mutagenesis will be used to determine the contribution of N-terminal basic residues (25 to 31) in heparin binding; (3) to study the activity of lactoferrin in the regulation of protein C anticoagulant pathway. Both the effect of lactoferrin on the generation of activated protein C and the specific binding of lactoferrin to chondroitin sulfate moiety of thrombomodulin will be examined. The completion of these studies will enable us to understand the biological role of lactoferrin in the regulation of inflammation and blood coagulation, and will provide new scientific background for the clinical evaluation and management of infectious diseases with thrombotic complications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RISK FACTORS FOR VENOUS THROMBOEMBOLISM IN THE COMMUNITY Principal Investigator & Institution: Heit, John A.; Professor; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: This is a study of genetic and environmental determinants of venous thromboembolism (VTE) in the Rochester Minnesota Olmsted County population. The specific aims of the study are: 1) to update the 1966-95 inception cohort to include Olmsted County residents with VTE during the five year period, 1996-2000; 2) to extend the analysis of risk factors for VTE by identifying two Olmsted County residents (controls) without VTE matched by age and gender to each definite or probable case within the 1996-2000 cohort, and to obtain plasma and genomic DNA from all cases and controls and perform a case-control study to test the hypothesis that first specific diseases are related to VTE and mutations of the factor five and prothrombin are independent risk factors for VTE in the community; and interactions between environmental and genetic factors. They will determine the population attributable risk for VTE associated with each risk factor, both individually and collectively for all significant risk factors. They will then compare two Olmsted County residents who received major surgery without developing VTE matched by date and type of surgery to a case with VTE within three months after surgery in order to look at risk factors related to surgery and genetic markers. They will do a similar analysis this time using two Olmsted County residents who were hospitalized for medical illness without developing VTE matched by gender and date of hospitalization to a case who developed VTE within three months after hospitalization and perform a case-control study to test the hypothesis again that risk factors and genetic markers are associated with elevation of risk of VTE. Finally, the investigators will plan to extend their analysis of current VTE in relationship to use of standard heparin and low molecular weight heparin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: RNA APTAMER-DIRECTED ANTICOAGULANT THERAPY Principal Investigator & Institution: Fortenberry, Yolanda M.; Pathology and Lab Medicine; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2006 Summary: (provided by applicant): Historically, unfractionated heparin has been used in the treatment and prevention of thromboembolic disorders. However, due to complications associated with heparin (such as bleeding), low molecular weight heparins (LMWHs) have been developed and are being used in place of unfractionated heparin. LMWHs have proven effective as antithrombotic agents; however, the effects of LMWHs cannot be readily reversed while unfractionated heparin can be reversed by protamine sulfate. The overall goal of this proposal is to develop an antithrombin (ATIII)-specific RNA aptamer that will combine the safely and efficacy of LMWH with the reversibility of unfractionated heparin. To accomplish this goal, an oligonucleotide antidote for this aptamer that will be used to rapidly reverse the anticoagulant properties of the aptamer will be developed. Proof of this concept is established by the development of an RNA aptamer and RNA aptamer antidote directed against coagulation factor Xa. In collaboration with this group, an antidote-controlled ATIIIspecific RNA aptamer will be developed. This aptamer will mimic the action of LMWH by binding to the D-helix of ATIII and enhance ATIII inhibition of factor Xa. This aptamer/antidote pair will have advantages over LMWHs because it will not only be able to control thrombosis similar to LMWHs but the availability of an antidote will allow for better therapeutic regulation and intervention. The experiments proposed in this proposal will characterize this family of antithrombin-specific RNA aptamers using both in vitro and in vivo approaches. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ROLE OF CYCLOPHILIN A IN THE HIV-1 LIFE CYCLE Principal Investigator & Institution: Gallay, Philippe A.; Assistant Professor; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2002; Project Start 15-FEB-2001; Project End 31-JAN-2004 Summary: Host cyclophilin A (CypA) is essential for the replication of the human immunodeficiency virus type 1 (HIV- I) and thus represents an attractive target for the elaboration of new anti-viral therapeutic agents to combat AIDS pathogenesis. Despite intense interest in the involvement of CypA in HIV- I replication, its precise role in the virus life cycle has yet to be elucidated. Our recent work suggests that CypA is exposed at the viral surface and is necessary for the initial step in HIV- I infection - the virus attachment to target cells. We demonstrated that CypA-deficient viruses do not replicate because they fail to attach to target cells. We showed that CypA is exposed at the viral membrane and mediates HIV- I attachment. We identified heparan suiphates (HS) as the exclusive cellular binding partner for CypA. Furthermore, we found that CypA binds directly to heparan via a domain rich in basic residues similar to known heparinbinding motifs. Finally, we showed that this interaction between exposed CypA and cell surface heparans represents the initial step of HIV- I attachment and is a necessary precursor to gp12O-binding to CD4. Our objective is to further understand the precise mechanistic role of CypA in the HIV-l life cycle in order to develop novel anti-HIV-l therapies. We propose to pursue the following aims: 1) to identify and characterize cell surface heparan sulfate proteoglycans necessary for CypA-mediated HIV- I attachment to target cells; 2) to define the events that control both the release of CypA from Gag and
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its relocation to the viral surface; and 3) to determine the direct participation of exposed CypA and/or other virus-associated proteins in HIV- I attachment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE OF GLYPICAN-1 IN PANCREATIC CANCER Principal Investigator & Institution: Korc, Murray; Chair, Department of Medicine; Medicine; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2004 Summary: (provided by applicant): Pancreatic ductal adenocarcinomas (PDACs) overexpress multiple tyrosine kinase receptors such as the type I FGF receptor (FGFR-1), and their ligands. Many of these ligands are heparin-binding growth factors (HBGFs), whose mitogenic actions are often dependent on interactions with heparan sulfate proteoglycans (HSPGs) that facilitate ligand binding to high affinity receptors. We have determined that PDACs overexpress glypican-1 but de not express high levels of other 5 members of the glypican family, raising the possibility that glypican-1 may have a unique and important role in PDAC. However, the exact role of glypcian-1 in PDAC and its mechanisms of action are not well understood. Therefore, we will use 4 complementary approaches to test the hypothesis that glypican-1 is of paramount importance in PDAC and that it acts by promoting mitogenesis, invasion and/or metastasis. We will first examine whether glypican-1 expression correlates with tumor grade and stage, or patient survival. Second, we will establish pancreatic cancer cell lines that overexpress glypican-1, as well as cell lines whose glypican-1 expression is suppressed by a glypican-1 antisense construct, in order to assess the role of glypican-1 in cancer cell growth, invasion, and metastasis in appropriate in vitro and in vivo model systems. Third, we will determine whether any tumorigenic effects of glypican-1 are enhanced by the presence of the type I fibroblast growth factor receptor (FGFR-1), since this receptor is overexpressed in PDAC and is activated by multiple HBGFs. To this end, we will transfect cultured human pancreatic ductal cells with cDNAs encoding glypican-1 in the absence or presence of the two major FGFR-1 isoforms. Fourth, we will explore the mechanisms whereby glypican-1 confers a growth advantage to cultured pancreatic cancer cells by examining its glycanation status and its interactions with FGFR complexes, and by engineering various glypican-1 chimeric proteins and comparing their actions with the actions of wild type glypican-1. Together, these studies will help to elucidate the role of glypican-1 in PDAC. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SMALLPOX VIRULENCE AND COMPLEMENT REGULATORY PROTEINS Principal Investigator & Institution: Atkinson, John P.; Professor of Medicine & Molecular Biolog; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: Public health concems have emerged regarding use of smallpox as a bioterrorist weapon since most Americans are no longer immune. Poxviruses subvert the complement system via the expression of regulatory proteins. In variola, vaccinia and ectromelia, the proteins are called SPICE (for smallpox inhibitor of complement enzymes), VCP (vaccinia virus complement control protein) and EMICE (an uncharactedzed analog in ectromelia that we have labeled "ectromelia inhibitor of complement enzymes"). These secreted virulence factors down-regulate complement activation by mimicking the functional repertoire of a family of host proteins called the
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Regulators of Complement Activation (RCA). The viral proteins are also structurally related to their host counterparts. Specific Aims: 1. To characterize the complement inhibitory profile of SPICE compared to its human counterparts. We will identify the principal complement-evading activity of SPICE and this will become a target for neutralization. These assessments will take place with the native soluble protein as well as after it attaches to cells via either its heparin-binding site(s) or by addition of an anchor. 2. To determine the complement regulatory sites of SPICE. These experiments will take advantage of the functional profiles (defined in Aim 1) and the sequences of active sites of RCA proteins that are homologous to corresponding regions of SPICE, VCP, and EMICE. These two sets of data provide a logical strategy for a mutational analysis to locate the active sites. 3. To characterize the complement regulatory activity of EMICE. This mousepox protein has not been evaluated for its complement inhibitory (virulence) activity. It is about 90% identical to SPICE and VCP. We will first characterize its regulatory activity for human and mouse complement. Second, we will assess its role in vivo as a virulence factor by infecting sensitive and resistant mouse strains with the ectromelia virus deleted of its complement regulator. The proposed experiments should provide novel information relative to the pathogenesis of poxvirus infections of man and mouse. Additionally, these results will serve as a guide to produce a less toxic small pox vaccine and to identify a viral target for mAb treatment of variola infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STRUCTURAL APOLIPOPROTEIN E
BASIS
OF
THE
INTERACTIONS
OF
Principal Investigator & Institution: Lund-Katz, Sissel C.; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 191044399 Timing: Fiscal Year 2002; Project Start 01-JAN-1997; Project End 31-JUL-2005 Summary: (provided by applicant): The overall objective is to gain a more complete understanding of the structure of apolipoprotein (apo) E, especially as it relates to the ability of the protein to bind to heparin, the low density lipoprotein receptor (LDLR), and lipid particles of different size. Point mutations are known to give isoforms of apo E that function abnormally in cholesterol and triglyceride transport. A range of engineered apo E molecules expressed in E. coli is being used to address 3 specific aims. 1) To understand how interaction with phospholipid changes the conformation of apo E so that it can bind to the LDLR. The hypothesis being tested is that changes in alphahelix organization alter the basic residue microenvironment in the LDLR binding domain (residues 136-150) which affects high affinity binding. NMR spectroscopy is used to monitor the microenvironments of lysine residues, and fluorescence and infrared spectroscopic methods are used to monitor the organization of apo E amphipathic alpha-helices in lipid-protein complexes. 2) To determine the type and organization of basic amino acids required in the apo E molecule for binding to heparin as opposed to the LDLR, and to understand why lipidation is required for binding of apo E to the LDLR but not for binding to heparin. The molecular mechanisms underlying changes in the energetics of binding arising from apo E polymorphism will also be investigated. 3) To understand the mechanisms responsible for the differing affinities of apo E isoforms for variously-sized serum lipoprotein particles, the molecular and thermodynamic parameters characterizing the binding of apo E and engineered variants to lipid particles of different sizes will be studied. The hypothesis being tested is that the length and properties (including the hydrophobicity of the nonpolar faces and the distribution of charged residues in the polar faces) of
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amphipathic alpha-helical segments in the C-terminal of the apo E molecule control lipid binding. Overall, achievement of these 3 aims will generate novel quantitative information about the ways in which apo E structure and polymorphism affect the functional properties of the protein in both physiological and pathological conditions. The design of ways to control the aberrant behavior of certain isoforms of apo E will be facilitated by this understanding. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STUDIES OF HERPES SIMPLEX VIRUS GLYCOPROTEINS Principal Investigator & Institution: Cohen, Gary H.; Professor and Chair; Microbiology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 30-SEP-1981; Project End 31-MAY-2005 Summary: (Adapted from the Investigator's abstract) For the two herpes simplex viruses (HSV-1 and HSV-2), four glycoproteins designated gB, gD and a complex of gH/gL are essential for virus entry. A fifth glycoprotein, gC, though not essential, is important for facilitating initial attachment by binding to cell surface heparin sulfate proteoglycans. gD triggers entry by interacting with one of several different cellular receptors. gB and gH/gL are necessary for fusion of the envelope with the plasma membrane. The longterm objective of the research efforts of Drs. Cohen and Eisenberg is to understand the mechanism by which these glycoproteins interact with each other and with cell molecules to mediate HSV entry. Within this proposal, they propose three specific aims: 1) to study immunological and biochemical properties of soluble gD, alone or in combination, with two of its receptors, HveA (a TNF receptor) or HveC (an adhesion molecule in the Ig superfamily); 2) to study the gD-receptor interaction when either the ligand or the receptor (or both) is membrane bound; and 3) to study events in virus entry that occur as a consequence of gD-receptor interactions. The investigators suggest that downstream interactions of the virus with the plasma membrane may involve gB and gH/gL of the virus and may additionally involve other cellular molecules. They have cloned the ectodomains of gD, gB, gH/gL, HveA and HveC into a baculovirus expression system and/or mammalian cells and have expressed and obtained purified proteins. In Aim 1, they will use these proteins to solve the structure of gD alone and/or in combination with receptor and/or antibody by X-ray diffraction analysis. They will map antibody and receptor binding domains on gD and look for conformational changes in gD that occur as a result of receptor binding. In Aim 2, they will use quantitative assays that present gD or its receptor in the context of a membrane and study the interaction of the other protein as a soluble form. One approach will be to bind HSV to an ELISA plate and then determine if added soluble receptor inhibits the infection of cells that are added in fluid phase. Such studies will indicate that they are evaluating receptor binding to a viable virus. In a second approach, they will bind virions to a biosensor chip and flow soluble receptor across the chip to measure receptor-virus interactions. A third approach will be to express the receptor in the murine leukemia virus (MuLV)-receptor pseudotype system and use these particles to study binding of gDt. In Aim 3, they will look for interactions among soluble forms of gD, gB and gH/gL in the presence and absence of gD receptors. In addition, they will study a series of gD/gH hybrid molecules for their ability to function in HSV infection in place of gD or gH/gL. Finally, they will study mutant forms of HSV including those that no longer require HveA or HveC for entry. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STUDIES ON THROMBIN ALLOSTERY Principal Investigator & Institution: Di Cera, Enrico; Professor; Biochem & Molecular Biophysics; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-DEC-1994; Project End 31-JAN-2004 Summary: Our laboratory has discovered the Na+-dependent allosteric enhancement of catalytic activity in thrombin and related serine proteases involved in blood coagulation and the complement system, identified the Na+ binding site and elucidated the importance of Na+ binding in the function and evolution of serine proteases. The proposed research project is aimed at gaining a complete functional and structural characterization of thrombin allostery and how it influences recognition of physiological substrates, effectors and inhibitors. We will use a combination of kinetic, mutational and structural studies to identify regions of the enzyme that are under the influence of Na+ binding and constitute the structural scaffold through which the Na+ site communicates changes of functional significance to binding epitopes for physiological ligands. We will determine what regions of the enzyme are involved in recognition of fibrinogen, protein C, the thrombin receptor PAR1, thrombomodulin, heparin and anti- thrombin III with unprecedented detail. The new information to emerged from the proposed studies will broaden our understanding of thrombin interactions in the blood and will enable the identification of molecular targets for new anti-coagulants. We will also exploit the knowledge gained on thrombin allostery to introduce Na+ binding and enhanced catalytic activity in the fibrinolytic enzyme tissue plasminogen activator. These mutational studies will produce more proficient derivatives of the enzyme that may benefit the current treatment of acute myocardial infarction and stroke. Developments from the proposed research plan will impact on the treatment and prevention of thrombotic disorders in which thrombin is directly involved, will have a broad impact on the study of allosteric proteins in general and will demonstrate that proteases with enhanced catalytic activity can be engineered rationally to benefit areas of medical and biotechnological importance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SYNDECAN AND BACTERIAL TRANSLOCATION IN SHOCK AND TRAUMA Principal Investigator & Institution: Wells, Carol L.; Professor; Lab Medicine and Pathology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2007 Summary: (provided by applicant): Normal enteric bacteria, such as Escherichia coli and Enterococcus faecalis, frequently cause complicating infections in patients with shock and trauma. A common finding in these patients is increased intestinal epithelial permeability, and experiments with cultured enterocytes have shown that bacterial adherence to and internalization by enterocytes is increased following opening of enterocyte tight junctions, exposing the enterocyte lateral surface. Syndecan-1, expressed on the basolateral surface of human enterocytes, is a cell surface transmembrane proteoglycan that expresses heparan sulfate (HS) on its extracellular domain. Our working hypothesis is that HS chains of cell surface proteoglycans, and specifically syndecan-1, may act as an enterocyte receptor or co-receptor for a variety of enteric bacteria. Preliminary data indicated that,like human enterocytes, HS and syndecan-1 are prominently expressed on the basolateral surface of cultured HT-29 enterocytes but not Caco-2 enterocytes. Experiments with HT-29 enterocytes (designed to open enterocyte
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tight junctions and interfere with bacterial binding to the HS chains on syndecan-1) suggested that HS may be a receptor for gram-positive but not gram-negative bacteria. The HS analog heparin, and HS itself, inhibited adherence and internalization of grampositive Listeria monocytogenes by HT-29 enterocytes, and experiments with related glycosaminoglycans indicated that this inhibition was specific for HS. Additional preliminary experiments with HT-29 enterocytes indicated that heparin and HS similarly inhibited internalization of gram-positive E. faecalis and Staphylococcus aureus, but not gram-negative Salmonella typhimurium, Proteus mirabilis, and E. coli. Heparin did not have a noticeable effect on internalization of any bacterial species using Caco-2 enterocytes, which express low levels of HS and syndecan-1 Other preliminary experiments indicated that heparin-treated L. monocytogenes was less invasive in orally inoculated mice than was untreated L monocytogenes. In this proposal several experimental tools are used to clarify the interactions of cultured enterocytes with a variety of gram-negative bacteria, while focusing on gram-positive L. monocytogenes, E. faecalis, and S. aureus. These tools include monoclonal antibodies, glycosamino glycans, and heparin disaccharides, and two cell lines transfected to over express syndecan-1, namely ARH-77 myeloma cells and Caco-2 enterocytes. Data from in vitro studies are used to design experiments in mice (outbred and syndecan-1 knockout) to clarify the role of HS and syndecan-1 in intestinal colonization and extra intestinal dissemination of enteric bacteria. Data from these experiments may indicate that enterocytes have a receptor (related to cell surface HS and perhaps syndecan-1) involved in adherence and internalization of a variety of gram-positive bacteria including E. faecalis and S. aureus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE ROLE OF HEPATIC LIPASE IN CHOLESTEROL HOMEOSTATIS Principal Investigator & Institution: Dichek, Helen L.; Pediatrics; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-MAY-2006 Summary: The enzyme hepatic lipase (HL) is central to cholesterol homeostasis. HL participates in the regulation of plasma cholesterol levels, a major risk factor for atherosclerosis. It also mediates steroid hormone production, by controlling access to exogenous cholesterol in steroid-producing tissues. In turn, increased production of the adrenal steroid cortisol (corticosterone in mice) as occurs in stress, depression and certain tumors of adrenal and pituitary origin, modulates the development of atherosclerosis: increased cortisol levels are linked to an increased risk for atherosclerosis. However, HL's precise role in atherosclerosis is unknown. HL exerts its role via at least two functions. Its catalytic function processes lipoproteins for both receptor-mediated endocytosis and selective cholesterol uptake. Its bridging function facilitates interactions between lipoproteins, receptors, and the plasma membrane, thereby modulating lipoprotein cholesterol flux. This proposal seeks to establish the respective contributions of the catalytic and bridging functions to the cellular uptake of lipoprotein cholesterol and atherosclerosis by generating transgenic mice that express wildtype HL and functional mutants of HL. These mice will be bred with mice deficient in endogenous HL(hl-/-) and with h1-/- mice that are also deficient in the low density lipoprotein (LDL) receptor to generate Ldlr-/-hl-/- mice. (The Ldlr-/- mice serves as a model for diet-induced atherosclerosis). Thus, we will determine the effect of the expression of wildtype and mutant HLs on plasma lipid and lipoprotein concentrations, composition and size, and lipoprotein turnover. The mechanisms of lipoprotein cholesterol uptake will be examined in primary hepatocyte cultures from the livers of these mice by determining the effects of wildtype and mutant HL on cellular binding
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and uptake of labeled lipoproteins in the presence of specific inhibitors of cellular receptors. The effect of expression of wildtype and mutant HL on atherosclerosis development will be established in high-fat diet fed wildtype and mutant HL expressing mice on the Ldlr-/-hl-/-background. In addition this proposal seeks to establish the role of HL in regulating the adrenal steroidogenic response to stress and to identify the contribution of the catalytic function of HL to the adrenal steroidogenic response to stress. This will be accomplished by determining plasma corticosterone response, adrenal cholesterol content and adrenal expression of receptors and enzymes involved in cholesterol metabolism, in response to chronic pharmacologic stimulation of corticosterone production in wildtype- and mutant HL-expressing mice and compared to nontransgenic mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TISSUE ENGINEERING OF SMALL DIAMETER VASCULAR GRAFT Principal Investigator & Institution: Chen, Changyi J.; Professor of Surgery; Surgery; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 20-SEP-2003; Project End 31-JUL-2007 Summary: (provided by applicant): The aim to produce a truly stable artificial blood vessel containing no synthetic material requires invasion and in growth of endothelial cell and smooth muscle cells as well as fibroblasts into the scaffold. This can be achieved either in vivo from the adjacent tissue or circulating cells after implantation, or in vitro by means of cultivated cells. Such graft should not induce substantial inflammatory reactions that could either damage its wall, setting the scene for long term aneurysm formation or trigger acute thrombosis. Based on such tissue engineering principles and our preliminary data, we propose a central hypothesis that a novel small diameter vascular graft can be tissue-engineered from the porcine carotid artery by decellularization, heparin covalent linkage, and heparin binding growth factors, and endothelial progenitor cell (EPC) seeding; and this graft may maintain its mechanical property and natural compliance; reduce host immune response; provide anticoagulation surface; and accelerate vascular cell growth and remodeling, thereby maintaining a long term potency in vivo. Three specific aims are proposed below to test our central hypothesis: Aim 1: To determine the mechanical property, natural compliance, host immune response, and anticoagulation property of decellularizedheparinized porcine carotid artery grafts (D-H grafts). We will test the hypothesis that D-H grafts may maintain their mechanical property and natural compliance, provide anticoagulation surface, and reduce host immune response. Both in vitro and animal models are included. Carotid artery bypass surgery using D-H grafts will be performed in dogs (xenogenic setting) and in pigs (allogenic setting). Aim 2: To determine the effect of bFGF binding to D-H grafts on vascular cell growth and repopulation of the grafts. We will test the hypothesis that bFGF binding to D-H grafts may promote vascular cell growth and repopulation of the grafts, thereby accelerating vascular healing and remodeling. Characteristics of bFGF binding and release and effect on cell proliferation and anticoagulation will be investigated in vitro. In vivo performance of bFGF bound DH grafts will be studied. Aim 3: To characterize cell proliferation and differentiation of EPC and its application with bFGF bound D-H grafts. We will test the hypothesis that bFGF bound D-H grafts may enhance EPC proliferation and differentiation, and EPC seeded bFGF bound D-H grafts may have better healing and remodeling characteristics as compared to un-seeded grafts. EPC will be isolated and characterized from dog or pig peripheral blood. The effect of bFGF and hemodynamics on EPC differentiation and proliferation will be investigated. In vivo performance of EPC seeded bFGF bound D-H
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grafts will be studied. This study represents a multidisciplinary approach including tissue engineering, cellular and molecular biology, and animal models. Success of this proposal will directly indicate the clinical applications of tissue engineered small diameter vascular grafts. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRIGGERED LOCAL RELEASE OF ACTIVE THROMBOLYTIC AGENTS Principal Investigator & Institution: Yang, Victor C.; Albert B. Prescott Professor of Pharmace; Pharmaceutical Sciences; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-SEP-1996; Project End 31-JAN-2004 Summary: Cardiovascular diseases which result from thrombosis of blood vessels are a leading cause of deaths. At present, the treatment is dissolution of the thrombus using a thrombolytic agent, namely a plasminogen activator (PA). Activation of plasminogen produces plasmin which degrades fibrin. Plasmin, however, also degrades clotting factors. Thrombolytic therapy which introduces systemic generation of plasmin, therefore, carries the risk of hemorrhage. Previously, we proposed a novel, pro-drug and triggered release approach which could permit targeted thrombolysis without the bleeding risk. The approach consists of two components: [i] a fibrin- targeting antibody linked to an anionic heparin (termed Ab-Hep); and [ii] a cation-modified PA (termed mPA+). These two components are linked via an electrostatic interaction. Since the used cations are small, m-PA+ would retain its catalytic activity. This activity, however, would be inhibited after binding to Ab-Hep due to blockage of the PA's active site by the appended macromolecules. Since protamine is a clinical heparin- binding antidote, it can be used safely to trigger the release of m-PA+ from the Ab-Hep-m-PA+ complex. Thus, the approach would permit injection of a fibrin-targeting but inactive PA drug (thereby alleviating the bleeding risk by aborting systemic generation of plasmin), and subsequently a triggered release of the active m-PA+ in close proximity of a fibrin deposit. Although it was a brand new project with minimal data, the previous application received full support from NIH shortly after submission based on its scientific merits and clinical significance. For reasons not clearly stated, however, the overall grant period was cut by NIH from 4 to 3 years. Despite being handicapped by a shortened time for renewal, our group has made remarkable progress and outstanding productivity. In a short 2-year period, 20 manuscripts and 10 abstracts have been published or submitted. The in vitro feasibility of the project, particularly on the prodrug and triggered-release features, have been demonstrated in plasma. In this new application, we plan to build upon those promising findings and further establish the project. Our integrated specific aims are: [i] develop analytical methods essential to the project; [ii] produce the desired m-PA+ by biological or chemical means; [iii] produce the Ab-Hep conjugates; [iv] test the functions of the final Ab-Hep-m-PA+ products in vitro; [v] examine their pharmacokinetic properties in rats; and [vi] test their functions in vivo using a rabbit jugular vein model and a clinically- simulated canine intracoronary thrombosis model. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CYSTITIS
URINE
ANTIPROLIFERATIVE
PEPTIDE
IN
INTERSTITIAL
Principal Investigator & Institution: Keay, Susan F.; Professor; Medicine; University of Maryland Balt Prof School Baltimore, Md 21201
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Timing: Fiscal Year 2002; Project Start 30-SEP-1997; Project End 31-MAR-2006 Summary: (Adapted from the Applicant's Abstract): Interstitial cystitis (IC) is a chronic bladder disease with often devastating effects on the lives of approximately 450,000 people in the U.S. The etiology of IC is unknown, and there is currently no reliably effective treatment. It is therefore important to continue to search for a cause of this debilitating disorder in order to systematically devise an effective therapy. The applicants report discovering two, specific and significant abnormalities in the urine of IC patients as compared to controls, which may be linked to the pathogenesis of this disease - the presence of a low molecular weight urine peptide that inhibits the proliferation of bladder epithelial cells in vitro (antiproliferative factor, or APF) and complex changes in the levels of specific urine epithelial cell growth factors, including significantly decreased urine levels of heparin-binding epidermal growth factor-like growth factor. Because a damaged bladder epithelium is a central finding in IC, it is possible that the APF and the growth factor abnormalities are directly involved in the pathogenesis of this disease. The proposed research is designed to determine the mechanisms by which the APF regulates bladder epithelial cell proliferation. In addition, specific effects of HPLC-purified APF on bladder epithelial cell physiology in vitro will be confirmed in vivo using a mouse model. The applicants suggest data from these studies should yield valuable information regarding the regulation of bladder epithelial proliferation and the pathogenesis of IC. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: VASCULAR DRUG DELIVERY Principal Investigator & Institution: Edelman, Elazer R.; Professor and Director; Health Sciences Technology; Massachusetts Institute of Technology Room E19-750 Cambridge, Ma 02139 Timing: Fiscal Year 2003; Project Start 01-AUG-1994; Project End 31-MAR-2007 Summary: (provided by applicant): NIH RO1 funding has enabled us to contribute to understanding the interplay between local drug delivery and arterial disease. We demonstrated the importance of directionality and site of drug administration, and arterial anatomic ultrastructure and disease. We completed a three-dimensional model of vascular drug delivery capable of predicting point-to-point drug concentrations throughout the arterial wall from delivery devices of any geometry and with any form of release. Having developed a rigorous quantitative framework for characterizing drug distribution, we will now correlate drug distribution with ultimate biological effect. Although we can predict where drug deposits, the importance of this next step, knowing where drug acts, cannot be overstated. The prevailing assumption is that biological effect maps directly with drug distribution, and while this may prove true for some drugs, the relationship between localization of drug and effect remains poorly understood. Preliminary data show that response to vasoactive compounds may depend more on cell interconnectivity than on local drug concentration. Moreover, response to many drugs may be affected by local injury, inflammatory processes or even changes in local mechanical state. Indeed, characterizing drug distribution may only be the starting point, i.e. one component of a vastly more complicated biological circuitry which ultimately determines how the distribution of biologic response evolves. In this revised grant application we now propose to therefore (a) examine whether drug distribution correlates with localization of ultimate biologic response, (b) delineate how cell interconnectivity and local tissue state modulate this correlation, (c) define how local pharmacokinetics dictates biologic response in vascular tissues, and (d) characterize how modifications of cell communications can enhance response to drug in injured
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tissue. Studies in cell culture in which cell connectivity, cell state, and drug administration can be easily defined and controlled, will be extended to whole arteries wherein local pharmacokinetics are defined, and in the myocardium, in which neither the mechanical nor pharmacokinetic factors influencing drug distribution are known. A range of drugs will be considered based on physicochemical properties, biological activity, clinical performance and mechanism of cell responsiveness. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: VISUALIZING SYNAPTIC CIRCUITRY IN THE RETINA Principal Investigator & Institution: Breakefield, Xandra O.; Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2004; Project Start 09-FEB-2004; Project End 31-JAN-2007 Summary: (provided by applicant): This research effort will focus on gene delivery of fluorescent proteins to neurons in the retina using HSV vectors in order to elucidate details of synaptic circuitry. In Aim 1, targeted gene delivery to specific neuronal subtypes will be undertaken by selective infection and by placing transgene expression under a cell specific promoter. The major heparin sulfate binding domain of the virion will be replaced with BDNF to increase infection of retinal ganglion cells that express high levels of the TrkB receptor on their cell surface. Transcriptional targeting will be undertaken by using the Thy-1 promoter, specifically expressed in this same neuronal population, either to drive expression of a reporter gene in HSV amplicon vectors, or by blocking expression of a reporter under a strong promoter in the vector through insertion of a IoxP-flanked stop codon between these sequences with subsequent infection of Thy-1-Cre transgenic mice to activate transgene expression. In Aim 2, we will attempt to label specific synaptic pathways by vector-mediated delivery of informative fluorescent fusion proteins. A GFP-tetanus toxin heavy chain fusion protein will be used to selectively label presynaptic contacts of the infected neurons. A BDNFGFP fusion protein will be used to label synaptic partners of the infected cell which are enriched for TrkB-BDNF receptors. Aim 3 will undertake labeling of synaptically connected neurons by expression of reporter genes carried in a replicating vector system intended to have minimal-to-no toxicity for the host neurons. Vector propagation will be controlled by placing an essential viral gene for ICP4 under a tight tetracycline regulated (tet-on) promoter in an HSV amplicon vector and coupling infection with a mutant helper virus deleted for this gene. Both vector and helper virus will express reporter genes, and co-infection with both will allow drug-dependent regulation of the levels of virions produced and passed onto synaptically connected neurons. The proposed targeting and labeling methods should be adaptable to other types of receptors and synaptic connections throughout the nervous system and should be very useful in dissecting and monitoring synaptic circuitry in living and fixed preparations. 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
3
Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.
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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 “heparin” (or synonyms) into the search box. This search gives you access to fulltext articles. The following is a sample of items found for heparin in the PubMed Central database: •
A heparin-binding synthetic peptide of heparin /heparan sulfateinteracting protein modulates blood coagulation activities. by Liu S, Zhou F, Hook M, Carson DD.; 1997 Mar 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19986
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A strategy for rapid sequencing of heparan sulfate and heparin saccharides. by Turnbull JE, Hopwood JJ, Gallagher JT.; 1999 Mar 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15832
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Activation of the calcium release channel (ryanodine receptor) by heparin and other polyanions is calcium dependent. by Bezprozvanny IB, Ondrias K, Kaftan E, Stoyanovsky DA, Ehrlich BE.; 1993 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=300932
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Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells. by Visentin GP, Ford SE, Scott JP, Aster RH.; 1994 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=293737
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Antithrombotic properties in rabbits of heparin and heparin fragments covalently coupled to human antithrombin III. by Mattsson C, Hoylaerts M, Holmer E, Uthne T, Collen D.; 1985 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=425441
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ASA or low-molecular-weight heparin in the initial management of acute ischemic stroke complicating atrial fibrillation? by Farquhar D.; 2001 Feb 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=80756
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Benefit of heparin in peripheral venous and arterial catheters: systematic review and meta-analysis of randomised controlled trials. by Randolph AG, Cook DJ, Gonzales CA, Andrew M.; 1998 Mar 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28499
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Binding to Heparan Sulfate or Heparin Enhances Neutrophil Responses to Interleukin 8. by Webb LM, Ehrengruber MU, Clark-Lewis I, Baggiolini M, Rot A.; 1993 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47095
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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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Characterization of a cDNA encoding the heparin and collagen binding domains of human thrombospondin. by Dixit VM, Hennessy SW, Grant GA, Rotwein P, Frazier WA.; 1986 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=386304
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Characterization of an amyloid beta precursor protein that binds heparin and contains tyrosine sulfate. by Schubert D, LaCorbiere M, Saitoh T, Cole G.; 1989 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=286848
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Cleavage of the antithrombin III binding site in heparin by heparinases and its implication in the generation of low molecular weight heparin. by Shriver Z, Sundaram M, Venkataraman G, Fareed J, Linhardt R, Biemann K, Sasisekharan R.; 2000 Sep 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27030
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Comparison of heparin and EDTA transport tubes for detection of cytomegalovirus in leukocytes by shell vial assay, pp65 antigenemia assay, and PCR. by Storch GA, Gaudreault-Keener M, Welby PC.; 1994 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=264108
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Conserved Surface-Exposed K/R-X-K/R Motifs and Net Positive Charge on Poxvirus Complement Control Proteins Serve as Putative Heparin Binding Sites and Contribute to Inhibition of Molecular Interactions with Human Endothelial Cells: a Novel Mechanism for Evasion of Host Defense. by Smith SA, Mullin NP, Parkinson J, Shchelkunov SN, Totmenin AV, Loparev VN, Srisatjaluk R, Reynolds DN, Keeling KL, Justus DE, Barlow PN, Kotwal GJ.; 2000 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112054
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Cost-utility of enoxaparin compared with unfractionated heparin in unstable coronary artery disease. by Nicholson T, McGuire A, Milne R.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59676
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Differences in the susceptibility of herpes simplex virus types 1 and 2 to modified heparin compounds suggest serotype differences in viral entry. by Herold BC, Gerber SI, Belval BJ, Siston AM, Shulman N.; 1996 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190219
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Effect of controlled adventitial heparin delivery on smooth muscle cell proliferation following endothelial injury. by Edelman ER, Adams DH, Karnovsky MJ.; 1990 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=53985
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Effect of Heparin and Heparin Fractions on Platelet Aggregation. by Salzman EW, Rosenberg RD, Smith MH, Lindon JN, Favreau L.; 1980 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=371340
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Effect of Heparin on the Inactivation of Serum Lipoprotein Lipase by the Liver in Unanesthetized Dogs. by Whayne TF Jr, Felts JM, Harris PA.; 1969 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=322346
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Enzymic Depolymerization of Macromolecular Heparin as a Factor in Control of Lipoprotein Lipase Activity. by Horner AA.; 1972 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=389795
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Evaluation of critical groups required for the binding of heparin to antithrombin. by Atha DH, Stephens AW, Rosenberg RD.; 1984 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=344757
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Fibrin monomer protects thrombin from inactivation by heparin-antithrombin III: implications for heparin efficacy. by Hogg PJ, Jackson CM.; 1989 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=287189
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Fractionation of heparin by chromatography on a tissue plasminogen activatorSepharose column. by Andrade-Gordon P, Strickland S.; 1990 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=53584
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Function of pulmonary M2 muscarinic receptors in antigen-challenged guinea pigs is restored by heparin and poly-L-glutamate. by Fryer AD, Jacoby DB.; 1992 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=443381
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Further Characterization of a Factor From Endotoxin-Treated Serum which Releases Histamine and Heparin from Mast Cells. by Hook WA, Snyderman R, Mergenhagen SE.; 1972 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=422462
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Growth-Inhibitory Effect of Heparin on Babesia Parasites. by Bork S, Yokoyama N, Ikehara Y, Kumar S, Sugimoto C, Igarashi I.; 2004 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=310193
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Hepatic uptake of a modified low molecular weight heparin in rats. by Stehle G, Friedrich EA, Sinn H, Wunder A, Harenberg J, Dempfle CE, Maier-Borst W, Heene DL.; 1992 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=443279
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Human tumor suppressor EXT gene family members EXTL1 and EXTL3 encode [alpha]1,4- N-acetylglucosaminyltransferases that likely are involved in heparan sulfate / heparin biosynthesis. by Kim BT, Kitagawa H, Tamura JI, Saito T, KuscheGullberg M, Lindahl U, Sugahara K.; 2001 Jun 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34642
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Identification and Characterization of Heparin Binding Regions of the Fim2 Subunit of Bordetella pertussis. by Geuijen CA, Willems RJ, Hoogerhout P, Puijk WC, Meloen RH, Mooi FR.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108189
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Identification of a Linear Heparin Binding Domain for Human Respiratory Syncytial Virus Attachment Glycoprotein G. by Feldman SA, Hendry RM, Beeler JA.; 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112745
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Identification of chondroitin sulfate E proteoglycans and heparin proteoglycans in the secretory granules of human lung mast cells. by Stevens RL, Fox CC, Lichtenstein LM, Austen KF.; 1988 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=279975
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Identification of Receptor and Heparin Binding Sites in Fibroblast Growth Factor 4 by Structure-Based Mutagenesis. by Bellosta P, Iwahori A, Plotnikov AN, Eliseenkova AV, Basilico C, Mohammadi M.; 2001 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87313
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Induction of mast cell proliferation, maturation, and heparin synthesis by the rat c-kit ligand, stem cell factor. by Tsai M, Takeishi T, Thompson H, Langley KE, Zsebo KM, Metcalfe DD, Geissler EN, Galli SJ.; 1991 Jul 15; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=52087
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Inhibition of chymotrypsin by heparin cofactor II. by Church FC, Noyes CM, Griffith MJ.; 1985 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=390730
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Inhibition of smooth muscle cell proliferation in injured rat arteries. Interaction of heparin with basic fibroblast growth factor. by Lindner V, Olson NE, Clowes AW, Reidy MA.; 1992 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=443269
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Inhibitory Effect of Heparin on Gentamicin Concentrations in Blood. by Regamey C, Schaberg D, Kirby WM.; 1972 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=444216
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Interaction of antithrombin III with bovine aortic segments. Role of heparin in binding and enhanced anticoagulant activity. by Stern D, Nawroth P, Marcum J, Handley D, Kisiel W, Rosenberg R, Stern K.; 1985 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=423436
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Involvement of cell surface heparin sulfate in the binding of lipoprotein lipase to cultured bovine endothelial cells. by Shimada K, Gill PJ, Silbert JE, Douglas WH, Fanburg BL.; 1981 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=370886
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Isolation and Characterization of Heparin from Human Lung. by Metcalfe DD, Lewis RA, Silbert JE, Rosenberg RD, Wasserman SI, Austen KF.; 1979 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=371305
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Isolation of osteogenin, an extracellular matrix-associated, bone-inductive protein, by heparin affinity chromatography. by Sampath TK, Muthukumaran N, Reddi AH.; 1987 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=299239
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Isolation of rabbit reticulocyte initiation factors by means of heparin bound to sepharose. by Waldman AA, Marx G, Goldstein J.; 1975 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=432756
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Lipoprotein lipaseBethesda: a single amino acid substitution (Ala-176----Thr) leads to abnormal heparin binding and loss of enzymic activity. by Beg OU, Meng MS, Skarlatos SI, Previato L, Brunzell JD, Brewer HB Jr, Fojo SS.; 1990 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=53923
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Low-dose heparin versus full-dose heparin with high-dose aprotinin during cardiopulmonary bypass. A preliminary report. by von Segesser LK, Garcia E, Turina MI.; 1993; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325049
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Low-molecular-weight heparin and abciximab for thrombo-occlusive saphenous vein graft disease. Report of 2 cases. by Yaryura R, Doucet J, Mathur VS.; 1997; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325487
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Mechanism of inhibitory effect of dextran sulfate and heparin on replication of human immunodeficiency virus in vitro. by Baba M, Pauwels R, Balzarini J, Arnout J, Desmyter J, De Clercq E.; 1988 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=281919
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Modulation of heparin cofactor II activity by histidine-rich glycoprotein and platelet factor 4. by Tollefsen DM, Pestka CA.; 1985 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=423524
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Multiple functional domains of the heparin molecule. by Oosta GM, Gardner WT, Beeler DL, Rosenberg RD.; 1981 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=319896
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Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome. by Manuelian T, Hellwage J, Meri S, Caprioli J, Noris M, Heinen S, Jozsi M, Neumann HP, Remuzzi G, Zipfel PF.; 2003 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=152934
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N-desulfated/acetylated heparin ameliorates the progression of renal disease in rats with subtotal renal ablation. by Purkerson ML, Tollefsen DM, Klahr S.; 1988 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=442474
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On the binding of tumor necrosis factor (TNF) to heparin and the release in vivo of the TNF-binding protein I by heparin. by Lantz M, Thysell H, Nilsson E, Olsson I.; 1991 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=295793
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Oral heparin results in the appearance of heparin fragments in the plasma of rats. by Larsen AK, Lund DP, Langer R, Folkman J.; 1986 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=323427
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Preferential Self-Association of Basic Fibroblast Growth Factor is Stabilized by Heparin during Receptor Dimerization and Activation. by Venkataraman G, Sasisekharan V, Herr AB, Ornitz DM, Waksman G, Cooney CL, Langer R, Sasisekharan R.; 1996 Jan 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40145
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Proposed heparin binding site in antithrombin based on arginine 47. A new variant Rouen-II, 47 Arg to Ser. by Borg JY, Owen MC, Soria C, Soria J, Caen J, Carrell RW.; 1988 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=329661
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Purification of genomic DNA using heparin to remove nuclear proteins. by Koller CA, Kohli V.; 1993 Jun 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=309703
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Receptor-like function of heparin in the binding and uptake of neutral lipids. by Bosner MS, Gulick T, Riley DJ, Spilburg CA, Lange LG 3rd.; 1988 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=282206
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Resolution of Experimental Pulmonary Emboli with Heparin and Streptokinase in Different Dosage Regimens. by Cade JF, Hirsh J, Regoeczi E, Gent M, Buchanan MR, Hynes DM.; 1974 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=301618
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Response of Plasma Histaminase Activity to Small Doses of Heparin in Normal Subjects and Patients with Hyperlipoproteinemia. by Baylin SB, Beaven MA, Krauss RM, Keiser HR.; 1973 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=302481
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Role of cysteines in Plasmodium falciparum circumsporozoite protein: Interactions with heparin can rejuvenate inactive protein mutants. by Rathore D, McCutchan TF.; 2000 Jul 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26982
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Sequencing of 3-O sulfate containing heparin decasaccharides with a partial antithrombin III binding site. by Shriver Z, Raman R, Venkataraman G, Drummond K, Turnbull J, Toida T, Linhardt R, Biemann K, Sasisekharan R.; 2000 Sep 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27029
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Structural Determinants of the Capacity of Heparin to Inhibit the Formation of the Human Amplification C3 Convertase. by Kazatchkine MD, Fearon DT, Metcalfe DD, Rosenberg RD, Austen KF.; 1981 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=371591
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Structural specificity of heparin binding in the fibroblast growth factor family of proteins. by Raman R, Venkataraman G, Ernst S, Sasisekharan V, Sasisekharan R.; 2003 Mar 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151345
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Structure-function relationships of heparin species. by Rosenberg RD, Armand G, Lam L.; 1978 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=392714
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The addition of endothelial cell growth factor and heparin to human umbilical vein endothelial cell cultures decreases plasminogen activator inhibitor-1 expression. by Konkle BA, Ginsburg D.; 1988 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=303551
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The Interaction of Heparin with an Apoprotein of Human Very Low Density Lipoprotein. by Shelburne FA, Quarfordt SH.; 1977 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=372443
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The nucleotide sequence of rat heparin binding growth factor 1 (HBGF-1). by Goodrich SP, Yan GC, Bahrenburg K, Mansson PE.; 1989 Apr 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=317675
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The use of heparin as a simple cost-effective means of controlling background in nucleic acid hybridization procedures. by Singh L, Jones KW.; 1984 Jul 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=320019
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Tissue culture adaptation of foot-and-mouth disease virus selects viruses that bind to heparin and are attenuated in cattle. by Sa-Carvalho D, Rieder E, Baxt B, Rodarte R, Tanuri A, Mason PW.; 1997 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191746
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 heparin, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “heparin” (or synonyms) 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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into the search box, and click “Go.” The following is the type of output you can expect from PubMed for heparin (hyperlinks lead to article summaries): •
A longitudinal study of maternal dose response to low molecular weight heparin in pregnancy. Author(s): Sephton V, Farquharson RG, Topping J, Quenby SM, Cowan C, Back DJ, Toh CH. Source: Obstetrics and Gynecology. 2003 June; 101(6): 1307-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12798541
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A positive in vitro assay is required to diagnose heparin-induced thrombocytopenia. Author(s): Kottke-Marchant K, Bontempo FA. Source: The Medical Clinics of North America. 2003 November; 87(6): 1215-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14680302
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A randomised comparison of a foot pump and low-molecular-weight heparin in the prevention of deep-vein thrombosis after total knee replacement. Author(s): Hidalgo-Ovejero AM, Garcia-Mata S, Martinez-Grande M, Otermin-Maya I. Source: The Journal of Bone and Joint Surgery. British Volume. 2003 May; 85(4): 619-20; Author Reply 620. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12793576
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Acute cardiorespiratory collapse from heparin: a consequence of heparin-induced thrombocytopenia. Author(s): Mims MP, Manian P, Rice L. Source: European Journal of Haematology. 2004 May; 72(5): 366-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15059074
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Additive thrombin inhibition by fast moving heparin and dermatan sulfate explains the anticoagulant effect of sulodexide, a natural mixture of glycosaminoglycans. Author(s): Cosmi B, Cini M, Legnani C, Pancani C, Calanni F, Coccheri S. Source: Thrombosis Research. 2003 March 15; 109(5-6): 333-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12818259
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Administration of eptifibatide to acute coronary syndrome patients receiving enoxaparin or unfractionated heparin: effect on platelet function and thrombus formation. Author(s): Lev EI, Hasdai D, Scapa E, Tobar A, Assali A, Lahav J, Battler A, Badimon JJ, Kornowski R. Source: Journal of the American College of Cardiology. 2004 March 17; 43(6): 966-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15028351
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Allergy to heparin: a new in vitro diagnostic technique. Author(s): Caballero MR, Fernandez-Benitez M. Source: Allergologia Et Immunopathologia. 2003 November-December; 31(6): 324-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14670287
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Analysis of heparin binding to human leukocytes using a fluorescein-5isothiocyanate labeled heparin fragment. Author(s): Harenberg J, Malsch R, Piazolo L, Huhle G, Heene DL. Source: Cytometry : the Journal of the Society for Analytical Cytology. 1996 January 1; 23(1): 59-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14650442
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Anticoagulation in hospitalized patients with renal insufficiency: a comparison of bleeding rates with unfractionated heparin vs enoxaparin. Author(s): Thorevska N, Amoateng-Adjepong Y, Sabahi R, Schiopescu I, Salloum A, Muralidharan V, Manthous CA. Source: Chest. 2004 March; 125(3): 856-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15006942
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Anticoagulation of pregnant women with mechanical heart valves using lowmolecular-weight heparin. Author(s): Bauersachs R, Lindhoff-Last E. Source: Archives of Internal Medicine. 2003 December 8-22; 163(22): 2788-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14662636
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Anticoagulation strategies for patients undergoing percutaneous coronary intervention: unfractionated heparin, low-molecular-weight heparins, and direct thrombin inhibitors. Author(s): Kokolis S, Cavusoglu E, Clark LT, Marmur JD. Source: Progress in Cardiovascular Diseases. 2004 May-June; 46(6): 506-23. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15224257
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Anticoagulation with low-molecular-weight heparin in patients with heart diseases. Author(s): Bechtold H, Janssen D. Source: European Journal of Medical Research. 2004 April 30; 9(4): 186-98. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15210399
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Antimicrobial activities of heparin-binding peptides. Author(s): Andersson E, Rydengard V, Sonesson A, Morgelin M, Bjorck L, Schmidtchen A. Source: European Journal of Biochemistry / Febs. 2004 March; 271(6): 1219-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15009200
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Antiproliferative factor, heparin-binding epidermal growth factor-like growth factor, and epidermal growth factor in men with interstitial cystitis versus chronic pelvic pain syndrome. Author(s): Keay S, Zhang CO, Chai T, Warren J, Koch K, Grkovic D, Colville H, Alexander R. Source: Urology. 2004 January; 63(1): 22-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14751340
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Antithrombin and heparin may limit the activation of Protein C. Author(s): Macias W, Yan SB. Source: Acta Anaesthesiologica Scandinavica. 2004 March; 48(3): 385. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14982578
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Antithrombotic drugs for the treatment of heparin-induced thrombocytopenia. Author(s): Jeske WP, Walenga JM. Source: Methods in Molecular Medicine. 2004; 93: 61-82. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14733328
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Antithrombotic effects of DX-9065a, a direct factor Xa inhibitor: a comparative study in humans versus low molecular weight heparin. Author(s): Shimbo D, Osende J, Chen J, Robbins J, Shimoto Y, Kunitada S, Fuster V, Badimon JJ. Source: Thrombosis and Haemostasis. 2002 November; 88(5): 733-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12428086
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Anti-Xa activity with low-molecular-weight heparin, enoxaparin, during pregnancy in women with mechanical heart valves. Author(s): Izaguirre R, De La Pena A, Ramirez A, Cortina E, Huerta M, Salazar E. Source: Proc West Pharmacol Soc. 2002; 45: 127-8. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12434554
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Argatroban, a new treatment option for heparin-induced thrombocytopenia. Author(s): Cleveland KW. Source: Critical Care Nurse. 2003 December; 23(6): 61-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14692173
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Attenuation of rebound ischemia after discontinuation of heparin therapy by glycoprotein IIb/IIIa inhibition with eptifibatide in patients with acute coronary syndromes: observations from the platelet IIb/IIIa in unstable angina: receptor suppression using integrilin therapy (PURSUIT) trial. Author(s): Lauer MA, Houghtaling PL, Peterson JG, Granger CB, Bhatt DL, Sapp SK, Simoons ML, Harrington RA, Topol EJ, Lincoff AM; Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) Trial Investigators. Source: Circulation. 2001 December 4; 104(23): 2772-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11733393
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Bacterial biofilm formation on urologic devices and heparin coating as preventive strategy. Author(s): Tenke P, Riedl CR, Jones GL, Williams GJ, Stickler D, Nagy E. Source: International Journal of Antimicrobial Agents. 2004 March; 23 Suppl 1: S67-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15037330
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Bacterial infection in cirrhosis impairs coagulation by a heparin effect: a prospective study. Author(s): Montalto P, Vlachogiannakos J, Cox DJ, Pastacaldi S, Patch D, Burroughs AK. Source: Journal of Hepatology. 2002 October; 37(4): 463-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12217599
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Bedside coagulometry during intravenous heparin therapy after coronary angioplasty. Author(s): Schroeder AP, Knudsen LL, Husted SE, Knudsen L, Ingerslev J. Source: Journal of Thrombosis and Thrombolysis. 2001 October; 12(2): 157-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11729367
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Benefit and risk of heparin for maintaining peripheral venous catheters in neonates: a placebo-controlled trial. Author(s): Klenner AF, Fusch C, Rakow A, Kadow I, Beyersdorff E, Eichler P, Wander K, Lietz T, Greinacher A. Source: The Journal of Pediatrics. 2003 December; 143(6): 741-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14657819
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Benefit-risk assessment of treatments for heparin-induced thrombocytopenia. Author(s): Messmore H, Jeske W, Wehrmacher W, Walenga J. Source: Drug Safety : an International Journal of Medical Toxicology and Drug Experience. 2003; 26(9): 625-41. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12814331
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Bilateral posterior segment intraocular hemorrhage after heparin therapy in a diabetic patient. Author(s): Levartovsky S, Reisin I, Reisin L, Leibowitz E. Source: Isr Med Assoc J. 2003 January; 5(1): 77. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12592970
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Bilateral posterior segment intraocular hemorrhage in a diabetic patients after therapy with heparin. Author(s): Levartovsky S, Reisin I, Reisin L, Leibowitz E. Source: Isr Med Assoc J. 2003 August; 5(8): 605. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12929308
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Bimodal expression of heparin-binding EGF-like growth factor in colonic neoplasms. Author(s): Ito Y, Higashiyama S, Takeda T, Okada M, Matsuura N. Source: Anticancer Res. 2001 March-April; 21(2B): 1391-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11396220
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Biological and clinical features of low-molecular-weight heparin-induced thrombocytopenia. Author(s): Gruel Y, Pouplard C, Nguyen P, Borg JY, Derlon A, Juhan-Vague I, Regnault V, Samama M; French Heparin-Induced Thrombocytopenia Study Group. Source: British Journal of Haematology. 2003 June; 121(5): 786-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12780795
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Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. Author(s): Lincoff AM, Bittl JA, Harrington RA, Feit F, Kleiman NS, Jackman JD, Sarembock IJ, Cohen DJ, Spriggs D, Ebrahimi R, Keren G, Carr J, Cohen EA, Betriu A, Desmet W, Kereiakes DJ, Rutsch W, Wilcox RG, de Feyter PJ, Vahanian A, Topol EJ; REPLACE-2 Investigators. Source: Jama : the Journal of the American Medical Association. 2003 February 19; 289(7): 853-63. Erratum In: Jama. 2003 April 2; 289(13): 1638. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12588269
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Bivalirudin as a replacement for unfractionated heparin in unstable angina/non-STelevation myocardial infarction: observations from the TIMI 8 trial. The Thrombolysis in Myocardial Infarction. Author(s): Antman EM, McCabe CH, Braunwald E. Source: American Heart Journal. 2002 February; 143(2): 229-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11835024
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Bivalirudin as alternative to both danaparoid and heparin in off-pump coronary artery bypass grafting. Author(s): Baciewicz FA Jr. Source: The Journal of Thoracic and Cardiovascular Surgery. 2003 December; 126(6): 2108-9; Author Reply 2109. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14688746
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Bivalirudin versus heparin and protamine in off-pump coronary artery bypass surgery. Author(s): Merry AF, Raudkivi PJ, Middleton NG, McDougall JM, Nand P, Mills BP, Webber BJ, Frampton CM, White HD. Source: The Annals of Thoracic Surgery. 2004 March; 77(3): 925-31; Discussion 931. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14992900
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Bivalirudin with planned or provisional abciximab versus low-dose heparin and abciximab during percutaneous coronary revascularization: results of the Comparison of Abciximab Complications with Hirulog for Ischemic Events Trial (CACHET). Author(s): Lincoff AM, Kleiman NS, Kottke-Marchant K, Maierson ES, Maresh K, Wolski KE, Topol EJ. Source: American Heart Journal. 2002 May; 143(5): 847-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12040347
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Bivalirudin, a bivalent, thrombin specific anticoagulant as an alternative to heparin in interventional procedures as an alternative to heparin in interventional procedures. Author(s): Chew DP. Source: Hamostaseologie. 2002 August; 22(3): 60-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12215763
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Bleeding and thrombosis in high-risk renal transplantation candidates using heparin. Author(s): Mathis AS, Dave N, Shah NK, Friedman GS. Source: The Annals of Pharmacotherapy. 2004 April; 38(4): 537-43. Epub 2004 February 06. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14766999
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Bleeding following coronary surgery after preoperative low-molecular-weight heparin. Author(s): Myhre U, Stenseth R, Karevold A, Bjella L, Lingaas PS, Olsen PO, Haaverstad R, Kirkeby-Garstad I, Levang OW. Source: Asian Cardiovascular & Thoracic Annals. 2004 March; 12(1): 3-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14977732
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Bone marrow biopsy related haemorrhage and low molecular weight heparin. Author(s): Morley NJ, Makris M. Source: British Journal of Haematology. 2003 November; 123(3): 562. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14617026
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Building a better heparin. Author(s): Caughey GH. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 February; 28(2): 129-32. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12540478
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Can heparin prevent adverse pregnancy outcome? Author(s): Romero R, Dekker G, Kupferminc M, Saade G, Livingston J, Peaceman A, Mazor M, Yoon BH, Espinoza J, Chaiworapongsa T, Gomez R, Arias F, Sibai B. Source: J Matern Fetal Neonatal Med. 2002 July;12(1):1-8. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12422903
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Can low molecular weight heparin replace unfractionated heparin during peripheral arterial reconstruction? An open label prospective randomized controlled trial. Author(s): Norgren L; Swedish EnoxaVasc Study Group. Source: Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter. 2004 May; 39(5): 977-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15111848
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Cardiac surgical patients exposed to heparin-bonded circuits develop less postoperative cerebral dysfunction than patients exposed to non-heparin-bonded circuits. Author(s): Mongero LB, Beck JR, Manspeizer HE, Heyer EJ, Lee K, Spanier TA, Smith CR. Source: Perfusion. 2001 March; 16(2): 107-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11334193
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Case reports on emergency treatment of cardiovascular syndromes through heparinmediated low-density lipoprotein/fibrinogen precipitation: a new approach to augment cerebral and myocardial salvage. Author(s): Jaeger BR, Kreuzer E, Knez A, Leber A, Uberfuhr P, Borner M, Milz P, Reichart B, Seidel D. Source: Therapeutic Apheresis : Official Journal of the International Society for Apheresis and the Japanese Society for Apheresis. 2002 October; 6(5): 394-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12423536
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Catheter-drawn blood cultures: is withdrawing the heparin lock beneficial? Author(s): Everts R, Harding H. Source: Pathology. 2004 April; 36(2): 170-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15203754
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Changes in blood viscosity by heparin and argatroban. Author(s): Hitosugi M, Niwa M, Takatsu A. Source: Thrombosis Research. 2001 December 1; 104(5): 371-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11738080
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Changes in hemostasis during pediatric heart surgery: impact of a biocompatible heparin-coated perfusion system. Author(s): Jensen E, Andreasson S, Bengtsson A, Berggren H, Ekroth R, Larsson LE, Ouchterlony J. Source: The Annals of Thoracic Surgery. 2004 March; 77(3): 962-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14992907
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Characterization of growth factor-binding structures in heparin/heparan sulfate using an octasaccharide library. Author(s): Ashikari-Hada S, Habuchi H, Kariya Y, Itoh N, Reddi AH, Kimata K. Source: The Journal of Biological Chemistry. 2004 March 26; 279(13): 12346-54. Epub 2004 January 05. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14707131
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Chondroitin sulfate of appican, the proteoglycan form of amyloid precursor protein, produced by C6 glioma cells interacts with heparin-binding neuroregulatory factors. Author(s): Umehara Y, Yamada S, Nishimura S, Shioi J, Robakis NK, Sugahara K. Source: Febs Letters. 2004 January 16; 557(1-3): 233-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14741373
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Comparing methods of establishing the aPTT therapeutic range of heparin. Author(s): Liepman CI, Koerber JM, Mattson JC, Westley SJ, Smythe MA. Source: The Annals of Pharmacotherapy. 2003 June; 37(6): 794-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12773063
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Comparison of benefits and complications of hirudin versus heparin for patients with acute coronary syndromes undergoing early percutaneous coronary intervention. Author(s): Roe MT, Granger CB, Puma JA, Hellkamp AS, Hochman JS, Ohman EM, White HD, Van de Werf F, Armstrong PW, Ellis SG, Califf RM, Topol EJ. Source: The American Journal of Cardiology. 2001 December 15; 88(12): 1403-6, A6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11741559
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Comparison of efficacy, safety, and cost of low-molecular-weight heparin with continuous-infusion unfractionated heparin for initiation of anticoagulation after mechanical prosthetic valve implantation. Author(s): Fanikos J, Tsilimingras K, Kucher N, Rosen AB, Hieblinger MD, Goldhaber SZ. Source: The American Journal of Cardiology. 2004 January 15; 93(2): 247-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14715362
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Comparison of initial efficacy and long-term follow-up of heparin-coated Jostent with conventional NIR stent. Author(s): Semiz E, Ermis C, Yalcinkaya S, Sancaktar O, Deger N. Source: Japanese Heart Journal. 2003 November; 44(6): 889-98. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14711184
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Comparison of outcomes up to six months of Heparin-Coated with noncoated stents after percutaneous coronary intervention for acute myocardial infarction. Author(s): Lev EI, Assali AR, Teplisky I, Rechavia E, Hasdai D, Sela O, Shor N, Battler A, Kornowski R. Source: The American Journal of Cardiology. 2004 March 15; 93(6): 741-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15019881
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Comparison of serum and heparin-plasma samples in different generations of dimension troponin I assay. Author(s): Dorizzi RM, Caputo M, Ferrari A, Lippa L, Rizzotti P. Source: Clinical Chemistry. 2002 December; 48(12): 2294-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12446498
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Connective tissue activation XXXVIII: heparin/heparanase activity of human platelets resides in a high molecular weight protein, not in connective tissue activating peptide III. Author(s): Castor CW, Kotlyar A, Edwards BE. Source: The Journal of Rheumatology. 2002 November; 29(11): 2337-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12415589
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Continuous administration of heparin in patients with deep vein thrombosis can increase plasma levels of diamine oxidase. Author(s): Klocker J, Perkmann R, Klein-Weigel P, Morsdorf G, Drasche A, Klingler A, Fraedrich G, Schwelberger HG. Source: Vascular Pharmacology. 2004 January; 40(6): 293-300. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15063833
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Cost analysis of "bridging therapy" with low-molecular-weight heparin versus unfractionated heparin during temporary interruption of chronic anticoagulation. Author(s): Amorosi SL, Tsilimingras K, Thompson D, Fanikos J, Weinstein MC, Goldhaber SZ. Source: The American Journal of Cardiology. 2004 February 15; 93(4): 509-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14969639
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Cost-effectiveness analysis of enoxaparin versus unfractionated heparin in patients with acute coronary syndrome in Poland: modelling study from the hospital perspective. Author(s): Orlewska E, Budaj A, Tereszkowski-Kaminski D. Source: Pharmacoeconomics. 2003; 21(10): 737-48. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12828495
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Costs and clinical outcomes associated with low-molecular-weight heparin vs unfractionated heparin for perioperative bridging in patients receiving long-term oral anticoagulant therapy. Author(s): Spyropoulos AC, Frost FJ, Hurley JS, Roberts M. Source: Chest. 2004 May; 125(5): 1642-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15136371
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Danaparoid for heparin-induced thrombocytopenia: an analysis of treatment failures. Author(s): Kodityal S, Manhas AH, Udden M, Rice L. Source: European Journal of Haematology. 2003 August; 71(2): 109-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12890149
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Deep venous thrombosis, myocardial infarction, and occlusion of vascular access associated with heparin-induced thrombocytopenia in a diabetic hemodialysis patient. Author(s): Igaki N, Matsuda T, Yatani H, Kawaguchi T, Kida A, Yanase K, Moriguchi R, Sakai M, Tamada F, Goto T. Source: Clinical and Experimental Nephrology. 2003 December; 7(4): 306-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14712362
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Deep venous thrombosis: outpatient therapy with low-molecular-weight heparin. Author(s): Tapson VF. Source: Manag Care. 1999 December; 8 Suppl: 2-6. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11729399
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Defining the scope of evidence-based practice for low-molecular-weight heparin therapy in high-risk patients with unstable angina and non-ST-elevation myocardial infarction. Author(s): Ferguson JJ. Source: Clin Cardiol. 2002 November; 25(11 Suppl 1): I16-22. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12428815
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Delayed systemic reactions with flare-ups of previously negative intradermal skin tests to heparin. Author(s): Garcia Robaina JC, Sanchez Machin I, Fernandez-Caldas E, de la Torre Morin F. Source: Allergy. 2003 July; 58(7): 685-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12823138
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Delayed-onset heparin-induced thrombocytopenia. Author(s): Kane R. Source: Annals of Internal Medicine. 2003 November 4; 139(9): 790. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14597468
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Delayed-onset heparin-induced thrombocytopenia. Author(s): De Palma JR. Source: Annals of Internal Medicine. 2003 November 4; 139(9): 790; Author Reply 790-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14597467
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Dendritic polyglycerol sulfates as new heparin analogues and potent inhibitors of the complement system. Author(s): Turk H, Haag R, Alban S. Source: Bioconjugate Chemistry. 2004 January-February; 15(1): 162-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14733596
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Development of oral heparin therapy for prophylaxis and treatment of deep venous thrombosis. Author(s): Money SR, York JW. Source: Cardiovascular Surgery (London, England). 2001 June; 9(3): 211-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11336843
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Differential expression of heparin-binding EGF-like growth factor (HB-EGF) mRNA in normal human keratinocytes induced by a variety of natural and synthetic retinoids. Author(s): Yoshimura K, Uchida G, Okazaki M, Kitano Y, Harii K. Source: Experimental Dermatology. 2003; 12 Suppl 2: 28-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14756521
Studies
79
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Differential tyrosine phosphorylation of fibroblast growth factor (FGF) receptor-1 and receptor proximal signal transduction in response to FGF-2 and heparin. Author(s): Lundin L, Ronnstrand L, Cross M, Hellberg C, Lindahl U, Claesson-Welsh L. Source: Experimental Cell Research. 2003 July 1; 287(1): 190-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12799194
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Diffuse alopecia in a hemodialysis patient caused by a low-molecular-weight heparin, tinzaparin. Author(s): Sarris E, Tsele E, Bagiatoudi G, Salpigidis K, Stavrianaki D, Kaklamanis L, Siakotos M. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2003 May; 41(5): E15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12778433
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Direct stenting with 3000 i.u. heparin. Author(s): Caussin C, Fsihi A, Ohanessian A, Jacq L, Rahal S, Lancelin B. Source: International Journal of Cardiovascular Interventions. 2003; 5(4): 206-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14630564
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Does my patient have heparin-induced thrombocytopenia? Author(s): King JE. Source: Nursing. 2003 November; 33(11): 24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14650380
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Does negative heparin-platelet factor 4 enzyme-linked immunosorbent assay effectively exclude heparin-induced thrombocytopenia? Author(s): Fohlen-Walter A, De Maistre E, Mulot A, Marchand-Arvier M, Lecompte T. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 August; 1(8): 1844-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12911605
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Don't miss HIT (heparin induced thrombocytopenia). Author(s): Horner BM, Myers SR. Source: Burns : Journal of the International Society for Burn Injuries. 2004 February; 30(1): 88-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14693093
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Dosing and timing of low-molecular-weight heparin thromboprophylaxis in total hip arthroplasty. Author(s): Colwell CW Jr. Source: Orthopedics. 2003 November; 26(11): 1155-61; Quiz 1162-3. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14627117
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Drug treatment of ulcerative colitis: unfractionated heparin, low molecular weight heparins and beyond. Author(s): Malhotra S, Bhasin D, Shafiq N, Pandhi P. Source: Expert Opinion on Pharmacotherapy. 2004 February; 5(2): 329-34. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14996629
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Drugs for the prevention and treatment of thrombosis in patients with heparininduced thrombocytopenia. Author(s): Lubenow N, Greinacher A. Source: American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions. 2001; 1(6): 429-43. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14728002
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Early onset of heparin-induced thrombocytopenia with thrombosis after open heart surgery: importance of an early diagnosis and Lepirudin treatment. Author(s): Paparella D, Galeone A, Micelli M, Memmola C, de Luca Tupputi Schinosa L. Source: Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis. 2004 March; 15(2): 183-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15091006
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Effect of complement inhibition and heparin coating on artificial surface-induced leukocyte and platelet activation. Author(s): Lappegard KT, Fung M, Bergseth G, Riesenfeld J, Lambris JD, Videm V, Mollnes TE. Source: The Annals of Thoracic Surgery. 2004 March; 77(3): 932-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14992902
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Effect of intravenous heparin administration on duration of hospitalization. Author(s): Dunn A, Bioh D, Beran M, Capasso M, Siu A. Source: Mayo Clinic Proceedings. 2004 February; 79(2): 159-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14959908
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Effect of phenprocoumon on monitoring of lepirudin, argatroban, melagatran and unfractionated heparin with the PiCT method. Author(s): Fenyvesi T, Jorg I, Harenberg J. Source: Pathophysiology of Haemostasis and Thrombosis. 2002 July-August; 32(4): 1749. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12759518
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Effect of single dose of intravenous heparin on plasma levels of angiogenic growth factors. Author(s): East MA, Landis DI, Thompson MA, Annex BH. Source: The American Journal of Cardiology. 2003 May 15; 91(10): 1234-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12745108
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Effect of unfractionated heparin and a low molecular weight heparin (enoxaparin) on coagulant activity of cultured human endothelial cells. Author(s): Martinez-Sales V, Vila V, Reganon E, Oms JG, Aznar J. Source: Haematologica. 2003 June; 88(6): 694-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12801846
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Effectiveness of bivalirudin as a replacement for heparin during cardiopulmonary bypass in patients undergoing coronary artery bypass grafting. Author(s): Koster A, Spiess B, Chew DP, Krabatsch T, Tambeur L, DeAnda A, Hetzer R, Kuppe H, Smedira NG, Lincoff AM. Source: The American Journal of Cardiology. 2004 February 1; 93(3): 356-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14759391
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Effectivity of heparin in assisted reproduction. Author(s): Fiedler K, Wurfel W. Source: European Journal of Medical Research. 2004 April 30; 9(4): 207-14. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15210401
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Effects of heparin and related molecules upon neutrophil aggregation and elastase release in vitro. Author(s): Brown RA, Lever R, Jones NA, Page CP. Source: British Journal of Pharmacology. 2003 June; 139(4): 845-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12813008
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Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-Segment elevation acute coronary syndromes: a systematic overview. Author(s): Petersen JL, Mahaffey KW, Hasselblad V, Antman EM, Cohen M, Goodman SG, Langer A, Blazing MA, Le-Moigne-Amrani A, de Lemos JA, Nessel CC, Harrington RA, Ferguson JJ, Braunwald E, Califf RM. Source: Jama : the Journal of the American Medical Association. 2004 July 7; 292(1): 8996. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15238596
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Emergency department-based atrial fibrillation treatment strategy with lowmolecular-weight heparin. Author(s): Wakai A. Source: Annals of Emergency Medicine. 2003 May; 41(5): 757-8; Author Reply 758-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12744251
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Emergency management of hemorrhagic complications in the era of glycoprotein IIb/IIIa receptor antagonists, clopidogrel, low molecular weight heparin, and thirdgeneration fibrinolytic agents. Author(s): Schroeder WS, Gandhi PJ. Source: Current Cardiology Reports. 2003 July; 5(4): 310-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12801451
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Endogenous heparin activity deficiency: the 'missing link' in atherogenesis? Author(s): Engelberg H. Source: Atherosclerosis. 2001 December; 159(2): 253-60. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11730804
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Endothelial P-selectin as a target of heparin action in experimental melanoma lung metastasis. Author(s): Ludwig RJ, Boehme B, Podda M, Henschler R, Jager E, Tandi C, Boehncke WH, Zollner TM, Kaufmann R, Gille J. Source: Cancer Research. 2004 April 15; 64(8): 2743-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15087389
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Enoxaparin and unfractionated heparin in acute coronary syndromes without STsegment elevation. Author(s): Cohen M, Antman EM. Source: Thrombosis and Haemostasis. 2002 November; 88(5): 884-6; 886-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12428118
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Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. Author(s): Ferguson JJ, Califf RM, Antman EM, Cohen M, Grines CL, Goodman S, Kereiakes DJ, Langer A, Mahaffey KW, Nessel CC, Armstrong PW, Avezum A, Aylward P, Becker RC, Biasucci L, Borzak S, Col J, Frey MJ, Fry E, Gulba DC, Guneri S, Gurfinkel E, Harrington R, Hochman JS, Kleiman NS, Leon MB, Lopez-Sendon JL, Pepine CJ, Ruzyllo W, Steinhubl SR, Teirstein PS, Toro-Figueroa L, White H; SYNERGY Trial Investigators. Source: Jama : the Journal of the American Medical Association. 2004 July 7; 292(1): 4554. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15238590
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Evaluation of a new point of care heparin test for cardiopulmonary bypass: the TAS heparin management test. Author(s): Wallock M, Jeske WP, Bakhos M, Walenga JM. Source: Perfusion. 2001 March; 16(2): 147-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11334198
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Exaggerated postprandial lipaemia and lower post-heparin lipoprotein lipase activity in middle-aged men. Author(s): Jackson KG, Knapper-Francis JM, Morgan LM, Webb DH, Zampelas A, Williams CM. Source: Clinical Science (London, England : 1979). 2003 October; 105(4): 457-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12812518
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Exaggerated response to heparin in a post-operative renal transplant recipient with lupus anticoagulant undergoing plasmapheresis. Author(s): Mathis AS, Shah NK. Source: Transplantation. 2004 March 27; 77(6): 957-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15077052
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Excretion of low molecular weight heparin in human milk. Author(s): Richter C, Sitzmann J, Lang P, Weitzel H, Huch A, Huch R. Source: British Journal of Clinical Pharmacology. 2001 December; 52(6): 708-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11736885
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Failure of low molecular-weight heparin in the prevention of prosthetic mitral valve thrombosis during pregnancy: case report and a review of options for anticoagulation. Author(s): Mahesh B, Evans S, Bryan AJ. Source: J Heart Valve Dis. 2002 September; 11(5): 745-50. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12358414
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Fibrillin-1 and -2 contain heparin-binding sites important for matrix deposition and that support cell attachment. Author(s): Ritty TM, Broekelmann TJ, Werneck CC, Mecham RP. Source: The Biochemical Journal. 2003 October 15; 375(Pt 2): 425-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12837131
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Fibroblast growth factor-2 binds to small heparin-derived oligosaccharides and stimulates a sustained phosphorylation of p42/44 mitogen-activated protein kinase and proliferation of rat mammary fibroblasts. Author(s): Delehedde M, Lyon M, Gallagher JT, Rudland PS, Fernig DG. Source: The Biochemical Journal. 2002 August 15; 366(Pt 1): 235-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12000311
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Filter anticoagulation is accomplished through the administration of dilute heparin. Author(s): Michaud D, Komant T, Pfefferle P. Source: Dynamics. 2000 Winter; 11(4): 10. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11982053
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Fixed-dose versus adjusted-dose low molecular weight heparin for the initial treatment of patients with deep venous thrombosis. Author(s): Harenberg J. Source: Current Opinion in Pulmonary Medicine. 2002 September; 8(5): 383-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12172440
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Fixed-dose, body weight-independent subcutaneous low molecular weight heparin Certoparin compared with adjusted-dose intravenous unfractionated heparin in patients with proximal deep venous thrombosis. Author(s): Riess H, Koppenhagen K, Tolle A, Kemkes-Matthes B, Grave M, Patek F, Drexler M, Siemens HJ, Harenberg J, Weidinger G, Brom J, Haas S; TH-4 Study Group. Source: Thrombosis and Haemostasis. 2003 August; 90(2): 252-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12888872
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Fluctuations in levels of antiphospholipid antibodies and increased coagulation activation markers in normal and heparin-treated antiphospholipid syndrome pregnancies. Author(s): Donohoe S, Quenby S, Mackie I, Panal G, Farquharson R, Malia R, Kingdom J, Machin S. Source: Lupus. 2002; 11(1): 11-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11898913
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Fondaparinux as a novel therapeutic alternative in a patient with heparin allergy. Author(s): Maetzke J, Hinrichs R, Staib G, Scharffetter-Kochanek K. Source: Allergy. 2004 February; 59(2): 237-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14763948
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Fondaparinux sodium lacks immunomodulatory effects of heparin. Author(s): Heinzelmann M, Bosshart H. Source: American Journal of Surgery. 2004 January; 187(1): 111-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14706599
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Fondaparinux: a synthetic heparin pentasaccharide as a new antithrombotic agent. Author(s): Walenga JM, Jeske WP, Samama MM, Frapaise FX, Bick RL, Fareed J. Source: Expert Opinion on Investigational Drugs. 2002 March; 11(3): 397-407. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11866668
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Food deprivation increases post-heparin lipoprotein lipase activity in humans. Author(s): Ruge T, Svensson A, Eriksson JW, Olivecrona T, Olivecrona G. Source: European Journal of Clinical Investigation. 2001 December; 31(12): 1040-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11903489
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Formation of polymerized mixed heparin/albumin surface layer and cellular adhesional responses. Author(s): Magoshi T, Matsuda T. Source: Biomacromolecules. 2002 September-October; 3(5): 976-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12217043
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Fractionation of cytosolic proteins on an immobilized heparin column. Author(s): Shefcheck K, Yao X, Fenselau C. Source: Analytical Chemistry. 2003 April 1; 75(7): 1691-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12705604
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Frequency of anti-heparin-platelet factor 4 antibodies in hemodialysis patients and correlation with recurrent vascular access thrombosis. Author(s): O'Shea SI, Sands JJ, Nudo SA, Ortel TL. Source: American Journal of Hematology. 2002 January; 69(1): 72-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11835336
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Frequency of heparin-induced thrombocytopenia in critical care patients. Author(s): Verma AK, Levine M, Shalansky SJ, Carter CJ, Kelton JG. Source: Pharmacotherapy. 2003 June; 23(6): 745-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12820817
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Full heparin anticoagulation should not be used in acute ischemic stroke. Author(s): Sandercock P. Source: Stroke; a Journal of Cerebral Circulation. 2003 January; 34(1): 231-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12511780
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Functional differences between integrin alpha4 and integrins alpha5/alphav in modulating the motility of human oral squamous carcinoma cells in response to the V region and heparin-binding domain of fibronectin. Author(s): Zhang Y, Lu H, Dazin P, Kapila Y. Source: Experimental Cell Research. 2004 April 15; 295(1): 48-58. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15051489
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Furin proteolytically processes the heparin-binding region of extracellular superoxide dismutase. Author(s): Bowler RP, Nicks M, Olsen DA, Thogersen IB, Valnickova Z, Hojrup P, Franzusoff A, Enghild JJ, Crapo JD. Source: The Journal of Biological Chemistry. 2002 May 10; 277(19): 16505-11. Epub 2002 February 22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11861638
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Further evidence that periodate cleavage of heparin occurs primarily through the antithrombin binding site. Author(s): Islam T, Butler M, Sikkander SA, Toida T, Linhardt RJ. Source: Carbohydrate Research. 2002 November 19; 337(21-23): 2239-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12433488
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Gabexate mesilate and heparin responsiveness in coronary patients. Author(s): Ranucci M. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2004 March; 10(3): Pi40-3. Epub 2004 March 01. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14976449
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Gastrin regulates the heparin-binding epidermal-like growth factor promoter via a PKC/EGFR-dependent mechanism. Author(s): Sinclair NF, Ai W, Raychowdhury R, Bi M, Wang TC, Koh TJ, McLaughlin JT. Source: American Journal of Physiology. Gastrointestinal and Liver Physiology. 2004 June; 286(6): G992-9. Epub 2004 February 05. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14764442
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Gender differences in the effect of type 2 diabetes on serum lipids, pre-heparin plasma lipoprotein lipase mass and other metabolic parameters in Japanese population. Author(s): Kobayashi J, Maruyama T, Watanabe H, Kudoh A, Tateishi S, Sasaki T, Murano S, Watanabe M. Source: Diabetes Research and Clinical Practice. 2003 October; 62(1): 39-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14581156
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Gene transfer of extracellular superoxide dismutase reduces arterial pressure in spontaneously hypertensive rats: role of heparin-binding domain. Author(s): Chu Y, Iida S, Lund DD, Weiss RM, DiBona GF, Watanabe Y, Faraci FM, Heistad DD. Source: Circulation Research. 2003 March 7; 92(4): 461-8. Epub 2003 January 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12600899
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Glucosamine sulfate does not crossreact with the antibodies of patients with heparininduced thrombocytopenia. Author(s): Weimann G, Lubenow N, Selleng K, Eichler P, Albrecht D, Greinacher A. Source: European Journal of Haematology. 2001 March; 66(3): 195-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11350488
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Glycoprotein IIb/IIIa antagonists and low-molecular weight heparin in acute coronary syndromes. Author(s): Vernon SM. Source: Cardiology Clinics. 2001 May; 19(2): 235-52, Vi. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11407108
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Glycosaminoglycan structures required for strong binding to midkine, a heparinbinding growth factor. Author(s): Zou P, Zou K, Muramatsu H, Ichihara-Tanaka K, Habuchi O, Ohtake S, Ikematsu S, Sakuma S, Muramatsu T. Source: Glycobiology. 2003 January; 13(1): 35-42. Epub 2002 October 30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12634322
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Glypican-1 is overexpressed in human breast cancer and modulates the mitogenic effects of multiple heparin-binding growth factors in breast cancer cells. Author(s): Matsuda K, Maruyama H, Guo F, Kleeff J, Itakura J, Matsumoto Y, Lander AD, Korc M. Source: Cancer Research. 2001 July 15; 61(14): 5562-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11454708
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Gordon Murray: heparin, hemodialysis and hubris. Author(s): Fellner SK, Purkerson ML. Source: American Journal of Nephrology. 2002 July; 22(2-3): 271-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12097752
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Group IID heparin-binding secretory phospholipase A(2) is expressed in human colon carcinoma cells and human mast cells and up-regulated in mouse inflammatory tissues. Author(s): Murakami M, Yoshihara K, Shimbara S, Sawada M, Inagaki N, Nagai H, Naito M, Tsuruo T, Moon TC, Chang HW, Kudo I. Source: European Journal of Biochemistry / Febs. 2002 June; 269(11): 2698-707. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12047378
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Guide to anticoagulant therapy: Heparin : a statement for healthcare professionals from the American Heart Association. Author(s): Hirsh J, Anand SS, Halperin JL, Fuster V; American Heart Association. Source: Circulation. 2001 June 19; 103(24): 2994-3018. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11413093
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Haemostatic molecular markers in patients undergoing radical retropubic prostatectomy for prostate cancer and submitted to prophylaxis with unfractioned or low molecular weight heparin. Author(s): Boncinelli S, Marsili M, Lorenzi P, Fabbri LP, Pittino S, Filoni M, Bressan F, Sarti E, Cinotti S, Morfini M. Source: Minerva Anestesiol. 2001 October; 67(10): 693-703. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11740417
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Hemodialysis using heparin-bound Hemophan in patients at risk of bleeding. Author(s): Lee KB, Kim B, Lee YH, Yoon SJ, Kang WH, Huh W, Kim DJ, Oh HY, Kim YG. Source: Nephron. Clinical Practice [electronic Resource]. 2004; 97(1): C5-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15153761
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Heparin cofactor II deficiency. Author(s): Tollefsen DM. Source: Archives of Pathology & Laboratory Medicine. 2002 November; 126(11): 1394400. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12421148
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Heparin dose, transfusion rates, and intraoperative graft patency in minimally invasive direct coronary artery bypass. Author(s): Donias HW, D'Ancona G, Pande RU, Schimpf D, Kawaguchi AT, Karamanoukian HL. Source: Heart Surg Forum. 2003; 6(3): 176-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12821433
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Heparin for pregnant women with acquired or inherited thrombophilias. Author(s): Walker MC, Ferguson SE, Allen VM. Source: Cochrane Database Syst Rev. 2003; (2): Cd003580. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12804477
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Heparin inhibits the motility and proliferation of human myometrial and leiomyoma smooth muscle cells. Author(s): Mason HR, Nowak RA, Morton CC, Castellot JJ Jr. Source: American Journal of Pathology. 2003 June; 162(6): 1895-904. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12759246
Studies
89
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Heparin solution locked in acute hemodialysis catheters: impact on activated partial thromboplastin time. Author(s): Sombolos KI, Fragia TK, Bamichas GI, Christidou FP, Stangou MI, Karagianni AC, Natse TA, Georgoulis IE. Source: Asaio Journal (American Society for Artificial Internal Organs : 1992). 2003 MayJune; 49(3): 287-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12790377
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Heparin therapy for mistaken cardiac diagnosis in Boerhaave's syndrome. Author(s): Vyas H, Desal D, Abraham P, Joshi A. Source: Indian J Gastroenterol. 2004 March-April; 23(2): 72-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15176542
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Heparin thromboprophylaxis in gastric bypass surgery. Author(s): Shepherd MF, Rosborough TK, Schwartz ML. Source: Obesity Surgery : the Official Journal of the American Society for Bariatric Surgery and of the Obesity Surgery Society of Australia and New Zealand. 2003 April; 13(2): 249-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12740133
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Heparin/aspirin therapy for implantation failure in IVF cycles. Author(s): Prakash A, Ola B. Source: Fertility and Sterility. 2004 May; 81(5): 1431; Author Reply 1431-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15136130
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Heparin-bonded lines reduce hospital-acquired bacteraemia. Author(s): Gilbert R, Howard R, Mok Q. Source: The Journal of Hospital Infection. 2003 June; 54(2): 163-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12818593
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Heparin-coated circuits (Duraflo II) with reduced versus full anticoagulation during coronary artery bypass surgery. Author(s): Ovrum E, Tangen G, Oystese R, Ringdal MA, Istad R. Source: Journal of Cardiac Surgery. 2003 March-April; 18(2): 140-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12757341
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Heparin-coated hemodialyzers--the holy grail for patients at risk of bleeding? Author(s): Evenepoel P. Source: Nephron. Clinical Practice [electronic Resource]. 2004; 97(1): C1-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15153759
90
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Heparin-induced hyperkalemia after cardiac surgery. Author(s): Day JR, Chaudhry AN, Hunt I, Taylor KM. Source: The Annals of Thoracic Surgery. 2002 November; 74(5): 1698-700. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12440638
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Heparin-induced thrombocytopenia in children. Author(s): Newall F, Barnes C, Ignjatovic V, Monagle P. Source: Journal of Paediatrics and Child Health. 2003 May-June; 39(4): 289-92. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12755937
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Heparin-induced thrombocytopenia: molecular pathogenesis. Author(s): Lee SH, Liu CY, PaoloVisentin G. Source: International Journal of Hematology. 2002 August; 76 Suppl 1: 346-51. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12430880
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Heparin-induced thrombocytopenia: pathogenesis and management. Author(s): Warkentin TE. Source: British Journal of Haematology. 2003 May; 121(4): 535-55. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12752095
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Heparin-induced thrombocytopenia-alternative anticoagulation in pregnancy and lactation. Author(s): Lindhoff-Last E, Bauersachs R. Source: Seminars in Thrombosis and Hemostasis. 2002 October; 28(5): 439-46. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12420239
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Hirudin in heparin-induced thrombocytopenia. Author(s): Lubenow N, Greinacher A. Source: Seminars in Thrombosis and Hemostasis. 2002 October; 28(5): 431-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12420238
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Histidine-rich glycoprotein plus zinc reverses growth inhibition of vascular smooth muscle cells by heparin. Author(s): Mori S, Shinohata R, Renbutsu M, Takahashi HK, Fang YI, Yamaoka K, Okamoto M, Yamamoto I, Nishibori M. Source: Cell and Tissue Research. 2003 June; 312(3): 353-9. Epub 2003 May 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12764609
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Identification and kinetics analysis of a novel heparin-binding site (KEDK) in human tenascin-C. Author(s): Jang JH, Hwang JH, Chung CP, Choung PH. Source: The Journal of Biological Chemistry. 2004 June 11; 279(24): 25562-6. Epub 2004 April 06. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15069070
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Impact of heparin management on release of tissue factor pathway inhibitor during cardiopulmonary bypass. Author(s): Fischer T, Kuppe H, Koster A. Source: Anesthesiology. 2004 April; 100(4): 1040. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15087657
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Improving cardiopulmonary bypass: heparin-coated circuits. Author(s): Vocelka C, Lindley G. Source: J Extra Corpor Technol. 2003 December; 35(4): 312-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14979422
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Improving the laboratory diagnosis of heparin-induced thrombocytopenia. Author(s): Rodgers GM. Source: The American Journal of Medicine. 2003 May; 114(7): 609-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12753887
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Increased pre-operative platelet counts are a possible predictor for reduced sensitivity to heparin. Author(s): Vuylsteke A, Mills RJ, Crosbie AE, Burns TI, Latimer RD. Source: British Journal of Anaesthesia. 2000 December; 85(6): 896-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11732526
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Induction of apoptosis and inhibition of growth of human hepatoma HepG2 cells by heparin. Author(s): Karti SS, Ovali E, Ozgur O, Yilmaz M, Sonmez M, Ratip S, Ozdemir F. Source: Hepatogastroenterology. 2003 November-December; 50(54): 1864-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14696420
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Induction of monocyte tissue factor expression by antibodies to heparin-platelet factor 4 complexes developed in heparin-induced thrombocytopenia. Author(s): Pouplard C, Iochmann S, Renard B, Herault O, Colombat P, Amiral J, Gruel Y. Source: Blood. 2001 May 15; 97(10): 3300-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11342462
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Inflammatory response after coronary revascularization: off-pump versus on-pump (heparin-coated circuits and poly2methoxyethylacrylate-coated circuits). Author(s): Hazama S, Eishi K, Yamachika S, Noguchi M, Ariyoshi T, Takai H, Odate T, Matsukuma S, Onohara D, Yanatori M. Source: Ann Thorac Cardiovasc Surg. 2004 April; 10(2): 90-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15209550
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Influence of heparin dosage on hemostasis under combined use of Nafamostat mesilate during deep hypothermic circulatory arrest. Author(s): Nakamura K, Onitsuka T, Yano M, Yano Y, Matsuyama M, Niina K. Source: Jpn J Thorac Cardiovasc Surg. 2003 May; 51(5): 186-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12776949
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Influence of low molecular weight heparin compared to conventional heparin for anticoagulation during haemodialysis on low density lipoprotein subclasses. Author(s): Wiemer J, Winkler K, Baumstark M, Marz W, Scherberich JE. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2002 December; 17(12): 2231-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12454238
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Inherited and acquired thrombophilias and poor pregnancy outcome: should we be treating with heparin? Author(s): Gebhardt GS, Hall DR. Source: Current Opinion in Obstetrics & Gynecology. 2003 December; 15(6): 501-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14624217
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Inhibition of neointimal proliferation in balloon-injured arteries using nonanticoagulant heparin-carrying polystyrene. Author(s): Fujita M, Ishihara M, Ono K, Matsumura K, Saito Y, Yura H, Morimoto Y, Shimizu M, Takase B, Ozaki S, Kikuchi M, Maehara T. Source: Journal of Cardiovascular Pharmacology. 2004 January; 43(1): 31-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14668565
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Inhibition of NF-kappa B activation and its target genes by heparin-binding epidermal growth factor-like growth factor. Author(s): Mehta VB, Besner GE. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 December 1; 171(11): 601422. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14634113
Studies
93
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Interactions of heparin with human skin cells: binding, location, and transdermal penetration. Author(s): Parisel C, Saffar L, Gattegno L, Andre V, Abdul-Malak N, Perrier E, Letourneur D. Source: Journal of Biomedical Materials Research. 2003 November 1; 67A(2): 517-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14566793
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Intralipid/heparin infusion suppresses serum leptin in humans. Author(s): Garcia-Lorda P, Nash W, Roche A, Pi-Sunyer FX, Laferrere B. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2003 June; 148(6): 669-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12773140
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Intra-operative heparin release during lung surgery. Author(s): Ashour M, Hajjar W, Al-Kattan K, Essa M, Al-Motrafi AA, Al-Saddique A, ElBakry A. Source: European Journal of Cardio-Thoracic Surgery : Official Journal of the European Association for Cardio-Thoracic Surgery. 2004 May; 25(5): 839-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15082291
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Intraperitoneal and subcutaneous pharmacokinetics of low molecular weight heparin in continuous ambulatory peritoneal dialysis patients. Author(s): Sifil A, Mermut C, Yenicerioglu Y, Cavdar C, Gumustekin M, Celik A, Yuksel F, Camsari T. Source: Adv Perit Dial. 2003; 19: 28-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14763030
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Intravenous heparin did not prevent exacerbations of hereditary angioedema in a patient on maintenance hemodialysis. Author(s): Perricone R, De Carolis C, Fontana L. Source: The Journal of Allergy and Clinical Immunology. 2003 May; 111(5): 1137; Reply 1137. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12743585
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Involvement of CD44 in induction of matrix metalloproteinases by a COOH-terminal heparin-binding fragment of fibronectin in human articular cartilage in culture. Author(s): Yasuda T, Poole AR, Shimizu M, Nakagawa T, Julovi SM, Tamamura H, Fujii N, Nakamura T. Source: Arthritis and Rheumatism. 2003 May; 48(5): 1271-80. Erratum In: Arthritis Rheum. 2003 June; 48(6): 1763. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12746900
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Is low-molecular-weight heparin safer than warfarin for secondary prevention of venous thromboembolism in cancer patients? Author(s): Caine GJ, Lip GY. Source: Archives of Internal Medicine. 2003 May 26; 163(10): 1243-4; Author Reply 1244. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12767973
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Keeping central venous lines open: a prospective comparison of heparin, vitamin C and sodium chloride sealing solutions in medical patients. Author(s): Rabe C, Gramann T, Sons X, Berna M, Gonzalez-Carmona MA, Klehr HU, Sauerbruch T, Caselmann WH. Source: Intensive Care Medicine. 2002 August; 28(8): 1172-6. Epub 2002 July 05. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12185445
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Kinetic analysis of glycoprotein C of herpes simplex virus types 1 and 2 binding to heparin, heparan sulfate, and complement component C3b. Author(s): Rux AH, Lou H, Lambris JD, Friedman HM, Eisenberg RJ, Cohen GH. Source: Virology. 2002 March 15; 294(2): 324-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12009874
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Lepirudin in heparin-induced thrombocytopenia and extracorporeal membranous oxygenation. Author(s): Dager WE, Gosselin RC, Yoshikawa R, Owings JT. Source: The Annals of Pharmacotherapy. 2004 April; 38(4): 598-601. Epub 2004 February 24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14982973
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Localization of the laminin alpha4 chain in the skin and identification of a heparindependent cell adhesion site within the laminin alpha4 chain C-terminal LG4 module. Author(s): Matsuura H, Momota Y, Murata K, Matsushima H, Suzuki N, Nomizu M, Shinkai H, Utani A. Source: The Journal of Investigative Dermatology. 2004 March; 122(3): 614-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15086543
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Long-term citrate anticoagulation for high-flux haemodialysis in a patient with heparin-induced thrombocytopenia type II. Author(s): Unver B, Sunder-Plassmann G, Horl WH, Apsner R. Source: Acta Medica Austriaca. 2002; 29(4): 146-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12424942
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Low molecular weight heparin (tinzaparin) vs. placebo in the treatment of mild to moderately active ulcerative colitis. Author(s): Bloom S, Kiilerich S, Lassen MR, Forbes A, Leiper K, Langholz E, Irvine EJ, O'Morain C, Lowson D, Orm S. Source: Alimentary Pharmacology & Therapeutics. 2004 April 15; 19(8): 871-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15080848
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Low molecular weight heparin and neuraxial anesthesia. Author(s): Horlocker TT. Source: Thrombosis Research. 2001 January 1; 101(1): V141-54. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11342094
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Low molecular weight heparin and the risk of haemorrhage following percutaneous biopsy, despite a normal standard clotting screen. Author(s): Cook C, Callaway M. Source: European Radiology. 2001; 11(12): 2536-8. Epub 2001 May 16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11734955
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Low molecular weight heparin for the prevention of hepatic veno-occlusive disease (VOD) after hematopoietic stem cell transplantation: a prospective phase II study. Author(s): Forrest DL, Thompson K, Dorcas VG, Couban SH, Pierce R. Source: Bone Marrow Transplantation. 2003 June; 31(12): 1143-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12796794
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Low molecular weight heparin for venous thromboembolism prophylaxis in urologic oncologic surgery. Author(s): Sawczuk IS, Williams D, Chang DT. Source: Cancer Investigation. 2002; 20(7-8): 889-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12449719
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Low molecular weight heparin induced priapism. Author(s): Lin PH, Bush RL, Lumsden AB. Source: The Journal of Urology. 2004 July; 172(1): 263. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15201790
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Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). Author(s): Kakkar AK, Levine MN, Kadziola Z, Lemoine NR, Low V, Patel HK, Rustin G, Thomas M, Quigley M, Williamson RC. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 May 15; 22(10): 1944-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15143088
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Low molecular weight protamine (LMWP) as nontoxic heparin/low molecular weight heparin antidote (I): preparation and characterization. Author(s): Chang LC, Lee HF, Yang Z, Yang VC. Source: Aaps Pharmsci [electronic Resource]. 2001; 3(3): E17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11741268
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Low molecular weight protamine (LMWP) as nontoxic heparin/low molecular weight heparin antidote (II): in vitro evaluation of efficacy and toxicity. Author(s): Chang LC, Liang JF, Lee HF, Lee LM, Yang VC. Source: Aaps Pharmsci [electronic Resource]. 2001; 3(3): E18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11741269
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Low-molecular weight heparin: treatment failure in a patient with primary antiphospholipid antibody syndrome. Author(s): Ahmed S, Karim A, Patel D, Siddiqui R, Mattana J. Source: The American Journal of the Medical Sciences. 2002 November; 324(5): 279-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12449450
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Low-molecular-weight heparin (LMWH) in the treatment of thrombosis. Author(s): Holzheimer RG. Source: European Journal of Medical Research. 2004 April 30; 9(4): 225-39. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15210403
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Low-molecular-weight heparin as bridging anticoagulation during interruption of warfarin: assessment of a standardized periprocedural anticoagulation regimen. Author(s): Douketis JD, Johnson JA, Turpie AG. Source: Archives of Internal Medicine. 2004 June 28; 164(12): 1319-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15226166
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Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials. Author(s): Quinlan DJ, McQuillan A, Eikelboom JW. Source: Annals of Internal Medicine. 2004 February 3; 140(3): 175-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14757615
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Low-molecular-weight heparin during pregnancy. Author(s): Bazzan M, Donvito V. Source: Thrombosis Research. 2001 January 1; 101(1): V175-86. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11342097
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Low-molecular-weight heparin prophylaxis: preoperative versus postoperative initiation in patients undergoing elective hip surgery. Author(s): Hull RD, Pineo GF, MacIsaac S. Source: Thrombosis Research. 2001 January 1; 101(1): V155-62. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11342095
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Low-molecular-weight heparin to prevent pre-eclampsia: there is no evidence and potential harm. Author(s): Middeldorp S. Source: The Netherlands Journal of Medicine. 2004 March; 62(3): 69-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15209469
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Low-molecular-weight heparin: the optimal duration of prophylaxis against postoperative venous thromboembolism after total hip or knee replacement. Author(s): Heit JA. Source: Thrombosis Research. 2001 January 1; 101(1): V163-73. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11342096
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Management dilemma of cardiopulmonary bypass in patients with type II heparininduced thrombocytopenia. Author(s): Saad RA, Horn L, Mankad PS. Source: British Journal of Haematology. 2002 December; 119(3): 880. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12437678
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Management of heparin resistance during cardiopulmonary bypass: the effect of five different anticoagulation strategies on hemostatic activation. Author(s): Koster A, Fischer T, Gruendel M, Mappes A, Kuebler WM, Bauer M, Kuppe H. Source: Journal of Cardiothoracic and Vascular Anesthesia. 2003 April; 17(2): 171-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12698397
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Management of heparin-induced thrombocytopenia: a critical comparison of lepirudin and argatroban. Author(s): Warkentin TE. Source: Thrombosis Research. 2003 May 1; 110(2-3): 73-82. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12893020
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Management of phlegmasia alba dolens using hirudin in a neurosurgical patient with heparin-induced thrombocytopenia. Author(s): Darwish RS, Amiridze NS, James RF, Schreibman D. Source: Journal of Neurosurgical Anesthesiology. 2004 April; 16(2): 171-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15021290
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Managing heparin-induced thrombocytopenia: preventing life- and limb-threatening thrombosis. Introduction. Author(s): Spinler SA. Source: American Journal of Health-System Pharmacy : Ajhp : Official Journal of the American Society of Health-System Pharmacists. 2003 October 15; 60 Suppl 5: S2-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14593976
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Massive pulmonary embolism due to late-onset heparin-induced thrombocytopenia following coronary artery bypass graft surgery: successful treatment with lepirudin. Author(s): Badmanaban B, Sachithanandan A, Hunter I, Graham A, Sarsam M. Source: Journal of Cardiac Surgery. 2003 July-August; 18(4): 316-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12869178
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Mechanism of activation of heparin cofactor II by calcium spirulan. Author(s): Hayakawa Y, Hirashima Y, Yamamoto H, Kurimoto M, Hayashi T, Lee JB, Endo S. Source: Archives of Biochemistry and Biophysics. 2003 August 1; 416(1): 47-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12859981
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Mechanism of catalysis of inhibition of factor IXa by antithrombin in the presence of heparin or pentasaccharide. Author(s): Wiebe EM, Stafford AR, Fredenburgh JC, Weitz JI. Source: The Journal of Biological Chemistry. 2003 September 12; 278(37): 35767-74. Epub 2003 June 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12832413
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Mechanism of complement activation during extracorporeal blood-biomaterial interaction: effects of heparin coated and uncoated surfaces. Author(s): Kopp R, Mottaghy K, Kirschfink M. Source: Asaio Journal (American Society for Artificial Internal Organs : 1992). 2002 November-December; 48(6): 598-605. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12455769
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Mechanisms responsible for catalysis of the inhibition of factor Xa or thrombin by antithrombin using a covalent antithrombin-heparin complex. Author(s): Paredes N, Wang A, Berry LR, Smith LJ, Stafford AR, Weitz JI, Chan AK. Source: The Journal of Biological Chemistry. 2003 June 27; 278(26): 23398-409. Epub 2003 April 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12695507
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Mechanisms responsible for the failure of protamine to inactivate low-molecularweight heparin. Author(s): Crowther MA, Berry LR, Monagle PT, Chan AK. Source: British Journal of Haematology. 2002 January; 116(1): 178-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11841415
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Mice expressing only covalent dimeric heparin binding-deficient lipoprotein lipase: muscles inefficiently secrete dimeric enzyme. Author(s): Lutz EP, Kako Y, Yagyu H, Heeren J, Marks S, Wright T, Melford K, BenZeev O, Radner H, Merkel M, Bensadoun A, Wong H, Goldberg IJ. Source: The Journal of Biological Chemistry. 2004 January 2; 279(1): 238-44. Epub 2003 October 21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14570890
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Midkine, a heparin-binding cytokine, plays key roles in intraperitoneal adhesions. Author(s): Inoh K, Muramatsu H, Ochiai K, Torii S, Muramatsu T. Source: Biochemical and Biophysical Research Communications. 2004 April 23; 317(1): 108-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15047154
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Midkine, a heparin-binding growth factor, is fundamentally involved in the pathogenesis of rheumatoid arthritis. Author(s): Maruyama K, Muramatsu H, Ishiguro N, Muramatsu T. Source: Arthritis and Rheumatism. 2004 May; 50(5): 1420-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15146411
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Miscellaneous treatments, II: niacin and heparin: unapproved uses, dosages, or indications. Author(s): Wolf R, Orion E, Matz H, Tuzun Y, Tuzun B. Source: Clinics in Dermatology. 2002 September-October; 20(5): 547-57. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12435525
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Multimerization of the Toxoplasma gondii MIC2 integrin-like A-domain is required for binding to heparin and human cells. Author(s): Harper JM, Hoff EF, Carruthers VB. Source: Molecular and Biochemical Parasitology. 2004 April; 134(2): 201-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15003840
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Multiple heparin binding domains of respiratory syncytial virus G mediate binding to mammalian cells. Author(s): Shields B, Mills J, Ghildyal R, Gooley P, Meanger J. Source: Archives of Virology. 2003 October; 148(10): 1987-2003. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14551820
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Mutagenesis studies toward understanding the mechanism of differential reactivity of factor Xa with the native and heparin-activated antithrombin. Author(s): Rezaie AR, Yang L, Manithody C. Source: Biochemistry. 2004 March 16; 43(10): 2898-905. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15005625
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Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome. Author(s): Manuelian T, Hellwage J, Meri S, Caprioli J, Noris M, Heinen S, Jozsi M, Neumann HP, Remuzzi G, Zipfel PF. Source: The Journal of Clinical Investigation. 2003 April; 111(8): 1181-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12697737
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N-desulfated heparin improves concanavalin A-induced liver injury partly through inhibiting T lymphocyte adhesion. Author(s): Yuan L, Geng JG, Xu Q. Source: Inflammation Research : Official Journal of the European Histamine Research Society. [et Al.]. 2003 September; 52(9): 383-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14504666
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N-desulfated non-anticoagulant heparin inhibits leukocyte adhesion and transmigration in vitro and attenuates acute peritonitis and ischemia and reperfusion injury in vivo. Author(s): Wan JG, Mu JS, Zhu HS, Geng JG. Source: Inflammation Research : Official Journal of the European Histamine Research Society. [et Al.]. 2002 September; 51(9): 435-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12365716
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Netrin binds discrete subdomains of DCC and UNC5 and mediates interactions between DCC and heparin. Author(s): Geisbrecht BV, Dowd KA, Barfield RW, Longo PA, Leahy DJ. Source: The Journal of Biological Chemistry. 2003 August 29; 278(35): 32561-8. Epub 2003 June 16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12810718
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Neuropeptide-induced transactivation of a neuronal epidermal growth factor receptor is mediated by metalloprotease-dependent formation of heparin-binding epidermal growth factor. Author(s): Shah BH, Farshori MP, Catt KJ. Source: The Journal of Biological Chemistry. 2004 January 2; 279(1): 414-20. Epub 2003 October 21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14573593
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New heparin dosing recommendations for patients with acute coronary syndromes. Author(s): Menon V, Berkowitz SD, Antman EM, Fuchs RM, Hochman JS. Source: The American Journal of Medicine. 2001 June 1; 110(8): 641-50. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11382373
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New insights in dialysis membrane biocompatibility: relevance of adsorption properties and heparin binding. Author(s): Chanard J, Lavaud S, Randoux C, Rieu P. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2003 February; 18(2): 252-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12543877
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No influence of heparin plasma and other (pre)analytic variables on D-dimer determinations. Author(s): Schutgens RE, Haas FJ, Ruven HJ, Spannagl M, Horn K, Biesma DH. Source: Clinical Chemistry. 2002 September; 48(9): 1611-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12194950
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Non-anticoagulant effects of heparin in carcinoma metastasis and Trousseau's syndrome. Author(s): Borsig L. Source: Pathophysiology of Haemostasis and Thrombosis. 2003; 33 Suppl 1: 64-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12955009
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Novel concatameric heparin-binding peptides reverse heparin and low-molecularweight heparin anticoagulant activities in patient plasma in vitro and in rats in vivo. Author(s): Schick BP, Maslow D, Moshinski A, San Antonio JD. Source: Blood. 2004 February 15; 103(4): 1356-63. Epub 2003 October 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14576044
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Novel drug development opportunities for heparin. Author(s): Lever R, Page CP. Source: Nature Reviews. Drug Discovery. 2002 February; 1(2): 140-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12120095
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Obstinate thrombosis during percutaneous coronary intervention in a case with heparin-induced thrombocytopenia with thrombosis syndrome successfully treated by argatroban anticoagulant therapy. Author(s): Sakai K, Oda H, Honsako A, Takahashi K, Miida T, Higuma N. Source: Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions. 2003 July; 59(3): 351-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12822157
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Optimal anticoagulation strategy in haemodialysis with heparin-coated polyacrylonitrile membrane. Author(s): Lavaud S, Canivet E, Wuillai A, Maheut H, Randoux C, Bonnet JM, Renaux JL, Chanard J. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2003 October; 18(10): 2097-104. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13679486
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Optimal heparin surface concentration and antithrombin binding capacity as evaluated with human non-anticoagulated blood in vitro. Author(s): Andersson J, Sanchez J, Ekdahl KN, Elgue G, Nilsson B, Larsson R. Source: Journal of Biomedical Materials Research. 2003 November 1; 67A(2): 458-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14566786
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Optimal low-molecular-weight heparin regimen in major orthopaedic surgery. A meta-analysis of randomised trials. Author(s): Zufferey P, Laporte S, Quenet S, Molliex S, Auboyer C, Decousus H, Mismetti P. Source: Thrombosis and Haemostasis. 2003 October; 90(4): 654-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14515186
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Optimizing adjunctive antithrombotic therapy in the treatment of acute myocardial infarction: a role for low-molecular-weight heparin. Author(s): Brieger D. Source: Clin Cardiol. 2004 January; 27(1): 3-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14743848
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Oral heparin administration with a novel drug delivery agent (SNAC) in healthy volunteers and patients undergoing elective total hip arthroplasty. Author(s): Berkowitz SD, Marder VJ, Kosutic G, Baughman RA. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 September; 1(9): 1914-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12941031
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Outcome of urgent and elective percutaneous coronary interventions after pharmacologic reperfusion with tenecteplase combined with unfractionated heparin, enoxaparin, or abciximab. Author(s): Dubois CL, Belmans A, Granger CB, Armstrong PW, Wallentin L, Fioretti PM, Lopez-Sendon JL, Verheugt FW, Meyer J, Van de Werf F; ASSENT-3 Investigators. Source: Journal of the American College of Cardiology. 2003 October 1; 42(7): 1178-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14522476
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Outpatient therapy with low molecular weight heparin for the treatment of venous thromboembolism: a review of efficacy, safety, and costs. Author(s): Segal JB, Bolger DT, Jenckes MW, Krishnan JA, Streiff MB, Eng J, Tamariz LJ, Bass EB. Source: The American Journal of Medicine. 2003 September; 115(4): 298-308. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12967695
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Overview of heparin-induced thrombocytopenia. Author(s): Spinler SA, Dager W. Source: American Journal of Health-System Pharmacy : Ajhp : Official Journal of the American Society of Health-System Pharmacists. 2003 October 15; 60 Suppl 5: S5-11. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14593977
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Oxidative and osmotic stress signaling in tumor cells is mediated by ADAM proteases and heparin-binding epidermal growth factor. Author(s): Fischer OM, Hart S, Gschwind A, Prenzel N, Ullrich A. Source: Molecular and Cellular Biology. 2004 June; 24(12): 5172-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15169883
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Pathophysiology, epidemiology, diagnosis and treatment of heparin-induced thrombocytopenia (HIT). Author(s): Picker SM, Gathof BS. Source: European Journal of Medical Research. 2004 April 30; 9(4): 180-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15210398
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Pericardial fluid and serum VEGF in response to different types of heparin treatment. Author(s): Gerrah R, Tshori S, Gilon D. Source: International Journal of Cardiology. 2004 April; 94(2-3): 193-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15093980
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Pharmacotherapy of heparin- induced thrombocytopenia. Author(s): Dager WE, White RH. Source: Expert Opinion on Pharmacotherapy. 2003 June; 4(6): 919-40. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12783589
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Phosphorylcholine or heparin coating for pediatric extracorporeal circulation causes similar biologic effects in neonates and infants. Author(s): Boning A, Scheewe J, Ivers T, Friedrich C, Stieh J, Freitag S, Cremer JT. Source: The Journal of Thoracic and Cardiovascular Surgery. 2004 May; 127(5): 1458-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15116008
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Platelet count monitoring and laboratory testing for heparin-induced thrombocytopenia. Author(s): Breddin HK. Source: Archives of Pathology & Laboratory Medicine. 2003 July; 127(7): 782-3; Author Reply 783. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12823032
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Pre-heparin lipoprotein lipase mass. Author(s): Kobayashi J. Source: J Atheroscler Thromb. 2004; 11(1): 1-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15067192
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Prevention of venous thromboembolism in the acute treatment phase after spinal cord injury: a randomized, multicenter trial comparing low-dose heparin plus intermittent pneumatic compression with enoxaparin. Author(s): Spinal Cord Injury Thromboprophylaxis Investigators. Source: The Journal of Trauma. 2003 June; 54(6): 1116-24; Discussion 1125-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12813332
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Prevention of venous thromboembolism in the rehabilitation phase after spinal cord injury: prophylaxis with low-dose heparin or enoxaparin. Author(s): Spinal Cord Injury Thromboprophylaxis Investigators. Source: The Journal of Trauma. 2003 June; 54(6): 1111-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12813331
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Proliferation-differentiation relationships in the expression of heparin-binding epidermal growth factor-related factors and erbB receptors by normal and psoriatic human keratinocytes. Author(s): Piepkorn M, Predd H, Underwood R, Cook P. Source: Archives of Dermatological Research. 2003 July; 295(3): 93-101. Epub 2003 May 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12768307
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P-selectin and antibodies against heparin-platelet factor 4 in patients with venous or arterial diseases after a 7-day heparin treatment. Author(s): Papalambros E, Sigala F, Travlou A, Bastounis E, Mirilas P. Source: Journal of the American College of Surgeons. 2004 July; 199(1): 69-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15217633
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Quantification of heparin-induced TFPI release: a maximum release at low heparin dose. Author(s): Kemme MJ, Burggraaf J, Schoemaker RC, Kluft C, Cohen AF. Source: British Journal of Clinical Pharmacology. 2002 December; 54(6): 627-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12492611
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R136K fibroblast growth factor-1 mutant induces heparin-independent migration of endothelial cells through fibrin glue. Author(s): Erzurum VZ, Bian JF, Husak VA, Ellinger J, Xue L, Burgess WH, Greisler HP. Source: Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter. 2003 May; 37(5): 1075-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12756357
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Randomized clinical trial of low molecular weight heparin with thigh-length or kneelength antiembolism stockings for patients undergoing surgery. Author(s): Howard A, Zaccagnini D, Ellis M, Williams A, Davies AH, Greenhalgh RM. Source: The British Journal of Surgery. 2004 July; 91(7): 842-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15227689
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Randomized, pilot study of intermittent pneumatic compression devices plus dalteparin versus intermittent pneumatic compression devices plus heparin for prevention of venous thromboembolism in patients undergoing craniotomy. Author(s): Macdonald RL, Amidei C, Baron J, Weir B, Brown F, Erickson RK, Hekmatpanah J, Frim D. Source: Surgical Neurology. 2003 May; 59(5): 363-72; Discussion 372-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12765806
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Recurrence rate of pre-eclampsia in women with thrombophilia influenced by lowmolecular-weight heparin treatment? Author(s): Kalk JJ, Huisjes AJ, de Groot CJ, van Beek E, van Pampus MG, Spaanderman ME, van Eyck J, Oei SG, Bezemer PD, de Vries JI. Source: The Netherlands Journal of Medicine. 2004 March; 62(3): 83-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15209472
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Reduction of out-of-hospital symptomatic venous thromboembolism by extended thromboprophylaxis with low-molecular-weight heparin following elective hip arthroplasty: a systematic review. Author(s): O'Donnell M, Linkins LA, Kearon C, Julian J, Hirsh J. Source: Archives of Internal Medicine. 2003 June 9; 163(11): 1362-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12796074
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Reduction of subacute stent thrombosis (SAT) using heparin-coated stents in a largescale, real world registry. Author(s): Gupta V, Aravamuthan BR, Baskerville S, Smith SK, Gupta V, Lauer MA, Fischell TA. Source: J Invasive Cardiol. 2004 June; 16(6): 304-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15155999
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Relationship of activated partial thromboplastin time to coronary events and bleeding in patients with acute coronary syndromes who receive heparin. Author(s): Anand SS, Yusuf S, Pogue J, Ginsberg JS, Hirsh J; Organization to Assess Strategies for Ischemic Syndromes Investigators. Source: Circulation. 2003 June 17; 107(23): 2884-8. Epub 2003 Jun 09. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12796128
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Retrospective database analysis of the prevention of venous thromboembolism with low-molecular-weight heparin in acutely III medical inpatients in community practice. Author(s): McGarry LJ, Thompson D. Source: Clinical Therapeutics. 2004 March; 26(3): 419-30. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15110135
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Reversal of direct thrombin inhibition after cardiopulmonary bypass in a patient with heparin-induced thrombocytopenia. Author(s): Stratmann G, deSilva AM, Tseng EE, Hambleton J, Balea M, Romo AJ, Mann MJ, Achorn NL, Moskalik WF, Hoopes CW. Source: Anesthesia and Analgesia. 2004 June; 98(6): 1635-9, Table of Contents. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15155316
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Risk of thrombosis in patients with malignancy and heparin-induced thrombocytopenia. Author(s): Opatrny L, Warner MN. Source: American Journal of Hematology. 2004 July; 76(3): 240-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15224359
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Safety and efficacy of enoxaparin vs unfractionated heparin in patients with non-STsegment elevation acute coronary syndromes who receive tirofiban and aspirin: a randomized controlled trial. Author(s): Blazing MA, de Lemos JA, White HD, Fox KA, Verheugt FW, Ardissino D, DiBattiste PM, Palmisano J, Bilheimer DW, Snapinn SM, Ramsey KE, Gardner LH, Hasselblad V, Pfeffer MA, Lewis EF, Braunwald E, Califf RM; A to Z Investigators. Source: Jama : the Journal of the American Medical Association. 2004 July 7; 292(1): 5564. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15238591
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Safety of heparin reversal with protamin and immediate sheath removal after coronary angioplasty. Author(s): Lohne F, Klow NE, Stavnes S, Brekke M, Hoffmann P, Stensaeth KH, Sovik E, Pettersen MS. Source: Acta Radiologica (Stockholm, Sweden : 1987). 2004 April; 45(2): 171-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15191101
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Spontaneous splenic rupture following the administration of intravenous heparin: case report and retrospective case review. Author(s): Ghobrial MW, Karim M, Mannam S. Source: American Journal of Hematology. 2002 December; 71(4): 314-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12447963
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Stenosis of the hepatic vein anastomosis after liver transplantation: treatment with a heparin-coated metal stent. Author(s): Frazer CK, Gupta A. Source: Australasian Radiology. 2002 December; 46(4): 422-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12452917
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Stroke in patients with heparin-induced thrombocytopenia and the effect of argatroban therapy. Author(s): LaMonte MP, Brown PM, Hursting MJ. Source: Critical Care Medicine. 2004 April; 32(4): 976-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15071388
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Subcutaneous adjusted-dose unfractionated heparin vs fixed-dose low-molecularweight heparin in the initial treatment of venous thromboembolism. Author(s): Prandoni P, Carnovali M, Marchiori A; Galilei Investigators. Source: Archives of Internal Medicine. 2004 May 24; 164(10): 1077-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15159264
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Suboptimal monitoring and dosing of unfractionated heparin. Author(s): Chung KK, Tofferi JK, Browne WT. Source: Annals of Internal Medicine. 2004 April 6; 140(7): 582; Author Reply 582-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15068994
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Successful pregnancy with low molecular weight heparin in two women with recurrent miscarriage of unknown etiology. Author(s): Miyashita Y, Waguri M, Nakanishi I, Suehara N, Fujita T. Source: American Journal of Reproductive Immunology (New York, N.Y. : 1989). 2003 February; 49(2): 90-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12765347
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Successful treatment of left atrial disk thrombus on an Amplatzer atrial septal defect occluder with abciximab and heparin. Author(s): Willcoxson FE, Thomson JD, Gibbs JL. Source: Heart (British Cardiac Society). 2004 May; 90(5): E30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15084578
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Superior antimicrobial activity of trisodium citrate over heparin for catheter locking. Author(s): Weijmer MC, Debets-Ossenkopp YJ, Van De Vondervoort FJ, ter Wee PM. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2002 December; 17(12): 2189-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12454232
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The efficacy and safety of the new heparin-induced extracorporeal low-density lipoprotein precipitation system (Plasmat Futura) in comparison with the currently used system (Plasmat Secura). Author(s): Blessing F, Wang Y, Nagel D, Seidel D. Source: Ther Apher Dial. 2004 February; 8(1): 33-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15128017
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The impact of heparin-coated cardiopulmonary bypass circuits on pulmonary function and the release of inflammatory mediators. Author(s): de Vroege R, van Oeveren W, van Klarenbosch J, Stooker W, Huybregts MA, Hack CE, van Barneveld L, Eijsman L, Wildevuur CR. Source: Anesthesia and Analgesia. 2004 June; 98(6): 1586-94, Table of Contents. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15155310
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The present and future of heparin, low molecular weight heparins, pentasaccharide, and hirudin for venous thromboembolism and acute coronary syndromes. Author(s): Haas S. Source: Semin Vasc Med. 2003 May; 3(2): 139-46. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15199477
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The ShdA adhesin binds to the cationic cradle of the fibronectin 13FnIII repeat module: evidence for molecular mimicry of heparin binding. Author(s): Kingsley RA, Keestra AM, de Zoete MR, Baumler AJ. Source: Molecular Microbiology. 2004 April; 52(2): 345-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15066025
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The value of heparin concentration monitoring in off-pump coronary bypass surgery. Author(s): Baykut D, Weichelt K, Wehrle J, Zerkowski HR, Bernet F. Source: European Journal of Medical Research. 2003 April 30; 8(4): 161-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12765862
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Thrombocytopenia due to acute venous thromboembolism and its role in expanding the differential diagnosis of heparin-induced thrombocytopenia. Author(s): Kitchens CS. Source: American Journal of Hematology. 2004 May; 76(1): 69-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15114601
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Thromboprophylaxis with low molecular weight heparin in thrombophiliacomplicated pregnancy. Author(s): Ebina Y, Yamada H, Kato EH, Yamamoto R, Sakuragi N, Fujimoto S. Source: The Journal of Obstetrics and Gynaecology Research. 2002 October; 28(5): 251-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12428694
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Treatment of acute pulmonary embolism during pregnancy with low molecular weight heparin: three case reports. Author(s): Kaaja RJ, Ulander VM. Source: Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis. 2002 October; 13(7): 637-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12439150
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Treatment of venous thromboembolism with low-molecular-weight heparin: a synthesis of the evidence published in systematic literature reviews. Author(s): Krishnan JA, Segal JB, Streiff MB, Bolger DT, Eng J, Jenckes MW, Tamariz LJ, Bass EB. Source: Respiratory Medicine. 2004 May; 98(5): 376-86. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15139566
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Type XIX collagen purified from human umbilical cord is characterized by multiple sharp kinks delineating collagenous subdomains and by intermolecular aggregates via globular, disulfide-linked, and heparin-binding amino termini. Author(s): Myers JC, Li D, Amenta PS, Clark CC, Nagaswami C, Weisel JW. Source: The Journal of Biological Chemistry. 2003 August 22; 278(34): 32047-57. Epub 2003 June 03. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12788917
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Unfractionated heparin and other antithrombin mediated anticoagulants. Author(s): Adler BK. Source: Clin Lab Sci. 2004 Spring; 17(2): 113-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15168893
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Unintended bias, clinical trial results, and the heparin post hoc crossover fallacy. Author(s): Opal SM. Source: Critical Care Medicine. 2004 March; 32(3): 874-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15090975
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Up-regulation of heparin binding epidermal growth factor-like growth factor and amphiregulin expression in Helicobacter pylori-infected human gastric mucosa. Author(s): Tuccillo C, Manzo BA, Nardone G, D'Argenio G, Rocco A, Di Popolo A, Della VN, Staibano S, De Rosa G, Ricci V, Del Vecchio BC, Zarrilli R, Romano M. Source: Dig Liver Dis. 2002 July; 34(7): 498-505. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12236483
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Use of a centrifugal vortex blood pump and heparin-bonded circuit for extracorporeal rewarming of severe hypothermia in acutely injured and coagulopathic patients. Author(s): Kirkpatrick AW, Garraway N, Brown DR, Nash D, Ng A, Lawless B, Cunningham J, Chun R, Simons RK. Source: The Journal of Trauma. 2003 September; 55(3): 407-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14501879
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Use of lepirudin during percutaneous vascular interventions in patients with heparin-induced thrombocytopenia. Author(s): Cochran K, DeMartini TJ, Lewis BE, O Brien J, Steen LH, Grassman ED, Leya F. Source: J Invasive Cardiol. 2003 November; 15(11): 617-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14608129
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Use of low molecular mass heparin (enoxaparin) in newborn infants: a prospective cohort study of 62 patients. Author(s): Streif W, Goebel G, Chan AK, Massicotte MP. Source: Archives of Disease in Childhood. Fetal and Neonatal Edition. 2003 September; 88(5): F365-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12937038
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Use of plasma exchange and heparin during cardiopulmonary bypass for a patient with heparin induced thrombocytopenia: a case report. Author(s): Kajitani M, Aguinaga M, Johnson CE, Scott MA, Antakli T. Source: Journal of Cardiac Surgery. 2001; 16(4): 313-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11833705
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Use of the low-molecular-weight heparin nadroparin during pregnancy. A review. Author(s): Makatsaria AD, Bitsadze VO, Dolgushina NV. Source: Current Medical Research and Opinion. 2003; 19(1): 4-12. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12661774
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Use patterns of low-molecular weight heparin and the impact on length of stay in patients hospitalized for atrial fibrillation. Author(s): Kim MH, Decena BF, Bruckman D, Eagle KA. Source: American Heart Journal. 2003 April; 145(4): 665-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12679763
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Utility of a weight-based heparin nomogram for patients with acute coronary syndromes. Author(s): Zimmermann AT, Jeffries WS, McElroy H, Horowitz JD. Source: Internal Medicine Journal. 2003 January-February; 33(1-2): 18-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12534874
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Validation of a weight-based nomogram for the use of intravenous heparin in transient ischemic attack or stroke. Author(s): Toth C, Voll C. Source: Stroke; a Journal of Cerebral Circulation. 2002 March; 33(3): 670-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11872885
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Variations of serum potassium level and risk of hyperkalemia in inpatients receiving low-molecular-weight heparin. Author(s): Gheno G, Cinetto L, Savarino C, Vellar S, Carraro M, Randon M. Source: European Journal of Clinical Pharmacology. 2003 September; 59(5-6): 373-7. Epub 2003 July 08. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12851802
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Vascular endothelial growth factor 165 (VEGF(165)) activities are inhibited by carboxymethyl benzylamide dextran that competes for heparin binding to VEGF(165) and VEGF(165).KDR Complexes. Author(s): Hamma-Kourbali Y, Vassy R, Starzec A, Le Meuth-Metzinger V, Oudar O, Bagheri-Yarmand R, Perret G, Crepin M. Source: The Journal of Biological Chemistry. 2001 October 26; 276(43): 39748-54. Epub 2001 August 20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11514538
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Vascular surgery using argatroban in a patient with a history of heparin-induced thrombocytopenia. Author(s): Tokuda Y, Matsumoto M, Sugita T, Nishizawa J, Matsuyama K, Yoshida K, Matsuo T. Source: Circulation Journal : Official Journal of the Japanese Circulation Society. 2003 October; 67(10): 889-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14578626
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VEGF162, a new heparin-binding vascular endothelial growth factor splice form that is expressed in transformed human cells. Author(s): Lange T, Guttmann-Raviv N, Baruch L, Machluf M, Neufeld G. Source: The Journal of Biological Chemistry. 2003 May 9; 278(19): 17164-9. Epub 2003 February 21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12598527
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Venous limb gangrene during overlapping therapy with warfarin and a direct thrombin inhibitor for immune heparin-induced thrombocytopenia. Author(s): Smythe MA, Warkentin TE, Stephens JL, Zakalik D, Mattson JC. Source: American Journal of Hematology. 2002 September; 71(1): 50-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12221676
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Venous thrombosis from air travel: the LONFLIT3 study--prevention with aspirin vs low-molecular-weight heparin (LMWH) in high-risk subjects: a randomized trial. Author(s): Cesarone MR, Belcaro G, Nicolaides AN, Incandela L, De S, Geroulakos G, Lennox A, Myers KA, Moia M, Ippolito E, Winford M. Source: Angiology. 2002 January-February; 53(1): 1-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11863301
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Venous thrombosis prophylaxis with low-molecular-weight heparin in hip and knee arthroplasty. Author(s): Colwell CW Jr. Source: Instr Course Lect. 2002; 51: 487-9. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12064138
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Vitamin K antagonists or low-molecular-weight heparin for the long term treatment of symptomatic venous thromboembolism. Author(s): van der Heijden JF, Hutten BA, Buller HR, Prins MH. Source: Cochrane Database Syst Rev. 2002; (1): Cd002001. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11869618
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von Willebrand factor binding to heparin in various types of von Willebrand disease. Author(s): Rastegar-Lari G, Legendre P, Ajzenberg N, Warszawski J, Meyer D, Baruch D. Source: The Hematology Journal : the Official Journal of the European Haematology Association / Eha. 2000; 1(3): 190-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11920189
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Warfarin-associated multiple digital necrosis complicating heparin-induced thrombocytopenia and Raynaud's phenomenon after aortic valve replacement for adenocarcinoma-associated thrombotic endocarditis. Author(s): Warkentin TE, Whitlock RP, Teoh KH. Source: American Journal of Hematology. 2004 January; 75(1): 56-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14695634
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Warfarin-induced skin necrosis and venous limb gangrene in the setting of heparininduced thrombocytopenia. Author(s): Srinivasan AF, Rice L, Bartholomew JR, Rangaswamy C, La Perna L, Thompson JE, Murphy S, Baker KR. Source: Archives of Internal Medicine. 2004 January 12; 164(1): 66-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14718324
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What is the incidence of heparin-induced thrombocytopenia (HIT) in children? Author(s): Martchenke J, Pate MF, Cruz M, Phromsivarak S. Source: Critical Care Nurse. 2004 February; 24(1): 66-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15007896
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When can unfractionated heparin really be useful in the treatment of ulcerative colitis? Author(s): Papa A, Danese S, Gasbarrini G, Gasbarrini A. Source: Gastroenterology. 2001 April; 120(5): 1306-7; Author Reply 1307-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11288745
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When should heparin preferably be administered during radiofrequency catheter ablation? Author(s): Anfinsen OG, Gjesdal K, Aass H, Brosstad F, Orning OM, Amlie JP. Source: Pacing and Clinical Electrophysiology : Pace. 2001 January; 24(1): 5-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11227969
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Which heparin is best. When cardiac catheterization is needed, know your heparins. Author(s): Knight D. Source: The American Journal of Nursing. 2003 December; 103(12): 81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14702571
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Wounding induces motility in sheets of corneal epithelial cells through loss of spatial constraints: role of heparin-binding epidermal growth factor-like growth factor signaling. Author(s): Block ER, Matela AR, SundarRaj N, Iszkula ER, Klarlund JK. Source: The Journal of Biological Chemistry. 2004 June 4; 279(23): 24307-12. Epub 2004 March 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15039441
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Zinc ions promote the interaction between heparin and heparin cofactor II. Author(s): Eckert R, Ragg H. Source: Febs Letters. 2003 April 24; 541(1-3): 121-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12706831
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CHAPTER 2. NUTRITION AND HEPARIN Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and heparin.
Finding Nutrition Studies on Heparin 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 “heparin” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.
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Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.
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The following is a typical result when searching for recently indexed consumer information on heparin: •
New heparin is no heavyweight. Source: Feinberg, A W Health-News. 2000 August; 6(8): 5-6 1081-5880
The following information is typical of that found when using the “Full IBIDS Database” to search for “heparin” (or a synonym): •
Anticoagulation with prostaglandins and unfractionated heparin during continuous venovenous haemofiltration: a randomized controlled trial. Author(s): Departments of Anaesthesiology and Intensive Care B, University of Vienna, School of Medicine, Vienna, Austria.
[email protected] Source: Kozek Langenecker, S A Spiss, C K Gamsjager, T Domenig, C Zimpfer, M WienKlin-Wochenschr. 2002 February 15; 114(3): 96-101 0043-5325
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Contribution of basic residues of the A helix of heparin cofactor II to heparin- or dermatan sulfate-mediated thrombin inhibition. Author(s): Department of Neurosurgery, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Japan.
[email protected] Source: Hayakawa, Yumiko Hirashima, Yutaka Kurimoto, Masanori Hayashi, Nakamasa Hamada, Hideo Kuwayama, Naoya Endo, Shunro FEBS-Lett. 2002 July 3; 522(1-3): 147-50 0014-5793
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Delivery of LMW heparin via surface coated chitosan/peg-alginate microspheres prevents thrombosis. Author(s): Departments of Cardiology and Lab Medicine Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
[email protected] Source: Chandy, T Rao, G H Wilson, R F Das, G S Drug-Delivolume 2002 Apr-June; 9(2): 87-96 1071-7544
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Effect of new synthetic heparin mimetics on whole blood thrombin generation in vivo and in vitro in rats. Author(s): Sanofi-Synthelabo Recherche, Toulouse, France. Source: Herault, J P Bernat, A Gaich, C Herbert, M Thromb-Haemost. 2002 February; 87(2): 238-44 0340-6245
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Facilitation of learning and modulation of frontal cortex acetylcholine by ventral pallidal injection of heparin glucosaminoglycan. Author(s): Institute of Physiological Psychology, University of Dusseldorf, 40225, Dusseldorf, Germany. Source: De Souza Silva, M A Jezek, K Weth, K Muller, H W Huston, J P Brandao, M L Hasenohrl, R U Neuroscience. 2002; 113(3): 529-35 0306-4522
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Hydration effects of heparin on antithrombin probed by osmotic stress. Author(s): Wake Forest University Medical School, Medicine Department, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.
[email protected] Source: McGee, Maria P Liang, Jie Luba, James Biophys-J. 2002 February; 82(2): 1040-9 0006-3495
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Inhibition of human angiogenesis with heparin and hydrocortisone. Author(s): Department of Surgery, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA. Source: Jung, S P Siegrist, B Wade, M R Anthony, C T Woltering, E A Angiogenesis. 2001; 4(3): 175-86 0969-6970
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Low molecular weight heparin and warfarin in the treatment of patients with antiphospholipid syndrome during pregnancy. Author(s): Department of Medicine E, Sheba Medical Center, Sackler School of Medicine and School of Engineering, Tel-Aviv University, Israel.
[email protected] Source: Pauzner, R Dulitzki, M Langevitz, P Livneh, A Kenett, R Many, A ThrombHaemost. 2001 December; 86(6): 1379-84 0340-6245
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Low-molecular-weight heparin for the prevention of obstetric complications in women with thrombophilias. Author(s): The Department of Obstetrics and Gynecology, Lis Maternity Hospital, TelAviv University, Tel-Aviv, Israel.
[email protected] Source: Kupferminc, M J Fait, G Many, A Lessing, J B Yair, D Bar Am, A Eldor, A Hypertens-Pregnancy. 2001; 20(1): 35-44 1064-1955
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Molecular weight-dependent influence of heparin on the form of tissue factor pathway inhibitor circulating in plasma. Author(s): Institute of Pharmacy, University of Regensburg, Regensburg, Germany.
[email protected] Source: Alban, S Semin-Thromb-Hemost. 2001 October; 27(5): 503-11 0094-6176
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Phosphorothioate oligonucleotides, suramin and heparin inhibit DNA-dependent protein kinase activity. Author(s): Department of Radiation Oncology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
[email protected] Source: Hosoi, Y Matsumoto, Y Tomita, M Enomoto, A Morita, A Sakai, K Umeda, N Zhao, H J Nakagawa, K Ono, T Suzuki, N Br-J-Cancer. 2002 April 8; 86(7): 1143-9 00070920
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The effect of unfractionated vs. low molecular weight heparin on tissue factor pathway inhibitor levels in hospital inpatients. Author(s): Department of Medicine, Massachusetts General Hospital, Boston 02114, USA.
[email protected] Source: Brown, J R Kuter, D J Thromb-Haemost. 2001 June; 85(6): 979-85 0340-6245
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The effects of danaparoid, dalteparin and heparin on tissue factor-induced experimental disseminated intravascular coagulation and bleeding time in the rat. Author(s): Pharmacology Group, Research & Development Division, Nippon Organon K. K., Osaka, Japan. Source: Miyake, Y Yokota, K Fujishima, Y Sukamoto, T Blood-Coagul-Fibrinolysis. 2001 July; 12(5): 349-57 0957-5235
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Use of enzyme and heparin paste in acute haemorrhoids. Author(s): Gupta Nursing Home, Nagpur, India. Source: Gupta, P J Rom-J-Gastroenterol. 2002 September; 11(3): 191-5 1221-4167
Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •
healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0
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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov
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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov
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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/
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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/
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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/
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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/
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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/
Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats
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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html
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Google: http://directory.google.com/Top/Health/Nutrition/
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Healthnotes: http://www.healthnotes.com/
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Open Directory Project: http://dmoz.org/Health/Nutrition/
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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/
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WebMDHealth: http://my.webmd.com/nutrition
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
The following is a specific Web list relating to heparin; 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 C Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin D Source: Healthnotes, Inc.; www.healthnotes.com
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Vitamin D Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin E Source: Prima Communications, Inc.www.personalhealthzone.com •
Minerals Chondroitin Alternative names: chondroitin sulfate, sodium chondroitin sulfate Source: Integrative Medicine Communications; www.drkoop.com Chondroitin Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10017,00.html Potassium Source: Healthnotes, Inc.; www.healthnotes.com Potassium Source: Integrative Medicine Communications; www.drkoop.com Vanadium Alternative names: Vanadate Source: Integrative Medicine Communications; www.drkoop.com Vinpocetine Source: Prima Communications, Inc.www.personalhealthzone.com
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Food and Diet Garlic Source: Prima Communications, Inc.www.personalhealthzone.com Omega-3 Fatty Acids Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,992,00.html
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CHAPTER 3. ALTERNATIVE MEDICINE AND HEPARIN Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to heparin. 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 heparin 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 “heparin” (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 heparin: •
A chronopharmacodynamic study on standard heparin, a low molecular weight heparin (nadroparin) and danaproid: establishing and comparing the daily variations of these drugs in rats. Author(s): Abrial D, Blanc A, Rehailia M, Mismetti P, Bouchut C, Laporte-Simitsidis S, Decousus H, Buisson B. Source: Haemostasis. 2000 September-October; 30(5): 233-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11251330
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A protocol for coadministration of i.v. iron dextran and heparin in chronic hemodialysis patients. Author(s): Davis P, Bednarz D, Briglia A, Paganini EP. Source: Anna J. 1998 October; 25(5): 533-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9887705
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A rapid screen for lupus anticoagulant with good discrimination from oral anticoagulants, congenital factor deficiency and heparin, is provided by comparing a sensitive and an insensitive APTT reagent. Author(s): Brancaccio V, Ames PR, Glynn J, Iannaccone L, Mackie IJ. Source: Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis. 1997 April; 8(3): 155-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9167015
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A sensitive and specific functional flow cytometric assay for the diagnosis of heparininduced thrombocytopenia. Author(s): Tomer A. Source: British Journal of Haematology. 1997 September; 98(3): 648-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9332321
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Adjuvant 5-fluorouracil and heparin prevents proliferative vitreoretinopathy : Results from a randomized, double-blind, controlled clinical trial. Author(s): Asaria RH, Kon CH, Bunce C, Charteris DG, Wong D, Khaw PT, Aylward GW. Source: Ophthalmology. 2001 July; 108(7): 1179-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11425671
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Alteration of integrins by heparin-binding EGF-like growth factor in human breast cancer cells. Author(s): Narita T, Kawakami-Kimura N, Sato M, Matsuura N, Higashiyama S, Taniguchi N, Kannagi R. Source: Oncology. 1996 September-October; 53(5): 374-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8784471
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Antithrombin increases pulmonary endothelins: inhibition by heparin and Ca2+ channel antagonism. Author(s): Stangl K, Dschietzig T, Alexiou K, Brunner F. Source: European Journal of Pharmacology. 1999 April 1; 370(1): 57-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10323280
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BAG-1 is a novel cytoplasmic binding partner of the membrane form of heparinbinding EGF-like growth factor: a unique role for proHB-EGF in cell survival regulation. Author(s): Lin J, Hutchinson L, Gaston SM, Raab G, Freeman MR. Source: The Journal of Biological Chemistry. 2001 August 10; 276(32): 30127-32. Epub 2001 May 04. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11340068
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Binding of the G domains of laminin alpha1 and alpha2 chains and perlecan to heparin, sulfatides, alpha-dystroglycan and several extracellular matrix proteins. Author(s): Talts JF, Andac Z, Gohring W, Brancaccio A, Timpl R. Source: The Embo Journal. 1999 February 15; 18(4): 863-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10022829
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Calcium enhances heparin catalysis of the antithrombin-factor Xa reaction by a template mechanism. Evidence that calcium alleviates Gla domain antagonism of heparin binding to factor Xa. Author(s): Rezaie AR. Source: The Journal of Biological Chemistry. 1998 July 3; 273(27): 16824-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9642241
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Characterization of a 30-kDa peripheral nerve glycoprotein that binds laminin and heparin. Author(s): Saito F, Yamada H, Sunada Y, Hori H, Shimizu T, Matsumura K. Source: The Journal of Biological Chemistry. 1997 October 17; 272(42): 26708-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9334255
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Concentration-dependent incompatibility of vinorelbine tartrate and heparin sodium. Author(s): Balthasar JP. Source: American Journal of Health-System Pharmacy : Ajhp : Official Journal of the American Society of Health-System Pharmacists. 1999 September 15; 56(18): 1891. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10511236
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Cytotoxic effects of basic FGF and heparin binding EGF conjugated with cytotoxin saporin on vascular cell cultures. Author(s): Chen C, Li J, Micko CJ, Pierce GF, Cunningham MR, Lumsden AB. Source: The Journal of Surgical Research. 1998 February 15; 75(1): 35-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9614854
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Delayed cutaneous reactions to heparin in antiphospholipid syndrome during pregnancy. Author(s): Kim J, Smith KJ, Toner C, Skelton H. Source: International Journal of Dermatology. 2004 April; 43(4): 252-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15090006
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Determination of heparin-induced thrombocytopenia: a rapid flow cytometric assay for direct demonstration of antibody-mediated platelet activation. Author(s): Tomer A, Masalunga C, Abshire TC. Source: American Journal of Hematology. 1999 May; 61(1): 53-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10331512
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Development of poly(Lactic acid)/chitosan co-matrix microspheres: controlled release of taxol-heparin for preventing restenosis. Author(s): Chandy T, Rao GH, Wilson RF, Das GS. Source: Drug Delivery. 2001 April-June; 8(2): 77-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11400866
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Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents. Author(s): Koenig A, Norgard-Sumnicht K, Linhardt R, Varki A. Source: The Journal of Clinical Investigation. 1998 February 15; 101(4): 877-89. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9466983
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Differentiation between the complement modulating effects of an arabinogalactanprotein from Echinacea purpurea and heparin. Author(s): Alban S, Classen B, Brunner G, Blaschek W. Source: Planta Medica. 2002 December; 68(12): 1118-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12494341
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Distinct yet complementary mechanisms of heparin and glycoprotein IIb/IIIa inhibitors on platelet activation and aggregation: implications for restenosis during percutaneous coronary intervention. Author(s): Day JR, Malik IS, Weerasinghe A, Poullis M, Nadra I, Haskard DO, Taylor KM, Landis RC. Source: Heart (British Cardiac Society). 2004 July; 90(7): 794-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15201252
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Divalent cations and heparin/heparan sulfate cooperate to control assembly and activity of the fibroblast growth factor receptor complex. Author(s): Kan M, Wang F, To B, Gabriel JL, McKeehan WL. Source: The Journal of Biological Chemistry. 1996 October 18; 271(42): 26143-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8824259
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EDTA is a better anticoagulant than heparin or citrate for delayed blood processing for plasma DNA analysis. Author(s): Lam NY, Rainer TH, Chiu RW, Lo YM. Source: Clinical Chemistry. 2004 January; 50(1): 256-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14709670
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Effect of glycemic control on plasma plant sterol levels and post-heparin diamine oxidase activity in type 1 diabetic patients. Author(s): Kojima H, Hidaka H, Matsumura K, Fujita Y, Yamada S, Haneda M, Yasuda H, Kikkawa R, Kashiwagi A.
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Effects of anticoagulants in amino acid analysis: comparisons of heparin, EDTA, and sodium citrate in vacutainer tubes for plasma preparation. Author(s): Chuang CK, Lin SP, Lin YT, Huang FY. Source: Clinical Chemistry. 1998 May; 44(5): 1052-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9590384
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Effects of heparin on polymerase chain reaction for blood white cells. Author(s): Yokota M, Tatsumi N, Nathalang O, Yamada T, Tsuda I. Source: Journal of Clinical Laboratory Analysis. 1999; 13(3): 133-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10323479
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Effects of hyperbaric oxygen treatment and heparin on the survival of unipedicled venous flaps: an experimental study in rats. Author(s): Yucel A, Bayramicli M. Source: Annals of Plastic Surgery. 2000 March; 44(3): 295-303. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10735222
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Effects of lithium heparin and tripotassium EDTA on hematologic values of Hermann's tortoises (Testudo hermanni). Author(s): Muro J, Cuenca R, Pastor J, Vinas L, Lavin S. Source: J Zoo Wildl Med. 1998 March; 29(1): 40-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9638624
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Endpoint-attached heparin blocks neutrophil sticking and spreading. Author(s): Videm V. Source: Biomaterials. 2004 January; 25(1): 43-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14580907
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Ethylenediaminetetraacetic acid (EDTA) in heparin. Author(s): Coyne E, Messmore HL, Walenga JM, Fareed J, Wehrmacher WH. Source: Thrombosis Research. 1998 June 1; 90(5): 245-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9694247
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Fine mapping of the sequences in domain 5 of high molecular weight kininogen (HK) interacting with heparin and zinc. Author(s): Pixley RA, Lin Y, Isordia-Salas I, Colman RW. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 August; 1(8): 1791-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12911595
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Hematologic evaluation of normal and anemic lambs with the Technicon H*1 using EDTA or heparin as anticoagulants. Author(s): Vatn S, Framstad T, Torsteinbo WO. Source: Vet Clin Pathol. 2000; 29(2): 62-68. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12070814
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Heparin in plasma samples causes nonspecific binding to histones on Western blots. Author(s): Alcantara FF, Iglehart DJ, Ochs RL. Source: Journal of Immunological Methods. 1999 June 24; 226(1-2): 11-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10410967
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Heparin modulates integrin function in human platelets. Author(s): Sobel M, Fish WR, Toma N, Luo S, Bird K, Mori K, Kusumoto S, Blystone SD, Suda Y. Source: Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter. 2001 March; 33(3): 587-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11241131
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Heparin removal after cardiopulmonary bypass in a patient with adverse reaction to protamine. Author(s): Tevaearai HT, Jegger D, Mueller XM, Horisberger J, von Segesser LK. Source: The Thoracic and Cardiovascular Surgeon. 1998 October; 46(5): 303-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9885123
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Heparin reverses Rhodamine 123 extrusion by multidrug resistant cells. Author(s): Maia RC, Wagner K, Cabral RH, Rumjanek VM. Source: Cancer Letters. 1996 August 23; 106(1): 101-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8827053
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Heparin/heparan sulfate interacting protein plays a role in apoptosis induced by anticancer drugs. Author(s): Liu JJ, Zhang J, Ramanan S, Julian J, Carson DD, Hooi SC. Source: Carcinogenesis. 2004 June; 25(6): 873-9. Epub 2004 January 16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14729579
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Heparin-binding EGF-like growth factor regulates elastin and FGF-2 expression in pulmonary fibroblasts. Author(s): Liu J, Rich CB, Buczek-Thomas JA, Nugent MA, Panchenko MP, Foster JA. Source: American Journal of Physiology. Lung Cellular and Molecular Physiology. 2003 November; 285(5): L1106-15. Epub 2003 July 25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12882762
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Heparin-binding epidermal-growth-factor-like growth factor gene expression is induced by scrape-wounding epithelial cell monolayers: involvement of mitogenactivated protein kinase cascades. Author(s): Ellis PD, Hadfield KM, Pascall JC, Brown KD. Source: The Biochemical Journal. 2001 February 15; 354(Pt 1): 99-106. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11171084
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Heparinoids: structure, biological activities and therapeutic applications. Author(s): Gunay NS, Linhardt RJ. Source: Planta Medica. 1999 May; 65(4): 301-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10364832
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Heparin-platelet factor (PF) 4 antibodies in patients with pseudothrombocytopenia: coincidence or association? Author(s): Schwarzinger I, Speiser W, Lubenow N, Greinacher A, Panzer S. Source: Thrombosis and Haemostasis. 2000 December; 84(6): 1123-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11154128
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Heterogeneity of the chondroitin sulfate portion of phosphacan/6B4 proteoglycan regulates its binding affinity for pleiotrophin/heparin binding growth-associated molecule. Author(s): Maeda N, He J, Yajima Y, Mikami T, Sugahara K, Yabe T. Source: The Journal of Biological Chemistry. 2003 September 12; 278(37): 35805-11. Epub 2003 July 02. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12840014
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High-dose heparin impairs nitric oxide pathway and vasomotion in rats. Author(s): Bachetti T, Pasini E, Clini E, Cremona G, Ferrari R. Source: Circulation. 1999 June 8; 99(22): 2861-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10359728
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Hirudin therapy during thrombolysis for venous thrombosis in heparin-induced thrombocytopenia. Author(s): Reilly MP, Weiss R, Askenase A, Tuite C, Soulen M, Mohler ER 3rd. Source: Vascular Medicine (London, England). 2000; 5(4): 239-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11213236
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Hypothermia-induced platelet aggregation in heparinized flowing human blood: identification of a high responder subpopulation. Author(s): Hall MW, Goodman PD, Alston SM, Solen KA. Source: American Journal of Hematology. 2002 January; 69(1): 45-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11835331
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Identification of a major heparin and cell binding site in the LG4 module of the laminin alpha 5 chain. Author(s): Nielsen PK, Gho YS, Hoffman MP, Watanabe H, Makino M, Nomizu M, Yamada Y. Source: The Journal of Biological Chemistry. 2000 May 12; 275(19): 14517-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10799535
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Influence of EDTA and heparin on lipopolysaccharide binding and cell activation, evaluated at single-cell level in whole blood. Author(s): Brunialti MK, Kallas EG, Freudenberg M, Galanos C, Salomao R. Source: Cytometry : the Journal of the Society for Analytical Cytology. 2002 February 15; 50(1): 14-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11857593
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Inhibitory effect of heparin on skin reactivity to autologous serum in chronic idiopathic urticaria. Author(s): Fagiolo U, Cancian M, Bertollo L, Peserico A, Amadori A. Source: The Journal of Allergy and Clinical Immunology. 1999 June; 103(6): 1143-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10359897
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Interaction between the carboxyl-terminal heparin-binding domain of fibronectin and (-)-epigallocatechin gallate. Author(s): Sazuka M, Isemura M, Isemura S. Source: Bioscience, Biotechnology, and Biochemistry. 1998 May; 62(5): 1031-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9648240
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Laminin E8 alveolarization site: heparin sensitivity, cell surface receptors, and role in cell spreading. Author(s): Chen L, Shick V, Matter ML, Laurie SM, Ogle RC, Laurie GW. Source: The American Journal of Physiology. 1997 March; 272(3 Pt 1): L494-503. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9124607
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Low-molecular-weight heparin and platelet glycoprotein IIb/IIIa receptor blockade in the treatment of acute coronary syndromes: complementary or competing therapies? Author(s): White HD. Source: J Invasive Cardiol. 2000 February; 12 Suppl A: 6A-13A. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10731290
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Low-molecular-weight heparin as a multipurpose anticoagulant for laboratory testing. Author(s): Kawamoto T, Hiino M, Takubo T, Tatsumi N.
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Low-molecular-weight heparins and Daflon for prevention of postoperative thromboembolism. Author(s): Tsimoyiannis EC, Floras G, Antoniou N, Papanikolaou N, Siakas P, Tassis A. Source: World Journal of Surgery. 1996 October; 20(8): 968-71; Discussion 972. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8798349
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Matrix metalloproteinase production by COOH-terminal heparin-binding fibronectin fragment in rheumatoid synovial cells. Author(s): Yasuda T, Shimizu M, Nakagawa T, Julovi SM, Nakamura T. Source: Laboratory Investigation; a Journal of Technical Methods and Pathology. 2003 February; 83(2): 153-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12594231
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Modulation of lipopolysaccharide-induced monocyte activation by heparin-binding protein and fucoidan. Author(s): Heinzelmann M, Polk HC Jr, Miller FN. Source: Infection and Immunity. 1998 December; 66(12): 5842-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9826363
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Non-anticoagulant heparin increases endothelial nitric oxide synthase activity: role of inhibitory guanine nucleotide proteins. Author(s): Kouretas PC, Hannan RL, Kapur NK, Hendrickson R, Redmond EM, Myers AK, Kim YD, Cahill PA, Sitzmann JV. Source: Journal of Molecular and Cellular Cardiology. 1998 December; 30(12): 2669-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9990538
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Pharmacokinetics and pharmacodynamics of low-molecular-weight heparins and glycoprotein IIb/IIIa receptor antagonists in renal failure. Author(s): Smith BS, Gandhi PJ. Source: Journal of Thrombosis and Thrombolysis. 2001 February; 11(1): 39-48. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11248789
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Pharmacokinetics and pharmacodynamics of sibrafiban, an orally administered GP IIb/IIIa antagonist, following coadministration of aspirin and heparin. Author(s): Reimann JD, Modi NB, Novotny W. Source: Journal of Clinical Pharmacology. 2000 May; 40(5): 488-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10806602
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Post-heparin serum lecithinase in man and its positional specificity. Author(s): Vogel WC, Bierman EL.
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Reversal of RT-PCR inhibition observed in heparinized clinical specimens. Author(s): Jung R, Lubcke C, Wagener C, Neumaier M. Source: Biotechniques. 1997 July; 23(1): 24, 26, 28. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9232220
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Role of the gamma-carboxyglutamic acid domain of activated factor X in the presence of calcium during inhibition by antithrombin-heparin. Author(s): Whinna HC, Lesesky EB, Monroe DM, High KA, Larson PJ, Church FC. Source: Journal of Thrombosis and Haemostasis : Jth. 2004 July; 2(7): 1127-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15219196
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Seasonal variation in the effect of a fixed dose of heparin on activated clotting time in patients prepared for open-heart surgery. Author(s): Hodoglugil U, Gunaydin B, Yardim S, Zengil H, Smolensky MH. Source: Chronobiology International. 2001 September; 18(5): 865-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11763993
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Simpler technique for measuring oxidative susceptibility by heparin affinity column isolation of lipoproteins. Author(s): Kaplan IV, Hobbs GA, Levinson SS. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 1999 May; 283(1-2): 89-103. Erratum In: Clin Chim Acta 1999 September; 287(1-2): 173. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10404734
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Sulfated polysaccharide from the leaves of Artemisia Princeps activates heparin cofactor II independently of the Lys173 and Arg189 residues of heparin cofactor II. Author(s): Hayashi T, Hayakawa Y, Hayashi T, Sasaki H, Sakuragawa N. Source: Thrombosis Research. 1997 July 1; 87(1): 105-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9253805
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The effects of heparin and extracorporeal circulation on platelet counts and platelet microaggregation during cardiopulmonary bypass. Author(s): Muriithi EW, Belcher PR, Rao JN, Chaudhry MA, Nicol D, Wheatley DJ. Source: The Journal of Thoracic and Cardiovascular Surgery. 2000 September; 120(3): 538-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10962416
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The fourth immunoglobulin-like loop in the extracellular domain of FLT-1, a VEGF receptor, includes a major heparin-binding site. Author(s): Park M, Lee ST.
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Source: Biochemical and Biophysical Research Communications. 1999 November 2; 264(3): 730-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10544000 •
The hemopexin-like domain (C domain) of human gelatinase A (matrix metalloproteinase-2) requires Ca2+ for fibronectin and heparin binding. Binding properties of recombinant gelatinase A C domain to extracellular matrix and basement membrane components. Author(s): Wallon UM, Overall CM. Source: The Journal of Biological Chemistry. 1997 March 14; 272(11): 7473-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9054449
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The heparin-binding 10 kDa fragment of connective tissue growth factor (CTGF) containing module 4 alone stimulates cell adhesion. Author(s): Ball DK, Rachfal AW, Kemper SA, Brigstock DR. Source: The Journal of Endocrinology. 2003 February; 176(2): R1-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12553878
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The HepG2 extracellular matrix contains separate heparinase- and lipid-releasable pools of ApoE. Implications for hepatic lipoprotein metabolism. Author(s): Burgess JW, Gould DR, Marcel YL. Source: The Journal of Biological Chemistry. 1998 March 6; 273(10): 5645-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9488694
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The medicinal plant Porana volubilis contains polysaccharides with anticoagulant activity mediated by heparin cofactor II. Author(s): Yoon SJ, Pereira MS, Pavao MS, Hwang JK, Pyun YR, Mourao PA. Source: Thrombosis Research. 2002 April 1; 106(1): 51-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12165289
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Therapeutic uses of heparinoids in renal disease patients. Author(s): Striker GE. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 1999 March; 14(3): 540-3. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10193791
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Thrombolysis using plasminogen activator and heparin reduces cerebral no-reflow after resuscitation from cardiac arrest: an experimental study in the cat. Author(s): Fischer M, Bottiger BW, Popov-Cenic S, Hossmann KA. Source: Intensive Care Medicine. 1996 November; 22(11): 1214-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9120116
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Treatment of proximal vein thrombosis with subcutaneous low-molecular-weight heparin vs intravenous heparin. An economic perspective. Author(s): Hull RD, Raskob GE, Rosenbloom D, Pineo GF, Lerner RG, Gafni A, Trowbridge AA, Elliott CG, Green D, Feinglass J. Source: Archives of Internal Medicine. 1997 February 10; 157(3): 289-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9040295
Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •
Alternative Medicine Foundation, Inc.: http://www.herbmed.org/
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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats
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Chinese Medicine: http://www.newcenturynutrition.com/
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drkoop.com: http://www.drkoop.com/InteractiveMedicine/IndexC.html
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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm
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Google: http://directory.google.com/Top/Health/Alternative/
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Healthnotes: http://www.healthnotes.com/
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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine
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Open Directory Project: http://dmoz.org/Health/Alternative/
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HealthGate: http://www.tnp.com/
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WebMDHealth: http://my.webmd.com/drugs_and_herbs
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/
The following is a specific Web list relating to heparin; 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 Angina Source: Integrative Medicine Communications; www.drkoop.com Atherosclerosis and Heart Disease Prevention Source: Prima Communications, Inc.www.personalhealthzone.com Cyclic Mastalgia Alternative names: Cyclic Mastitis, Fibrocystic Breast Disease Source: Prima Communications, Inc.www.personalhealthzone.com
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Dermatitis Herpetiformis Source: Healthnotes, Inc.; www.healthnotes.com Dysmenorrhea Alternative names: Painful Menstruation Source: Prima Communications, Inc.www.personalhealthzone.com Heart Attack Source: Healthnotes, Inc.; www.healthnotes.com Heart Attack Source: Integrative Medicine Communications; www.drkoop.com High Cholesterol Source: Prima Communications, Inc.www.personalhealthzone.com Migraine Headaches Source: Prima Communications, Inc.www.personalhealthzone.com Miscarriage Source: Integrative Medicine Communications; www.drkoop.com Myocardial Infarction Source: Integrative Medicine Communications; www.drkoop.com Nausea Source: Prima Communications, Inc.www.personalhealthzone.com Prostate Cancer Source: Healthnotes, Inc.; www.healthnotes.com Psoriasis Source: Prima Communications, Inc.www.personalhealthzone.com Rheumatoid Arthritis Source: Prima Communications, Inc.www.personalhealthzone.com Spontaneous Abortion Source: Integrative Medicine Communications; www.drkoop.com Stroke Source: Healthnotes, Inc.; www.healthnotes.com Varicose Veins Source: Prima Communications, Inc.www.personalhealthzone.com •
Herbs and Supplements Aesculus Alternative names: Horse Chestnut; Aesculus hippocastanum L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org
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Aloe Alternative names: Aloe vera L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Aortic Glycosaminoglycans Source: Prima Communications, Inc.www.personalhealthzone.com Bromelain Source: Prima Communications, Inc.www.personalhealthzone.com Coleus Forskohlii Source: Prima Communications, Inc.www.personalhealthzone.com Devil's Claw Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,970,00.html Eleuthero Alternative names: Siberian Ginseng, Eleuthero; Acanthopanax/Eleutherococcus senticosus Rupr. & Maxim. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Eugenia Clove Alternative names: Cloves; Eugenia sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Feverfew Source: Prima Communications, Inc.www.personalhealthzone.com Ginger Source: Prima Communications, Inc.www.personalhealthzone.com Ginkgo Source: Prima Communications, Inc.www.personalhealthzone.com Ginkgo Biloba Source: Healthnotes, Inc.; www.healthnotes.com Ginkgo Biloba Alternative names: Maidenhair Tree Source: Integrative Medicine Communications; www.drkoop.com Heparin Source: Healthnotes, Inc.; www.healthnotes.com Heparin Alternative names: Hep-Lock Source: Prima Communications, Inc.www.personalhealthzone.com Horse Chestnut Source: Prima Communications, Inc.www.personalhealthzone.com
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Maidenhair Tree Alternative names: Ginkgo Biloba Source: Integrative Medicine Communications; www.drkoop.com OPCS (Oligomeric Proanthocyanidins) Source: Prima Communications, Inc.www.personalhealthzone.com Phosphatidylserine Source: Prima Communications, Inc.www.personalhealthzone.com Red Clover Source: Prima Communications, Inc.www.personalhealthzone.com Reishi Source: Prima Communications, Inc.www.personalhealthzone.com Tetracycline Source: Healthnotes, Inc.; www.healthnotes.com Vanadate Alternative names: Vanadium Source: Integrative Medicine Communications; www.drkoop.com Vanadyl Alternative names: Vanadium 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 HEPARIN Overview In this chapter, we will give you a bibliography on recent dissertations relating to heparin. 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 “heparin” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on heparin, we have not necessarily excluded non-medical dissertations in this bibliography.
Dissertations on Heparin 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 heparin. 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: •
Efficacy of 4% trisodium citrate compared to saline or diluted heparin solution in patency of central venous triple lumen catheters in critically ill patients by Michaud, Dominique Camille Yvon, MN from University of Alberta (Canada), 2003, 105 pages http://wwwlib.umi.com/dissertations/fullcit/MQ82239
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Manipulating the surface active and anticoagulant properties of heparin through amphiphilic molecular constructs by Mintz, Rosita Candida, PhD from Case Western Reserve University, 2004, 221 pages http://wwwlib.umi.com/dissertations/fullcit/3118146
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Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.
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CHAPTER 5. PATENTS ON HEPARIN Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.8 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “heparin” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on heparin, we have not necessarily excluded non-medical patents in this bibliography.
Patents on Heparin By performing a patent search focusing on heparin, 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
8Adapted
from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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will tell you how to obtain this information later in the chapter. The following is an example of the type of information that you can expect to obtain from a patent search on heparin: •
Biocompatible medical articles and process for their production Inventor(s): Al-Lamee; Kadam Gayad (Yorkshire, GB) Assignee(s): Polybiomed Limited (Sheffield, GB) Patent Number: 6,756,125 Date filed: September 23, 2002 Abstract: An article of metal, glass, ceramics or plastics having a surface for contact with tissue or with circulating blood, has a surface coating of an organopolysiloxane and heparin, in which coating the organopolysiloxane is adherent to the surface of the article and has cationic groups that form ionic bonds with anionic groups of the heparin. The surface for contact with circulating blood may be an interior surface of a cannula or tubing or of a blood oxygenator or it may be a working surface of a blood filter. The polymer may be poly-[dimethylsiloxane-co-methyl-(3-hydroxypropyl)siloxane]-graftpoly(eth ylene glycol) [3-(trimethylammonio) propyl chloride] ether. A method is also provided for forming a coated article as aforesaid, said method comprising contacting said surface with a solution in a volatile organic solvent of an organopolysiloxane and with heparin, the organopolysiloxane being adherent to the surface of the article and having cationic groups that form ionic bonds with the anionic groups of the heparin, and removing said volatile solvent. Excerpt(s): This invention relates to medical articles that can be placed in contact with a stream of blood or other tissue and which have surfaces that are anti-thrombogenic. It also relates to a process for treating a medical article to impart anti-thrombogenic properties to a surface thereof. Articles for contact with circulating blood, whether intracorporeally or during extracorporeal blood circulation, can give rise to coagulation. In particular, plastics materials have been found to be thrombogenic, even in the case of relatively blood-compatible materials such as polytetrafluoroethylene and silicone rubber. In order to minimize trauma in blood circulating in contact with articles having non-biological surfaces, bonding of heparin to such surfaces has been disclosed, the heparin imparting anti-thrombogenic properties. Bonding of heparin to surfaces was first described by V. I. Gott et. Al., Science, 142, 1297 (1963), the surfaces being graphitized, treated with benzalkonium chloride and then with heparin. Subsequently a simpler surface treatment was developed based on coating the surface e.g. by simple immersion with a thin layer of tridodecylmethyl ammonium heparinate, see V. I. Gott et. al., Ann. Thoracic Surg., 14, 219 (1972) and A. H. Krause et. al, Ann. Thoracic Surg., 14, 123 (1972). According to a data sheet issued by Polysciences Limited of Northampton, England in 1984 the process was used to make shunts for use in artery bypass. Greater stability to washing can be achieved by cross-linking the bonded heparin molecules with dialdehydes, see U.S. Pat. No. 3,810,781 (Eriksson), and an increased level of heparin uptake can be achieved in the case of plastics articles by glowor corona-treating the surface of the article, see U.S. Pat. No. 4,613,517. The use of socalled "Duraflo II heparin" coatings to reduce blood trauma in extracorporeal circuits e.g. of cardiopulmonary bypass machines is disclosed by Li-Chien Hsu, Cardiac Surgery: state of the art reviews-Vol. 7, No. 2, 265 (1993). The effectiveness of so-called "heparin bonded circuits" in reducing the need for blood transfusion during coronary artery bypass surgery is disclosed by G. M. Mahoney et. al., European Journal of Cardiothoracic Surgery.
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Web site: http://www.delphion.com/details?pn=US06756125__ •
Biocompatible metallic materials grafted with biologically active compounds and preparation thereof Inventor(s): Goo; Hyun Chul (Seoul, KR), Kim; Soo Hyun (Seoul, KR), Kim; Young Ha (Seoul, KR), Lee; Won Kyu (Daejeon, KR), Park; Ki Dong (Seoul, KR) Assignee(s): Korea Institute of Science and Technology (Seoul, KR) Patent Number: 6,617,027 Date filed: March 26, 2001 Abstract: Disclosed are surface-modified medical metallic materials and preparation thereof. The medical metallic material is prepared by coating a gold or silver thin layer onto a base metal, adsorbing a polyfunctional sulfur compound onto the gold or silver thin layer, and chemically bonding a biologically active material such as heparin or estradiol to the functional group of the sulfur compound. The biologically active material is firmly bonded to the base metal via the sulfur compound. Being significantly improved in antithrombogenicity and biocompatibility, the metallic materials are suitable for use in various implants, including stents, artificial cardiac valves and catheters. Excerpt(s): The present invention relates to medical metallic materials, especially medical tools for use in circulatory systems, whose surface is modified to improve antithrombogenicity and biocompatibility. More particularly, the present invention relates to the reliable introduction of a biologically active compound onto the surface of a base metal via a linker, thereby bringing about a great improvement in the antithrombogenicity and biocompatibility of the base metal. Also, the present invention is concerned with a method for preparing such a medical metallic material and with the use of the metallic material in the medical field. For use in substituting for congenitally or postnatally defective valves of the heart, artificial cardiac valves are generally classified into two groups: valves made of tissues and mechanical valves, which are made of metallic materials. Tissue values show excellent biocompatibility, but poor internal durability due to calcification. On the other hand, mechanical valves endure for extended periods in vivo, but have the disadvantage of forcing the patients to take anticoagulants throughout their lifetime because they are likely to generate thrombus. In spite of extensive research, satisfactory advance has not been yet achieved in the antithrombogenicity of mechanical valves. Indeed, not only is it virtually impossible to prevent thrombogenesis, a normal physiological function of the body, but also its mechanism has not been disclosed completely. Extensively conducted for the treatment of coronary stenosis is percutaneous transluminal coronary angioplasty in which an intraaortic balloon catheter is inserted within the coronary artery to expand the blood vessel. This operation brings about relatively good results, and development has been and continues to be ongoing in the processes and tools for percutaneous transluminal coronary angioplasty. However, such problems as acute closure and restenosis still remain unsolved. Web site: http://www.delphion.com/details?pn=US06617027__
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Combinations of heparin cofactor II agonist and platelet IIb/IIIa antagonist, and uses thereof Inventor(s): Cardin; Alan D. (Cincinnati, OH), Van Gorp; Cornelius L. (Springboro, OH) Assignee(s): IntimaX Corporation (Cincinnati, OH) Patent Number: 6,518,244 Date filed: March 9, 2001 Abstract: Combined use of a heparin cofactor II agonist and a platelet GPIIb/IIIa receptor antagonist to inhibit both platelet aggregation and thrombin generation resulting from disease, injury or responses to wound repairs. The combined use of the heparin cofactor II agonist and the platelet GPIIb/IIIa receptor antagonist can achieve these therapeutic benefits while at the same time minimizing or reducing the risk of hemorrhagic side effects (e.g., prolonged bleeding), and without causing undesired antigenic responses. Moreover, certain subtherapeutic amounts of the heparin cofactor II agonist with certain subtherapeutic amounts of a platelet GPIIb/IIIa receptor antagonist can, in combination, be therapeutically effective in inhibiting both platelet aggregation and thrombin generation. Excerpt(s): The present application relates to combinations of a heparin cofactor II agonist and a platelet glycoprotein IIb/IIIa receptor (GPIIb/IIIa) antagonist that are useful in inhibiting both platelet aggregation and thrombin generation resulting from disease, or injury responses to wound repairs. The present application particularly relates to the use of subtherapeutic amounts of a heparin cofactor II agonist and subtherapeutic amounts of a platelet GPIIb/IIIa receptor antagonist that, in combination, are therapeutically effective in inhibiting both platelet aggregation and thrombin generation. Cardiovascular disease is the primary cause of death in the USA. According to the American Heart Association, 2.5 million individuals suffer from venous thrombosis and 600,000 suffer from pulmonary embolism each year. In 1996, approximately 830,000 cardiac surgeries and 700,000 cardiac catheterization procedures were performed in the USA as a result of arterial and venous thromboses. Usually, anticoagulant therapy is implemented either alone or in combination with anti-platelet and/or anti-fibrinolytic therapies, particularly in acute care settings where the immediate reopening of a blocked vessel becomes imperative. The drugs used in these therapies, however, have certain dose-limiting side effects, the foremost being hemorrhagic (i.e., prolonged bleeding) and when used in combination, these side effects can become potentiated, further limiting effective dosing and duration of the needed drug treatment. See Fareed, "Drug Interactions with Antiplatelet Agents" IBC 3.sup.rd Annual Mini-Symposium on Advances in Antiplatelet Therapies (Waltham, Mass. 2000). With current anticoagulants, the bleeding effects are due to an action on one or more of the enzymes that regulate hemostasis in the global circulation, versus their action in a more specific and limited sense on enzymes of the hemostatic mechanism that promote the disease process at the vascular wall, e.g., low selectivity. Likewise, antiplatelet drugs exhibit strong interactions with the anticoagulants (such as heparin), antithrombin drugs and thrombolytic agents, and safety considerations, for example, preclude their administration to patients at high risk for intracranial hemorrhage, particularly elderly patients with poorly controlled hypertension and previous manifestations of cerebrovascular disease. Web site: http://www.delphion.com/details?pn=US06518244__
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Compliant dehyrated tissue for implantation and process of making the same Inventor(s): Cheung; David T. (Arcadia, CA), Duran; Carlos M. G. (Missoula, MT), Pang; David C. (Missoula, MT) Assignee(s): International Heart Institute of Montana Foundation (Missoula, MT) Patent Number: 6,630,001 Date filed: June 24, 1998 Abstract: A process for preparing pliable soft tissue specimen which are resistant to cracking and devoid of viable cells includes the steps of treating native soft tissue obtained from a donor by a gradually increasing gradient of aliphatic alcohol or other suitable water miscible polar organic solvent until the last alcohol (or other solvent) solution has at least 25% by volume of the organic liquid. Thereafter, the tissue specimen is treated with a solution containing glycerol or low molecular weight (<1000 D) polyethylene glycol, and polyethylene glycol of a molecular weight between approximately 6,000 to 15,000 D and heparin. Thereafter, the tissue specimen is briefly immersed in aqueous heparin solution, frozen and lyophilized. The tissue specimen is suitable for implantation as a homograft or xenograft, with or without rehydration. Excerpt(s): The present invention is in the field of implant materials. More particularly, the present invention is directed to compliant dehydrated implant materials which have no viable cells, and can be stored and transported without being immersed in liquid. The present invention is also directed to the process of producing said implant materials. The use of autografts, homografts and xenografts for augmenting or replacing defective tissues in humans and animals has been known for a long time. From the standpoint of providing suitable materials for implantation, augmenting or replacing hard tissues, such as bone, presents a different type of problem than augmenting or replacing soft tissues. In the selection of substitute materials for hard tissue graft, the strength and hardness of the graft are important whereas compliance and flexibility are, generally speaking, less crucial. On the other hand, in the selection of soft tissue materials for implantation, compliance and flexibility of the graft material are usually of utmost importance because the soft tissue replacement material usually must closely match the healthy functional tissue that will be replaced. In this regard it must be remembered that natural soft tissue containing collagen is strong and able to withstand repeated three-dimensional stress as well as bending and deformation. Often natural soft tissue acts as a physical barrier that must maintain its structural integrity. Ideally, replacement or augmentation soft tissue that is utilized in implantation should have the same characteristics as the natural soft tissue that it replaces, and should be easy to obtain, store and transport. These, however are difficult goals that the prior art has been striving to attain, and up to the present invention only with moderate success. Web site: http://www.delphion.com/details?pn=US06630001__
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Composition comprising heparin as a non-thrombogenic surface coating agent Inventor(s): Holmer; Erik (Stockholm, SE) Assignee(s): Carmeda AB (Stockholm, SE) Patent Number: 6,559,132 Date filed: February 27, 2001
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Abstract: The present invention relates to a composition comprising heparin to be used as a non-thrombogenic surface when in contact with arterial blood flow. It also relates to a device treated on the surface thereof with such a composition. Excerpt(s): This application is a 371 of PCT/NO99/00278, filed Sep. 9, 1999. The present invention relates to a composition comprising heparin to be used as a nonthrombogenic surface coating agent when in contact with arterial blood flow. It also relates to a device treated on the surface thereof with such a composition. Thrombosis is a major health problem in the industrialized world. Thrombosis related diseases cause the death of several millions of people every year and the health care costs have been estimated to be over 90 billion US dollars just for the USA. Web site: http://www.delphion.com/details?pn=US06559132__ •
Controlled release of non heparin-binding growth factors from heparin-containing matrices Inventor(s): Hubbell; Jeffrey A. (Zurich, CH), Sakiyama-Elbert; Shelly E. (Zurich, CH) Assignee(s): Eidgenossische Technische Hochschule (Zurich, CH), Universitat Zurich (Zurich, CH) Patent Number: 6,723,344 Date filed: May 3, 2001 Abstract: Matrices that support cell adhesion and growth are disclosed that deliver low heparin-binding affinity growth factor protein peptides in a controlled manner. These matrices comprise covalently or non-covalently bound heparin or heparin-like polymers, which serve to sequester the low heparin-binding affinity growth factor protein peptides within the matrix. The controlled release of some low heparin-binding affinity growth factor or peptides thereof occurs by degradation of some matrix component or dissociation of the low heparin-binding affinity growth factor protein peptides from the bound heparin. This differs from many controlled delivery devices in that release is not controlled solely by diffusion, and the rate of release may therefore be regulated by altering the rate of degradation of the matrix component or the amount of heparin bound within the matrix. The controlled release of such low heparin-binding affinity growth factor proteins such as NGF-.beta., NT-3 and BDNF, is demonstrated. The invention also identifies basic domains that can be utilized to identify other low heparin-binding affinity growth factor protein peptides useful in delivery as part of the matrices described herein. Excerpt(s): The present invention relates to the field of three-dimensional matrices that contain pharmacologically active molecules, particularly growth factors. The invention also relates to the use of growth factors or proteins in a matrix designed to promote cell and tissue growth. The invention further relates to the use of growth factors with low heparin-binding affinity. In addition, the invention relates to the field of articles of manufacture useful as implantable devices and wound dressings as the matrix of the invention is designed to be used in conjunction with such devices to provide protracted and controlled release of growth factor, thus promoting wound healing in the patient. Many growth factors are thought of as "heparin-binding" growth factors. Families with one or more members that bind heparin include fibroblast growth factors and bone morphogenetic proteins (BMPs) (1, 2). Additional growth factors that bind heparin include transforming growth factor.beta.1 (TGF-.beta.1), interleukin-8, neurotrophin-6, vascular endothelial cell growth factor, heparin-binding epidermal growth factor,
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hepatocyte growth factor, connective tissue growth factor, midkine, and heparinbinding growth associate molecule (3-11). These factors have shown the potential to enhance healing in many different types of tissue including vasculature, skin, nerve, and liver. Controlled delivery devices based on heparin-affinity of these growth factors have been designed previously (12-14). These drug delivery devices have previously been used to deliver "heparin-binding" growth factors. Such "heparin-binding" growth factors are typically considered to be those which bind to heparin with a relatively high affinity, often characterized by elution from heparin-affinity columns at NaCl concentrations well above physiological levels (>140 mM). In such delivery systems, the heparin-binding affinity of the growth factor is usually used to sequester the growth factors to immobilized heparin of some form. For example, Edelman et al. have used heparin-conjugated Sepharose beads to bind basic fibroblast growth factor (bFGF) and then encapsulated the beads with alginate (12, 19). These beads serve as reservoirs that release bFGF slowly based on the binding and dissociation constants of bFGF and heparin. Web site: http://www.delphion.com/details?pn=US06723344__ •
Fast-acting pharmaceutical compositions and methods of use Inventor(s): McKay; Douglas William (450 Moosa Blvd., Suite C, Eunice, LA 70535) Assignee(s): none reported Patent Number: 6,569,839 Date filed: November 30, 1999 Abstract: A pharmaceutical composition comprising at least one local anesthetic, at least one anti-inflammatory agent and at least one antibiotic are disclosed. The local anesthetic has a peak effect no later than about 10 minutes after administration to a mammal, and the anesthetic and anti-inflammatory have a half-life of no greater than about 36 hours after administration. The pharmaceutical composition, thus, advantageously provides rapid relief of pain with a substantially low residual accumulation of active components so that the pharmaceutical composition can be repeatedly or continuously administered to a wound. Embodiments include preparing a medicinal solution including Lidocaine as the local anesthetic, Hydrocortisone sodium succinate as the anti-inflammatory agent, Chloramphenicol as the antibiotic agent and, optionally, Heparin as an anticoagulant. The medicinal solution is continuously administered to treat a wound of a mammal to maintain a constant positive physiological pressure in the treated wound at a pressure to enable permeation of the medicinal solution and fluids from the wound with concomitant periodical suctioning of debris from the wound. Excerpt(s): The present invention relates to pharmaceutical compositions useful for the treatment of a wound or joint, with particular applicability to post operative closed muscular skeletal wounds. The pharmaceutical composition provides alleviation of pain, while promoting healing of the wound and early rehabilitation. Of major concern in the care of wounds, such as incurred in joint surgery, are relief of post-operative pain, avoidance of infection, hastening of healing, early joint motion, and a decrease in the length of necessary hospital services. Traditional post-operative management of orthopaedic wounds or traumatic wounds have varied in approach. However, an important consideration in the management of wounds is to prevent the painful accumulation of blood and debris and to prevent infection following the formation of an open wound. Pain relief and reduced swelling can be minimized by leaving a surgical
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wound or traumatic wound open thereby encouraging the free flow of debris and accumulated fluid out of the wound. Irrigation of the open wound with a sterile solution further promotes the removal of debris, blood, extra-cellular fluid, etc. The same debris and blood in an open wound, however, provide an excellent culture medium for bacterial growth and, hence, such techniques invite infection and promote contamination. Wound closure, conversely, prevents the beneficial flow of debris and fluid from the wound with concomitant pain relief but advantageously reduces the occurrence of bacterial infection and otherwise exterior contamination. Web site: http://www.delphion.com/details?pn=US06569839__ •
Glycosaminoglycan-antithrombin III/heparin cofactor II conjugates Inventor(s): Andrew; Maureen (Oakville, CA), Berry; Leslie (Burlington, CA) Assignee(s): Hamilton Civic Hospitals Research Development Inc. (Ontario, CA) Patent Number: 6,562,781 Date filed: November 30, 1995 Abstract: Novel conjugates of glycosaminoglycans, particularly heparin and dermatan sulfate, and amine containing species and therapeutic uses thereof are described. In particular, mild methods of conjugating heparins to proteins, such as antithrombin III and heparin cofactor II, which provide covalent conjugates which retain maximal biological activity are described. Uses of these conjugates to prevent thrombogenesis, in particular in lung airways, such as found in infant and adult respiratory distress syndrome are also described. Excerpt(s): This invention relates to new chemical compounds comprising covalent conjugates of glycosaminoglycans, particularly heparins, methods for their preparation, their pharmaceutical compositions and therapeutic uses thereof. Heparin is a sulfated polysaccharide which consists largely of an alternating sequence of hexuronic acid and 2-amino-2-deoxy-D-glucose. Heparin and a related compound, dermatan sulfate, are of great importance as anticoagulants for clinical use in the prevention of thrombosis and related diseases. They are members of the family of glycosaminoglycans, (GAGs), which are linear chains of sulfated repeating disaccharide units containing a hexosamine and a uronic acid. Anticoagulation using GAGs (such as heparin and dermatan sulfate) proceeds via their catalysis of inhibition of coagulant enzymes (the critical one being thrombin) by serine protease inhibitors (serpins) such as antithrombin III (ATIII) and heparin cofactor II (HCII). Binding of the serpins by the catalysts is critical for their action and occurs through specific sequences along the linear carbohydrate chain of the glycosaminoglycan (GAG). Heparin acts by binding to ATIII via a pentasaccharide sequence, thus potentiating inhibition of a variety of coagulant enzymes (in the case of thrombin, heparin must also bind to the enzyme). Heparin can also potentiate inhibition of thrombin by binding to the serpin HCII. Dermatan sulfate acts by specifically binding to HCII via a hexasaccharide sequence, thus potentiating only the inhibition of thrombin. Since glycosaminoglycans (particularly heparin) can bind to other molecules in vivo or be lost from the site of action due to a variety of mechanisms, it would be advantageous to keep the GAG permanently associated with the serpin by a covalent bond. Covalent complexes between ATIII and heparin have been produced previously; see, e.g., Bjork et al., (1982) FEBS Letters 143(1):96-100, and by Collen et al., U.S. Pat. No. 4,623,718. These conjugates required covalent modification of the heparin prior to its conjugation. The product by Bjork et al. (produced by reduction of the Schiff base between the aldehyde of a 2,5-D-anhydromannose terminus of heparin, produced by
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partial depolymerization of heparin to heparin fragments with nitrous acid, and a lysyl amino of ATIII) had undetectable antithrombin activity. The product by Collen et al. (produced by conjugation of carboxyl groups within the chain of the heparin molecule and lysyl amino groups of ATIII through amino-hexyl tolyl spacer arms) had a random attachment to the carboxyls of the uronic acids of the heparin moiety that might affect the ATIII binding sequence and in fact the specific anti-Xa (a coagulation protease which activates prothrombin to thrombin) activity was approximately 65% of the starting noncovalently linked unmodified heparin (J. Biol. Chem. 257:3401-3408 (1982)). The specific anti-thrombin activity would also be, therefore, 65% or less since both Xa and thrombin require heparin binding to ATIII. The bimolecular rate constant of the product by Collen et al. for inhibition of thrombin was claimed to be comparable to that of non-covalent mixtures of heparin saturated with ATIII (J. Biol. Chem. 259:5670-5677 (1984)). However, large molar excesses of heparin or covalent complex over thrombin (>10:1) were used to simplify the kinetics, which would mask the effect of any subpopulation of molecules with low activity. Specific antithrombin activities were not given. Web site: http://www.delphion.com/details?pn=US06562781__ •
Heparin delivery method Inventor(s): Chan; Randy (San Jose, CA), Yan; John Y. (Los Gatos, CA) Assignee(s): Advanced Cardiovascular Systems, Inc. (Santa Clara, CA) Patent Number: 6,605,114 Date filed: October 29, 1999 Abstract: A method for delivering heparin, wherein an implantable stent is coated with a material that attracts heparin and with which heparin forms a bond. The stent is exposed to a heparin containing solution just prior to implantation or is first implanted and then exposed to heparinized blood. As heparin becomes detached from the stent, the implantation site is exposed to heparin to restore an effective level and thereby prevent thrombosis. Excerpt(s): The present invention relates to endovascular stents and more particularly pertains to coatings that are applied to stents in order to reduce thrombogenicity. Stents are implanted within blood vessels in an effort to maintain their patency by preventing collapse of the lumen and/or by impeding restenosis. Unfortunately, the presence of a foreign object within the blood flow may have a thrombogenic effect. It has therefore been found to be desirable to use various anti-coagulant drugs in an effort to reduce the likelihood of the development of restenosis and provide an antithrombogenic effect. A drug that has been found to be particularly effective for such purpose is heparin. By maintaining an effective concentration of the drug in and about the implantation site until the stent is encapsulated by tissue, the risk of thrombogenesis is substantially mitigated. To that end, various approaches have been employed in the administration of heparin. Web site: http://www.delphion.com/details?pn=US06605114__
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Inhibition of L-selectin and P-selection mediated binding using heparin Inventor(s): Koenig; Andrea (La Jolla, CA), Varki; Ajit (Del Mar, CA) Assignee(s): The Regents of the University of California (Oakland, CA) Patent Number: 6,596,705 Date filed: February 8, 1999 Abstract: The present invention provides methods of inhibiting L-selectin and P-selectin mediated binding in a subject by administering heparin to the subject in an amount that does not produce substantial anticoagulant activity or undesirable bleeding in the subject. In addition, the invention provides methods of treating a subject having a pathology characterized, at least in part, by abnormal L-selectin or P-selectin mediated binding by administering heparin to the subject in an amount that results in attaining a concentration of less than about 0.2-0.4 units heparin per ml of plasma in the subject. Excerpt(s): The present invention relates generally to molecular biology and, more specifically, to methods of modulating L-selectin and P-selectin mediated binding in a subject by administering heparin to the subject in an amount that does not produce substantial anticoagulation activity or undesirable bleeding. L-selectin, E-selectin and Pselectin mediate the initial adhesive events directing the homing of lymphocytes into lymphoid organs, as well as the interactions of leukocytes and other inflammatory cells with endothelium at sites of inflammation. L-selectin is expressed on leukocytes, Eselectin is expressed on endothelium and P-selectin is expressed on platelets and endothelium. The three selectins bind to specific carbohydrate structures on opposing cells, for example, L-selectin binds to platelets and endothelium, whereas P-selectin and E-selectin bind to leukocytes. Selectin adhesion is involved in disorders such as pathologic reperfusion injury, inflammatory disorders and autoimmune disorders. Selectin interactions also can mediate primary adhesive mechanisms involved in the metastasis of certain epithelial cancers. Thus, selectins are potential therapeutic targets for the treatment of pathologies characterized by undesirable or abnormal interactions mediated by selecting. Web site: http://www.delphion.com/details?pn=US06596705__
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Inhibition of TNF activity Inventor(s): Aderka; Dan (Tel Aviv, IL), Eshed (Englender); Talma (Givatayim, IL) Assignee(s): Applied Research Systems ARS Holding N.V. (Curacao, AN) Patent Number: 6,608,044 Date filed: November 20, 2000 Abstract: The bioactivity of TNF is inhibited by administering heparin or a derivative thereof along with a soluble TNF receptor. The heparin or derivative thereof can be administered simultaneously with the soluble TNF receptor, either in separate compositions or in compositions containing both heparin or a derivative thereof and at least one soluble TNF receptor. The heparin or derivative may also be administered without the soluble TNF receptor and still effect some amount of inhibition of TNF bioactivity. Excerpt(s): The present application is the national stage under 35 U.S.C. 371 of PCT/IL99/00709, filed Dec. 30, 1999. The present invention is directed to a method and pharmaceutical compositions for inhibiting activity of tumor necrosis factor (TNF).
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Tumor necrosis factor (TNF) is a pro-inflammatory cytokine produced by a wide spectrum of cells. It has a key role in defending the host, mediating complex cellular responses of different, and even contrasting, nature (Aggarwal et al, 1996). In excess, TNF may have detrimental systemic effects. Two specific high affinity cell surface receptors, the p55 TNF-receptor (p55 TNF-R) and the p75 TNF-receptor (p75 TNF-R), function as transducing elements, providing the intracellular signal for cell responses to TNF. The extracellular parts of the TNF-Rs, known as soluble TNF-Rs, were formerly referred to as TBP-I and TBP-II respectively (see Wallach, U.S. Pat. No. 5,359,037 and Tartaglia et al., 1992; Loetscher et al., 1991). Web site: http://www.delphion.com/details?pn=US06608044__ •
Low-molecular heparin modification and remedy for skin ulcer Inventor(s): Okayama; Minoru (Kyoto, JP), Toda; Ken-ichi (Kyoto, JP), Yamashina; Ikuo (2, Higashi Morigamae-Cho, Shimogamo, Kyoto, JP 606-0866) Assignee(s): Yamashina; Ikuo (Kyoto, JP) Patent Number: 6,569,840 Date filed: May 9, 2000 Abstract: The invention is direct to modified heparins, especially low-molecular weight modified heparins that are adapted for used in preparing an agent for treating a skin ulcer. The low-molecular weight modified heparins have been substantially deprived of the anticoagulant activity, yet they retain the ability to bind to cell growth factors, cytokines and cell adhesion molecules. Excerpt(s): This is a 371 of PCT/JP98/05191 filed Nov. 18, 1998. This invention relates to modified heparins and an agent for remedying skin ulcer. More particularly, this invention relates to using as an agent for remedying skin ulcer modified heparins, especially low molecular weight modified heparins which have been substantially deprived of the anticoagulant activity yet retain the ability to bind to cell growth factors, cytokines and cell adhesion molecules, and also relates to modified heparins, especially low molecular weight modified heparins adapted for use in preparing an agent for remedying skin ulcer. Heparin is one of glycosaminoglycans and is characterized by having anticoagulant activity. A lot of heparin has been found in liver, lung, intestine, spleen and other organs of healthy edible animals, and heparin is largely produced by mast cells around capillary vessels. A heparin is glycosaminoglycan including various amounts of O-sulfate, N-sulfate and N-acetyl groups and belongs to a heteropolysaccharide having a molecular weight of 6,000.about.20,000. Web site: http://www.delphion.com/details?pn=US06569840__
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Method for performing activated clotting time test with reduced sensitivity to the presence of aprotinin and for assessing aprotinin sensitivity Inventor(s): Aiken; Jennifer C. (Wheat Ridge, CO), DeBiase; Barbara A. (Wheat Ridge, CO), Henderson; Jon H. (Wheat Ridge, CO) Assignee(s): Sienco, Inc. (Wheat Ridge, CO) Patent Number: 6,632,678 Date filed: January 3, 2001
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Abstract: A coagulation test for determining the activated clotting time (ACT) of blood in the presence of heparin that produces test results that are substantially insensitive to the drug aprotinin. The activator is formulated to be a combination of celite and bentonite. The ACT results obtained with this formulation are similar to celite ACT tests on heparinized blood while simultaneously being unaffected by aprotinin. Additionally, a method for quantifying the aprotinin effect of different ACT formulations is disclosed. Excerpt(s): This invention relates to the determination of the activated clotting time (ACT) of blood or plasma, specifically for patients receiving the drugs heparin and aprotinin. Heparin is an anticoagulant drug used during surgeries requiring the use of extracorporial circuits, such as cardiopulmonary bypass (CPB). Heparin prevents blood clots from forming while blood is flowing through the circuit. In order to ensure sufficient anticoagulation, doctors must be able to measure heparin's anticoagulant effect on blood. The anticoagulant effect of heparin is often managed using the activated clotting time (ACT) as determined by in vitro diagnostic tests. The ACT is prolonged after heparin administration. For example, without heparin, the ACT is generally about 120 seconds, while the ACT after heparin administration is typically beyond 480 seconds. An ACT of greater than 480 seconds is considered by many clinicians to be the minimum amount of heparin anticoagulation effect necessary for CPB surgery. The object of an ACT test is to indicate if adequate heparin has been administered to the patient in order to proceed with the surgical procedure without risk of forming blood clots. Heparin is metabolized during surgery. Consequently, heparin must be administered both before and during CPB surgery in order to maintain a sufficient level of anticoagulation. Also, the anticoagulant effect of heparin varies from patient to patient. Therefore, different patients require different amounts of heparin, both before and during CPB surgery. Web site: http://www.delphion.com/details?pn=US06632678__ •
Method of covalent coupling Inventor(s): Gouda; Ibrahim (Sollentuna, SE), Larm; Olle (Bromma, SE) Assignee(s): Medicarb AB (Bromma, SE) Patent Number: 6,653,457 Date filed: June 27, 2002 Abstract: A method of preparing conjugates by means of covalent coupling of a polysaccharide selected from heparin, heparin derivatives, at least partially deacerylated dermatan sulphate and dextran sulphate and a solid substance containing primary amino groups, said method comprising the following steps: a) reduction of the saccharide so that its terminal monosaccharide unit is converted to an alditol; b) periodate oxidation of the alditol formed in step a) to the formation of a terminal aldehyde group under cleavage of the monosaccharide unit between two vicinal groups selected from hydroxyl and amino groups; and c) reductive coupling of the alditol via the aldehyde group to the amino group of the solid substrate. Excerpt(s): The present invention relates to the manufacture of conjugates between oligo- or polysaccharides and aminated substrates. The invention also covers the products hereby obtained. Covalent coupling of saccharides to substrates can be made mainly in two different ways, on the one hand through so-called "end-point attachment" (EPA), on the other hand by so-called "multipoint attachment" (MPA). In the first case the saccharide is coupled via its terminal reducing monosaccharide unit. In the second
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case, which is relevant with polysaccharides, it is coupled via several monosaccharide units inside the polysaccharide. Most of the high molecular carbohydrates present in nature, which are coupled to some other high molecular compound, are immobilized via their reducing monosaccharide unit, and such natural conjugates are for example glycoproteins, glycolipides, proteoglycines and lipopolysaccharides. Coupling via "endpoint attachment" means contrary to "multipoint attachment" that the molecule in an immobilized state to a high degree maintains its natural conformation and thereby maintains its capacity to specifically interact with other molecules, such as plasma proteins, growth factors, antibodies, lectins and enzymes. Web site: http://www.delphion.com/details?pn=US06653457__ •
Method, reagent and test cartridge for determining clotting time Inventor(s): Bruegger; Berndt B. (Camarillo, CA) Assignee(s): Roche Diagnostics Corporation (Indianapolis, IN) Patent Number: 6,699,718 Date filed: August 24, 2000 Abstract: The invention is a method, reagent and test cartridge for the determination of the clotting time of a blood sample by means of a reagent containing tissue factor and a sulfatide. In an alternative embodiment, the reagent may contain tissue factor and at least one of the group consisting of a phosphatide and a sulfatide. This invention is preferably used to monitor the effectiveness of heparin therapy in patients that have been administered low to moderate heparin doses to achieve blood heparin levels from 0 to about 3 U/mL, and may also be used for determining clotting time at higher heparin levels of up to about 6 U/mL. Excerpt(s): The present invention relates to the field of determining the clotting time of blood samples and more specifically relates to the determination of the clotting time of blood samples from patients receiving heparin treatment, particularly patients that have been administered low to moderate heparin doses, as well as that of patients that have been administered high heparin doses. The activated clotting time (ACT) assay is a blood test that monitors the effectiveness of heparin dosing. The levels of heparin that the ACT assay is monitoring are generally beyond the range of the activated partial thromboplastin time (APTT) assay. Some APTT assays can monitor plasma heparin levels as high as 1.5 U/mL (which is equivalent to a blood heparin level of about 0.75 U/mL), while the ACT assay can monitor blood heparin levels generally as high as 6 U/mL. The higher end of the blood heparin range (high range; HR) is often used in cardiac pulmonary bypass surgery, while blood levels under 3 U/mL (moderate to low range; LR) but above the effective range of the APTT assay, are used in situations such as cardiac catheterization, extracorporeal membrane oxygenation (ECMO), hemodialysis, and percutaneous transluminal coronary angioplasty (PTCA). There are various commercially available ACT assays. These typically differ in the specific component that activates clotting, which difference can affect the blood heparin range in which the assay is reliable. Consequently, these assay types are often categorized by the heparin range and corresponding surgical or medical application. One example of such a test is known as the Hemochron.RTM. sold by International Technidyne Corporation. The basic procedure for this test is as follows: A two mL sample of blood is added to a test tube containing dried celite (diatomaceous earth) and a small magnetic bar. The test tube is capped and shaken, then placed in an instrument that starts spinning of the magnetic bar. When the blood begins to clot, the magnetic bar slows or stops spinning.
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The instrument then notes the length of time till the magnet stopped spinning as the celite ACT time. A variation of this test is known as the Hemochron.RTM. glass ACT assay wherein the test tube is plastic and contains glass particles with a magnetic bar and the sample is only 0.4 mL of blood. Web site: http://www.delphion.com/details?pn=US06699718__ •
Methods for quality control of prothrombin time (PT) and activated partial thromboplastin time (APTT) assays using coagulation controls Inventor(s): Hawkins; Pamela L. (Ballwin, MO) Assignee(s): Trinity Biotech Manufacturing, Ltd. (Jamestown, NY) Patent Number: 6,528,273 Date filed: January 26, 2001 Abstract: Coagulation control compositions suitable for use in connection with PT and/or APTT assays are disclosed along with their methods of preparation and methods of use. Preferred coagulation controls comprise plasma and an anticoagulant having activity for enhancing the activity of antithrombin III (ATIII) or of heparin cofactor II (HCII) against thrombin or against a clotting factor selected from the group consisting of factors IXa, Xa and XIa. The anticoagulant is preferably a glycosaminoglycan such as heparin, a heparin derivative or a heparin analog. The anticoagulant is preferably combined with (1) an abnormal plasma (e.g. activated plasma or factor-deficient plasma) and/or (2) a primate plasma (e.g. human plasma), and a non-primate mammalian plasma (e.g. bovine plasma). In the latter case, the nonprimate mammalian plasma is preferably present in the coagulation control composition in an amount of not more than about 12% by volume, relative to total volume. Excerpt(s): The present invention generally relates to diagnostic coagulation assays, and specifically, to control samples suitable for use in connection therewith. The invention particularly relates to coagulation controls suitable for both prothrombin time and activated partial thromboplastin time assays. Coagulation control materials are used in the clinical laboratory for quality control of the prothrombin time (PT) and activated partial thromboplastin time (APTT) assays. PT assays employ thromboplastin reagents and have been used extensively for evaluating blood coagulation associated with the extrinsic pathway. APTT assays employ an intrinsic pathway activator, such as micronized silica, and a phospholipid component of a thromboplastin reagent (without tissue factor protein) for evaluating coagulation associated with the intrinsic pathway. Both PT and APTT assays are used clinically for screening patients' plasma for coagulation factor deficiencies. Clinical screenings are employed, for example, during routine checkups and prior to surgery. PT and APTT assays are also used for monitoring treatment with anticoagulants. For example, PT assays are routinely employed to monitor oral anti-coagulant treatment with coumarin (Warfarin.TM., Coumadin.TM.), and APTT assays are typically used for monitoring anticoagulant treatment with heparin. Coagulation controls are used for quality control evaluations of the PT and APTT assay systems. The controls are essential in view of potential variation in reagents employed in these assays, potential inaccuracies in the devices used to measure clotting time, and potential effects of inaccurate anticoagulant dosage. Commercial coagulation controls have been designed to mimic three physiologic conditions: (1) "Control Level I" controls mimic normal coagulation and are intended to be representative of an individual without coagulation deficiencies; (2) "Control Level II" controls are intended to mimic the coagulation of an individual undergoing mild anticoagulant therapy; and
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(3) "Control Level III" controls are intended to mimic the coagulation of an individual undergoing relatively high anticoagulant therapy. Web site: http://www.delphion.com/details?pn=US06528273__ •
Nucleic acid coating compositions and methods Inventor(s): Osaki; Shigemasa (Sandy, UT), Tsang; Ray (Salt Lake City, UT), Zamora; Paul O. (Gaithersburg, MD) Assignee(s): BioSurface Engineering Technologies, Inc. (College Park, MD) Patent Number: 6,596,699 Date filed: January 22, 2002 Abstract: A nucleic acid coating composition including a polyanion bound, directly or through one or more intermediates, to a medical device surface, with a condensate comprising a polycation and nucleic acid bound to the polyanion, devices incorporating such coating compositions, and methods for making. In one embodiment, a silyl-heparin complex is provided, bound to a medical device surface by hydrophobic interaction with the silyl moiety, with a polycation and nucleic acid condensate bound to the heparin by electrostatic interaction. Excerpt(s): The present invention relates to coatings, methods of making and using coating compositions, and coated contacting surfaces of medical devices, wherein the coating includes a negatively-charged polymeric substrate forming a part of the coating surface, with a condensate complex of nucleic acid and a positively-charged polymer bound thereto by non-covalent means. Note that the following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-a-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes. There is a need for localized or regional (loco-regional) delivery of nucleic acids, such as DNA, for use in treatment of a variety of diseases by gene therapy and as a preventative or adjunct to other therapeutic modalities. However, systemic administration of DNA constructs, such as those including adenovirus vectors, frequently results in adverse consequences, and requires a substantially greater amount of gene construct than would be required with effective loco-regional transfection. In addition, for many conditions there is a need for controlled or sustained release of nucleic acids over a period of time, such that the gene construct may be continuously delivered. A number of methods and devices for gene transfection have been developed, but all involve significant limitations. There is thus a need for a biologically compatible method of loco-regional delivery of gene constructs, which may be incorporated and used with traditional implantable medical devices, or may be used with bioresorbable devices. Web site: http://www.delphion.com/details?pn=US06596699__
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Occlusion device with non-thrombogenic properties Inventor(s): Buonomo; Peter M. (Shorewood, MN), Corcoran; Michael P. (Woodbury, MN), Marino; Joseph A. (Apple Valley, MN) Assignee(s): Cardia, Inc. (Burnsville, MN) Patent Number: 6,656,206 Date filed: January 23, 2002 Abstract: A method of forming a PVA foam structure for use in an occlusion device such that the PVA foam structure comprises non-thrombogenic properties. The method comprises forming a PVA gel and incorporating heparin into the PVA gel. The PVA foam structure is then treated with the PVA gel and heparin mixture, such as by soaking the PVA foam structure in the gel. Excerpt(s): This invention relates to an occlusion device for the closure of physical anomalies like vascular or septal apertures, such as patent ductus arteriosus, patent foramen ovale, atrial septal defects, or ventricular septal defects. More specifically, this invention relates to a method of forming a polyvinyl alcohol (PVA) foam treated with heparin for use in occlusion devices. The resulting PVA foam structure minimizes blood clotting. Normally, permanently repairing certain cardiac defects in adults and children requires open heart surgery, a risky, expensive, and painful procedure. To avoid the risks and discomfort associated with open heart surgery, modern occlusion devices have been developed are that small, implantable devices capable of being delivered to the heart through a catheter. Rather than surgery, a catheter inserted into a major blood vessel allows an occlusion device to be deployed by moving the device through the catheter. One method of inserting an occlusion device begins by using a guide catheter introduced through the femoral vein and lower vena cava and placed in the right ventricle of the heart. After passing through the defect in the atrial septum, the distal portion of the implant is forced out of the catheter and unfolded in the left atrium, much like unfolding an umbrella. The unfolded portion is drawn back against the septum due to the pre-tensioning of the fixation devices. Then, the proximal parts of the implant are likewise pushed out of the catheter and independently unfolded in the right atrium. The insertion forceps used to guide the occlusion device through the catheter are then separated from the center piece. This procedure is performed in a cardiac cathlab and avoids the risks and pain associated with open heart surgery. These modem occlusion devices can repair patent foramen ovale, patent ductus arteriosis, atrial septal defects, ventricular septal defects, and other cardiac and non-cardiac apertures. One such device is that disclosed in PCT application PCT/US98/15961, entitled Occlusion Device for the Closure of a Physical Anomaly Such as a Vascular Aperture or an Aperture in a Septum, filed on Jul. 31, 1998 by Bernhard Schneidt, now issued U.S. Pat. No. 6,174,322. This patent discloses a non-thrombogenic occlusion device that is insertable into an anomaly via a catheter. In addition, a similar device filed as German Appln. 297 14 242.9 on Aug. 8, 1997, discloses an occlusion device which can be inserted via a catheter. Another devices is that disclosed in U.S. Pat. No. 6,206,907, entitled Occlusion Device with Stranded Wire Support Arms, filed on May 7, 1999, invented by Joseph A. Marino, Michael P. Corcoran, and Peter M. Buonomo. Web site: http://www.delphion.com/details?pn=US06656206__
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Oral delivery of macromolecules Inventor(s): Byun; Youngro (Gwangju, KR), Lee; Yong-Kyu (Gwangju, KR) Assignee(s): Mediplex Corporation, Korea (Seoul, KR) Patent Number: 6,656,922 Date filed: April 30, 2001 Abstract: Polysaccharides, which are widely used as an anticoagulation drugs, especially heparin, are clinically administered only by intravenous or subcutaneous injection because of their strong hydrophilicity and high negative charge. Amphiphilic heparin derivatives were synthesized by conjugation to bile acids, sterols, and alkanoic acids, respectively. These heparin derivatives were slightly hydrophobic, exhibited good solubility in water, and have high anticoagulation activity. These slightly hydrophobic heparin derivatives are efficiently absorbed in the gastrointestinal tract and can be used in oral dosage forms. Methods of using these amphiphilic heparin derivatives and similarly modified macromolecules for oral administration are also disclosed. Excerpt(s): This invention relates to derivatives of macromolecules, including polysaccharide derivatives, having increased hydrophobicity as compared to the unmodified macromolecules or polysaccharides. More particularly, the invention relates to oral delivery and absorption of hydrophobized macromolecules and amphiphilic polysaccharide derivatives, such as amphiphilic heparin derivatives, wherein the bioactivity of the macromolecule or polysaccharide is preserved. In preferred embodiments of the invention, the hydrophobized macromolecules and amphiphilic polysaccharide derivatives have a molecular weight of greater than 1000, yet are absorbed after oral administration. Heparin is a polysaccharide composed of sulfated Dglucosamine and D-glucuronic acid residues. Due to its numerous ionizable sulfate groups, heparin possesses a strong electronegative charge. It is also a relatively strong acid that readily forms water-soluble salts, e.g. heparin sodium. It is found in mast cells and can be extracted from many body organs, particularly those with abundant mast cells. The liver and lungs are especially rich in heparin. The circulating blood contains no heparin except after profound disruption of mast cells. Heparin has many physiological roles, such as blood anticoagulation, inhibition of smooth muscle cell proliferation, and others. In particular, heparin is a potent anticoagulant agent that interacts strongly with antithrombin III (ATIII) to prevent the formation of fibrin clots. Heparin is one of the most potent anticoagulants used for treatment and prevention of deep vein thrombosis and pulmonary embolism. In vivo, however, applications of heparin are very limited. Because of its hydrophilicity and high negative charge, heparin is not absorbed efficiently from the GI tract, nasal or buccal mucosal layers, and the like. Therefore, the only routes of administration used clinically are intravenous and subcutaneous injections. Moreover, since heparin is soluble in relatively few solvents, it is hard to use for coating surfaces of medical devices or in delivery systems. To improve the properties of heparin, R. J. Linhardt et al., 83 J. Pharm. Sci. 1034-1039 (1994), coupled lauryl (C.sub.12) and stearyl (C.sub.18) groups to single heparin chains, resulting in a derivatized heparin having increased hydrophobicity but with low anticoagulation activity. This result demonstrated that coupling a small linear aliphatic chain to heparin was ineffective in enhancing the hydrophobicity of heparin while preserving activity. Thus, known heparin derivatives have been ineffective in preserving anticoagulation activity. Web site: http://www.delphion.com/details?pn=US06656922__
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Plaster for topical use containing heparin and diclofenac Inventor(s): Donati; Elisabetta (Cavallasca, IT), Rapaport; Irina (Rovio, CH) Assignee(s): Altergon S.A. (Lugano, CH) Patent Number: 6,592,891 Date filed: April 14, 2000 Abstract: Plaster for topical use having an analgesic activity and at the same time being able to re-absorb haematomas, comprising:a substrate layer;an adhesive layer in the form of a hydrogel matrix containing a pharmaceutically acceptable diclofenac salt, heparin or a heparinoid;a protective film which can be removed at the moment of use. Excerpt(s): Plaster for topical use having an analgesic activity and being able to reabsorb haematomas, containing diclofenac in association with heparin or a heparinoid. Known and available on the market are creams for topical use with a base of heparinoids, possibly in association with hyaluronidase, for re-absorption of haematomas and ecchymoses. Though remarkably effective, these creams involve a number of drawbacks. In fact, they do not present a more specific analgesic activity, which would be particularly necessary in the case of serious ecchymoses. Web site: http://www.delphion.com/details?pn=US06592891__
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Process for the preparation in pure form of the protease activating blood clotting VII, its proenzyme or a mixture of both proteins by means of affinity chromatography Inventor(s): Feussner; Annette (Marburg, DE), Roemisch; Juergen (Marburg, DE), Stoehr; Hans-Arnold (Wetter, DE) Assignee(s): Aventis Behring GmbH (Marburg, DE) Patent Number: 6,670,455 Date filed: August 4, 2000 Abstract: A process for the preparation in pure form of the protease activating blood clotting factor VII and/or its proenzyme by the use of a chromatography separation processes and/or fractional precipitation is described. The process used may include adsorption on calcium phosphate/hydroxyapatite, a hydrophobic matrix, a chelate matrix, a matrix on which heparin or a substance related to heparin, such as heparin sulfate or dextran sulfate, is immobilized, or a matrix that is coated with an immobilized monoclonal or polyclonal antibody directed against the protein to be isolated, or F(ab) or F(ab).sub.2 fragments of antibodies directed against the protein to be isolated. A pharmaceutical preparation and a reagent are described which contain the said protease and/or its proenzyme. Excerpt(s): The invention relates to a process for the preparation in pure form of the protease activating blood clotting factor VII, its proenzyme or a mixture of both proteins, and of pharmaceutical preparations which contain the proteins mentioned individually or as a mixture. German patent application 19 903 693.4 has already disclosed a protease for the activation of blood clotting factor VII, a process for its production, for its detection and for its inactivation, and pharmaceutical preparations which contain this protease. This protease, first isolated from plasma, occurs there together with a nonactivated form, which is designated below as "proenzyme". The protease activates blood clotting factor VII and accelerates clotting, as was shown by numerous experiments. In the further investigation of the biological properties of this
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protein, identified as serine protease, it emerged that single-chain plasminogen activators, such as prourokinase, are also effectively activated. Moreover, inactivation of factors V and VIII in vitro was observed. In addition to the sequenced regions already described in German patent application 19 903 693.4, N-terminal sequencings of protease fractions were carried out. The following amino acid sequences characterize the FVII-activating protease: IYGGFKSTAGKHP; LLESLDPDXTPD; EFHEQSFRVEKI; SKFTXAXPXQFK; where X means not identified. The sequences of the protease mentioned elucidated up to now show that they agree 100% with sequences of the protease published by Choi-Miura (Choi-Miura et al. J. Biochem. 1996; 119: 1157 to 1165). The investigations until now have especially concentrated on the protease in its activated form. The inactive form of the protease present in the plasma as a proenzyme was only recently discovered by means of a protein band pattern in the SDS-PAGE after reduction of the sample. Since, on the activation of the protease, a cleavage at a site of the primary structure typical for serine proteases and thus activation takes place, two or more bands are visible on electrophoresis. On reduction of the chains which are connected by disulfide bridges, the individual bands become visible in accordance with their lower molecular weight, the proenzyme remaining as a large individual chain. This was also clear in more complex solutions after transfer of the proteins to membranes and subsequent Western blotting using suitable antibodies. Web site: http://www.delphion.com/details?pn=US06670455__ •
Protamine fragment compositions and methods of use Inventor(s): Byun; Youngro (Kwangsan-Ku Kwangju, KR), Yang; Victor C. (Ann Arbor, MI) Assignee(s): The Regents of The University of Michigan (Ann Arbor, MI) Patent Number: 6,624,141 Date filed: November 16, 2000 Abstract: Provided are bioactive, low-toxicity protamine fragments, compositions, combinations, kits and methods of using these components in a variety of embodiments, including neutralizing heparin and reducing post-operative bleeding. Improved protamine fragment-insulin solutions and methods for treating diabetes are also provided. Excerpt(s): The present invention relates generally to the fields of protein biochemistry and medicine. More particularly, it concerns bioactive, low-toxicity fragments of protamine, and a number of different uses of such protamine fragment compositions. Provided are protamine fragments, compositions, combinations and kits and various methods and uses of such fragments, e.g., in the neutralization of heparin and for association with a variety of therapeutic proteins, including insulin. Heparin consists of a heterogeneous mixture of sulfated glycosaminoglycans with a molecular weight ranging from 3,000 to 40,000 daltons. It is made of a repeating unit of D-glucuronic acid and N-acetyl-D-glucosamine residues (Bourin and Lindahl, 1993). The anticoagulant function of heparin was discovered over 70 years ago (Howell, 1922). Heparin exerts its anticoagulant activity primarily via interaction with antithrombin III (Rosenberg, 1987). Antithrombin III (ATIII) is a circulating inhibitor of the serine proteases in the coagulation cascade, acting more particularly on thrombin and factor Xa but also on factors IXa, XIa, and XIIa. It possesses an arginine center that binds to the active serine site of thrombin (and also the other coagulation factors) to form a covalent bond (Griffith, 1983). Normally this reaction proceeds rather slowly. Binding of heparin to
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ATIII, however, induces a conformational change of ATIII, rendering the arginine center more accessible to thrombin interaction, and producing a 1000-fold acceleration of the inhibitory effect (Rosenberg, 1987). The binding of heparin to ATIII involves a unique pentasaccharide sequence containing a 3-O-sulfated glucosamine residue (Choay et al., 1981), and entails interaction between specific lysine residues on ATIII and sulfate and carboxylate groups in heparin (Choay et al., 1981; Rosenberg et al., 1979). Web site: http://www.delphion.com/details?pn=US06624141__ •
Protease for activating clotting factor VII Inventor(s): Feussner; Annette (Marburg, DE), Romisch; Jurgen (Marburg, DE), Stohr; Hans-Arnold (Wetter, DE) Assignee(s): Aventis Behring GmbH (Marburg, DE) Patent Number: 6,528,299 Date filed: April 21, 1999 Abstract: A protease for activating the blood clotting factor VII, which is inhibited by the presence of aprotinin, is increased in its activity by calcium ions and/or heparin or heparin-related substances, and in SDS-PAGE, on subsequent staining in the nonreduced state, comprises one or more bands in the molecular weight range from 50 to 75 kDa; and in SDS-PAGE, on subsequent staining in the reduced state, comprises a band at 40 to 55 kDa, one or more bands in the molecular weight range from 10 to 35 kDa, and a band in the molecular weight range between 60 and 65 kDa, which corresponds to a proenzyme. Pharmaceutical preparations containing the protease or its proenzyme are suitable for the prophylaxis and treatment of bleeding events, e.g. in the presence of FVIII inhibitors, wound healing and for the treatment of disorders which are caused by fibrin-containing thrombin. Excerpt(s): The invention relates to a protease for activating the blood clotting factor VII, to a process for isolating it, detecting it and inactivating it, and to medicinal preparations which comprise this protease. The blood clotting system comprises two different, cascade-like pathways for activating clotting factors which are present in the plasma. The intrinsic or the entrinsic pathway is preferentially used for initiating clotting, depending on the triggering mechanism. When a tissue is damaged, thromboplastin (tissue factor, TF with phospholipids) is exposed by the affected cells as the starter of the extrinsic clotting pathway. The membrane-located thromboplastin can bind both clotting factor VII (FVII) and circulating, activated FVII (FVIIa). In the presence of calcium ions and lipids, this TF-FVIIa complex leads to the binding of FX, which is converted into its activated form (FXa) by limited proteolysis. FXa in turn leads, by activating prothrombin to form thrombin, to the formation of fibrin and thereby ultimately to closure of the wound. Web site: http://www.delphion.com/details?pn=US06528299__
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Treating metal surfaces to enhance bio-compatibility and/or physical characteristics Inventor(s): Al-Lamee; Kadam Gayad (Leeds, GB), Taktak; Yousef Samih (Matlock, GB) Assignee(s): Polybiomed Limited (GB) Patent Number: 6,599,558 Date filed: December 2, 1999 Abstract: A metal, glass or ceramics surface is treated to enhance its compatibility with biological material such as blood or blood related products. Treatment involves covalently bonding to the surface by means of a catalyst functional molecules each of has at least one alkoxysilane group which can form at least one first covalent bond by reaction with the oxide or hydroxide of said surface and at least one other group which can participate in free-radical polymerisation. Free-radical polymerisation from said functional molecules is then effected to build bio-compatible and/or hydrophilic polymer chains. The compatibility of the metal surface with biological material may be further improved by bonding bio-active molecules, such as heparin or heparin derived molecules to the polymer chains. Suitable metal surfaces are those of medical devices such as heat exchangers, coronary and peripheral stents and guide wires used in angioplasty. In the case of a stent, restenosis may be inhibited by incorporating into the coating a radio-labelled compound, foe example radio-labelled heparin and/or by incorporating a compound that inhibits cell proliferation e.g. mitoxantrone. Excerpt(s): The present invention relates to a method of treating metal surfaces to enhance the bio-compatibility and/or physical characteristics of said surfaces. The invention also relates to bio-compatible metal articles. The invention is particularly relevant to surfaces of medical devices. Many medical techniques are known in which human or animal blood is brought into contact with foreign surfaces, either within the body or outside the body. In some situations, usually due to mechanical characteristics, it is necessary to use metallic surfaces, as required by coronary stents (vascular endoprostheses) located within arteries or, for example, within heat exchanger assemblies external to the body. Thus, in the first application, the mechanical strength of the metal object is required whereas in the external application it is the heat transfer characteristics that are required. However, in both applications, blood or related blood products are brought into contact with metal surfaces, which may in turn have detrimental effects upon the blood itself. Heparin is a naturally occurring substance that consists of a polysaccharide with a heterogeneous structure and a molecular weight ranging from approximately 6000 to 30000 Dalton (atomic mass units). It prevents uncontrolled clotting by suppressing the activity of the coagulation system through complexing with antithrombin (III), whose activity it powerfully enhances. Approximately one in three heparin molecules contains a sequence of highly specific structures to which antithrombin binds with high affinity. When bound to the specific sequence, the coagulation enzymes are inhibited at a rate that is several order of magnitude higher than in the absence of Heparin. Thus, the heparin molecule is not in itself an inhibitor but acts as a catalyst for natural control mechanisms without being consumed during the anticoagulation process. The catalytic nature of heparin is a desirable property for the creation of a bio-active surface, because the immobilised heparin is not functionally exhausted during exposure to blood but remains a stable active catalyst on the surface. Web site: http://www.delphion.com/details?pn=US06599558__
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Use of low-molecular-weight heparins for the prevention and treatment of cerebral edemas Inventor(s): Mary; Veronique (Evry, FR), Pratt; Jeremy (Paris, FR), Stutzman; Jean-Marie (Villecresnes, FR), Uzan; Andre (Paris, FR), Wahl; Florence (Paris, FR) Assignee(s): Aventis Pharma S.A. (Antony, FR) Patent Number: 6,579,858 Date filed: November 29, 1999 Abstract: Cerebral edema is prevented and treated by administering an effective amount of a low molecular weight heparin. Excerpt(s): The present invention relates to the use of low-molecular-weight heparins for the prevention and treatment of cerebral edemas. The invention also relates to the use of low-molecular-weight heparins for the preparation of a medicament for the prevention and treatment of cerebral edemas. Standard heparin is a sulphated polysaccharide having an average molecular weight of 12,000-15,000 daltons which is isolated from bovine, ovine and porcine intestinal mucous membranes. Heparin is clinically used for the prevention and treatment of thromboembolic disorders but sometimes causes haemorrhages. Web site: http://www.delphion.com/details?pn=US06579858__
Patent Applications on Heparin As of December 2000, U.S. patent applications are open to public viewing.9 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to heparin: •
Analysis of sulfated polysaccharides Inventor(s): QI, Yi-Wei; (Charlestown, MA), Sasisekharan, Ram; (Cambridge, MA), Shriver, Zachary; (Boston, MA), Sundaram, Malikarjun; (Ashland, MA), Venkataraman, Ganesh; (Bedford, MA) Correspondence: Fish & Richardson PC; 225 Franklin ST; Boston; MA; 02110; US Patent Application Number: 20030203385 Date filed: March 11, 2003 Abstract: The invention relates to methods and products associated with analyzing and monitoring heterogeneous populations of sulfated polysaccharides. In particular therapeutic heparin products including low molecular weight heparin products and methods of analyzing and monitoring these products are described. Excerpt(s): This application claims priority under 35 USC.sctn.119(e) to U.S. Provisional Patent Application Serial No. 60/393,973, filed on Jul. 5, 2002, U.S. Provisional Patent Application Serial No. 60/383,903, filed on May 28, 2002, and U.S. Provisional Patent Application Serial No. 60/363,240, filed on Mar. 11, 2002, the entire contents of which are hereby incorporated by reference. The invention relates to methods and products
9
This has been a common practice outside the United States prior to December 2000.
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associated with analyzing and monitoring heterogeneous populations of sulfated polysaccharides. In particular, therapeutic heparin products including low molecular weight heparin products and methods of analyzing and monitoring these products are described. Coagulation is a physiological pathway involved in maintaining normal blood hemostasis in mammals. Under conditions in which a vascular injury occurs, the coagulation pathway is stimulated to form a blood clot to prevent the loss of blood. Immediately after the vascular injury occurs, blood platelets begin to aggregate at the site of injury forming a physical plug to stop the leakage. In addition, the injured vessel undergoes vasoconstriction to reduce the blood flow to the area and fibrin begins to aggregate forming an insoluble network or clot, which covers the ruptured area. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Analytical test cartridge; and, methods Inventor(s): Sin, Kee Van; (Lino Lakes, MN) Correspondence: Merchant & Gould PC; P.O. Box 2903; Minneapolis; MN; 55402-0903; US Patent Application Number: 20040002161 Date filed: June 28, 2002 Abstract: An analytical test cartridge is provided. The analytical test cartridge can be used for medical analyses of liquid samples removed from a patient, for example blood. The analytical test cartridge is configured to provide for titration experiments. An example of a titration experiment that can be performed with the arrangement, is titration of heparin with protamine. Methods of assembly and use are provided. Excerpt(s): Analyses of patient fluids, for example blood, have become an increasingly important part of medicine. As a result, various analytical systems have been developed to allow for convenient sample handling and evaluation. In many instances the analytical system utilizes a portable analysis station that can be moved to various locations, for convenience. Two such analysis systems are the IRMA Blood Analysis System (IRMA), and the Blood Analysis Portal System (PORTAL), both of which are available from Diametrics Medical, Inc. of Roseville, Minn., 55113, the assignee of the present application. General features of such systems are characterized, for example, in U.S. Pat. No. 6,066,243 ('243), assigned to Diametrics Medical, Inc., the complete disclosure of which is incorporated herein by reference. In general, such cartridges have relatively short useful lifetimes, with respect to the expected lifetime of the analytical componentry with which they are used. As a result, such cartridges are sometimes referred to as "disposable cartridges" or "disposable test cartridges." Indeed, in many instances, the removable cartridge is a single use cartridge. Besides the '243 and '853 references cited and incorporated above, the assignee of the present application, Diametric Medical, Inc., is also assignee of the following U.S. patents that describe technology related to, or useable with, disposable cartridges and their use, namely: U.S. Pat. Nos. 5,384,031; 5,223,433; 6,060,319; and 5,232,667. The complete disclosure of each of the patents identified in the previous sentence is incorporated herein by reference. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Antibodies to trisulfated heparin disaccharide in painful sensory axonal neuropathy Inventor(s): Pestronk, Alan; (St. Louis, MO) Correspondence: Hamilton, Brook, Smith & Reynolds, P.C.; 530 Virginia Road; P.O. Box 9133; Concord; MA; 01742-9133; US Patent Application Number: 20040038311 Date filed: August 20, 2002 Abstract: Methods aiding in the diagnosis of certain painful, predominantly sensory, polyneuropathies are disclosed, in which the amount of antibodies to trisulfated disaccharide is assessed in a test sample. Also disclosed are kits that can be used in the methods of the invention. Excerpt(s): The binding of serum IgM antibodies, including M-proteins, to glycolipids or glycoproteins is associated with several chronic polyneuropathy syndromes (O'Leary, C. P. and Willison, J. J., Curr. Opin. Neurol. 13:583-588 (2000); Quarles, R. H. and Weiss, M. D., Muscle Nerve 22:800-822 (1999)). IgM binding to myclin-associated glycoprotein (MAG) is a marker for a demyelinating sensory-motor polyneuropathy syndrome (Nobile-Orazio, "Neuropathies associated with anti-MAG antibodies and IgM monoclonal gammopathies," in Latov, N., Wokke, J. H. J., Kell, J. J. Jr., Eds., Immunology and Infectious Diseases of the Peripheral Nerves, Cambridge, UK: Cambridge University Press, 1998:168-189; Erb, S. et al., J. Neurol. 247:767-772 (2000)). IgM binding to sulfatide (Lopate, G., et al., J. Neurol. Neurosurg. Psychiatry 62:581-585 (1997); Carpo, M. et al., J. Neurol. Sci. 176:144-150 (2000); Erb, S. et al., J. Neurol. 247:767-772 (2000)) and to.beta.-tubulin (Connoly, A. M. et al., Neurology 48:243-248 (1997)) may also be associated with demyelinating sensory-motor polyneuropathies. IgM binding to GM1 ganglioside is related to a multifocal motor neuropathy that commonly has conduction block as the predominant demyelinating feature on electrophysiological testing (Parry, G., Muscle Nerve 19:269-276 (1996); Pestronk, A. and Choksi, R., Neurology 49:12891292 (1997); Pestronk, A., Neurology 51:S22-S24(1998)). Serum IgM with selective binding to GD1b ganglioside is associated with an axonal sensory polyneuropathy and ophthalmoplegia (O'Leary, C. P. and Willison, J. J., Curr. Opin. Neurol. 13:583-588 (2000); Susuki, K. et al., J. Neuroimmunol. 112:181-187 (2001)). However, the antigenic targets of serum antibodies in approximately 40% of patients with IgM M-proteins and polyncuropathies, especially those with primary axonal involvement, have been undefined. Because polyneuropathies are potentially treatable, correct identification of a patient's particular polyneuropathies is important. Methods of diagnosing such polyneuropathies based on specific disease-related criteria would facilitate identification of treatable disease and expedite commencement of treatment. The current invention pertains to methods for diagnosing, in an individual, the presence or absence of a painful, predominantly sensory, polyneuropathy. The methods include assaying a test sample of bodily fluid, blood, serum or other tissue from an individual for the presence of antibodies, such as IgM antibodies, that bind to a trisulfated disaccharide sample (e.g., to a sample containing IdoA2S-GlcNs-6S). In the methods, a trisulfated disaccharide sample, which can include trisulfated disaccharide that is a component of an oligosaccharide (e.g., heparin oligosaccharide), and/or tri sulfated disaccharide that is not a component of an oligosaccharide, is contacted with the test sample. The amount of antibody that binds to the tri sulfated disaccharide is then assessed and compared to a reference amount, or to the amount of anti-trisulfated disaccharide antibody in at least one negative control sample of a comparable bodily fluid or tissue. The presence of the polyneuropathy is indicated by an amount of anti-trisulfated disaccharide antibody that is greater than a reference amount, or by an amount of anti-trisulfated disaccharide
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antibody that is significantly greater in the test sample than in the negative control sample(s). The absence of the polyneuropathy is indicated by an amount of antitrisulfated disaccharide antibody that is less than a reference amount, or by an amount of anti-trisulfated disaccharide antibody that is not significantly greater in the test sample than in the negative control sample(s). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Apparatus and method for in-vivo plasmapheresis using periodic backflush Inventor(s): Cooper, Tommy; (Friendswood, TX), Gorsuch, Reynolds G.; (Yountville, CA), Handley, Harold H.; (Novato, CA) Correspondence: Knobbe Martens Olson & Bear Llp; 2040 Main Street; Fourteenth Floor; Irvine; CA; 92614; US Patent Application Number: 20030236482 Date filed: April 4, 2003 Abstract: Apparatus and method for in-vivo plasmapheresis utilizing a plurality of elongated hollow microporous filter fibers periodically interrupt diffusion of blood plasma from a patient, and, for a selected time, backflush fluid into the fibers at a pressure and interval sufficient to cleanse the fiber pores, after which plasma diffusion is resumed. The backflush fluid, preferably a normal saline solution, may contain an anticoagulant such as heparin in suitable concentration for systemic anti-coagulation or for treating the fiber for thromboresistance. Excerpt(s): In U.S. Pat. Nos. 4,950,224, 5,152,743, 5,151,082, 5,735,809 and 5,980,481 there are disclosed methods and apparatus for carrying out in-vivo plasmapheresis for separating plasma from other blood components within the body and blood vessels of a patient. In the apparatus pumping is used to create a trans-membrane pressure and motivate the flow of fluid from within the in-vivo system, whereby blood plasma is pumped from the patient to a treatment system such as a dialyzer or other apparatus in which toxic metabolic waste in the plasma is removed. After the plasma is treated for removal of waste products, excess fluids, toxins, and/or other deleterious plasma proteins, the treated plasma is returned and reintroduced to the patient's blood stream. Methods of toxin removal from blood, as taught by the aforesaid patents and referred to as plasma dialysis, ultrafiltration or blood purification, are unique from and substantially superior to conventional hemodialysis as presently practiced for both acute and chronic kidney failure, primarily because removal of whole blood from the patient's vasculature is eliminated from the procedure using plasma, or portions of the plasma. The methods and apparatus described in the aforesaid patents are incorporated herein by reference. In U.S. Pat. Nos. 5,224,926, 5,735,809 and 5,968,004 there are disclosed improved filter assemblies including elongated hollow fibers and various filter assembly designs incorporating such hollow fibers to be used in the above-described methods and apparatus. In U.S. patent application Ser. No. 09/549,131, filed Apr. 13, 2000 (TRANSVI.007), there is disclosed specialized hollow fiber membranes which are superior in biocompatibility, performance and morphology for use in the aforesaid invivo plasmapheresis. In U.S. patent application Ser. No. 09/981,783, filed Oct. 17, 2001 (TRANSVI.011A) there is disclosed a plasmapheresis filter device and catheter assembly incorporating the aforesaid specialized hollow fiber membranes. In U.S. patent application Ser. No. 10/219,082, filed Aug. 13, 2002 (TRANSVI.012A) there are disclosed apparatus and methods for therapeutic apheresis using the aforesaid specialized hollow fiber membranes, filter device and catheter assembly. Such fibers, filter device, catheter
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assembly, apparatus and methods as disclosed in the aforesaid patents and applications are incorporated herein by reference. In the aforesaid systems, the hollow fiber membranes function as filters, where the primary purpose of said membranes is separation of specific blood or plasma components from whole blood. In such systems, the blood (permeate) flows on the outside of the fiber and the plasma (exudate) is diffused through the fiber membrane to the interior lumen of the hollow fiber. However, as use is continued, performance of the fibers as filters becomes degraded over time. For example, clogging or fouling of the filter occurs on the surface of the filter as the pore void spaces become more occluded with particulate matter from the permeate building up within the pore void such that the minute volume of the exudate is progressively degraded to the point of failure and cessation of exudate flow. Such clogging or fouling of the filter membranes, as well as clotting problems with prior art filter systems as disclosed in the aforesaid application Ser. No. 09/549,131 (TRANSVI.007), causes major operational and economic problems with current ex-vivo systems performing Continuous Renal Replacement Therapy (CRRT) for acute and chronic kidney failure. It is reported by Ramesh, Prasad, et al., in Clinical Neprology, Vol. 53, p. 55-60 (January 2000), that over 50% of such filters fail in 10 hours and over 75% fail in 30 hours of usage. Because short-term filter replacement is both undesirable and unacceptable, clogging or fouling failure of filters used in in-vivo systems described in the aforesaid patents would be totally unacceptable for both medical and economic reasons. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Assay for low molecular weight heparin Inventor(s): LaDuca, Frank M.; (East Brunswick, NJ), Lee, Ted C. K.; (Matawan, NJ), McBride, Amanda B.; (Turnersville, NJ) Correspondence: Synnestvedt & Lechner Llp; 2600 Aramark Tower; 1101 Market Street; Philadelphia; PA; 19107-2950; US Patent Application Number: 20040033551 Date filed: August 16, 2002 Abstract: A prothrombin time reagent for determination of low molecular weight heparin in fresh whole blood and in anti-coagulant treated blood is provided. The reagent is composed of recombinant animal tissue factor, and a mixture of synthetic phospholipids, which mixture includes a phosphatidylalcohol. A formulation buffer which includes a sensitivity adjuster is used in formulating the reagent. The recombinant animal tissue factor includes rabbit brain. The synthetic phospholipids of the mixture include palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoylphosphatidylserine (POPS), and a phosphatidylalcohol. The phosphatidyl alcohol includes dioleoylphosphatidylethanol, dioleoylphosphatidylmethanol, dioleoylphosphatidylpropanol, dioleoylphosphatidylbutanol, and dioleoylphosphatidylinositol. The sensitivity adjuster included in the formulation buffer is.gamma.-Cyclodextrin. The formulated reagent is air-dried and remains stable for at least 3 weeks at 37.degree. C. Excerpt(s): The present invention relates generally to assays for determining the concentration of low molecular weight heparin in a blood sample. Blood coagulation tests may be performed for a variety of purposes, including determining the bleeding susceptibility of patients undergoing surgery, and monitoring patients undergoing anticoagulation therapy for the prevention of blood clots. A variety of coagulation tests are presently in use, for example, the Activated Partial Thromboplastin Test (APTT), and
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Prothrombin Time (PT) test. Both tests measure clotting time to evaluate a patient's baseline hemostatic state or to monitor the response to anticoagulant therapy. The APTT test is used for the evaluation of the intrinsic and common coagulation pathways, and for monitoring therapy with unfractionated heparin and other anticoagulants. The APTT measures the time in seconds required for a fibrin clot to form in a plasma sample to be tested after a partial thromboplastin reagent (an activating agent) and calcium chloride have been added to the sample. The APTT test is widely used for monitoring heparin therapy. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Bioactive medical films Inventor(s): Zamora, Paul O.; (Gaithersburg, MD) Correspondence: Peacock Myers And Adams P C; P O Box 26927; Albuquerque; NM; 871256927 Patent Application Number: 20040151764 Date filed: October 10, 2003 Abstract: A wound dressing, method of making, and method of use, utilizing a polymeric film having complexed thereto by hydrophobic interaction a construct including a polyanion covalently bonded to a hydrophobic prosthetic moiety, with one or more bioactive molecules directly complexed to the polyanion. The polyanion may be heparin or a heparin-activity molecule. The prosthetic group may include a hydrophobic silyl-containing moiety. Bioactive molecules include adhesive molecules, growth factor molecules, and therapeutic molecules, including antibiotics. Excerpt(s): This application is a continuation-in-part application of U.S. patent application Ser. No. 10/450,309, entitled "Bioactive Coating Compositions and Methods", to Paul O. Zamora, et al., filed on Jan. 28, 2003, and the specification thereof is incorporated herein by reference. This application claims the benefit of the filing of U.S. Provisional Patent Application Serial No. 60/418,127, entitled "Bioactive Medical Films", filed on Oct. 10, 2002, and the specification thereof is incorporated herein by reference. This application also claims priority to U.S. Pat. No. 6,342,591, entitled "Amphipathic Coating for Modulating Cellular Adhesion Composition and Methods", to Paul 0. Zamora, et al., issued on Jan. 29, 2002, and the specification thereof is incorporated herein by reference. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Biologically active peptides from functional domains of bactericidal/permeabilityincreasing protein and uses thereof Inventor(s): Little, Roger G. II; (Benicia, CA) Correspondence: Janet M. Mcnicholas, PH.D.; Mcandrews, Held & Malloy, LTD.; 34th Floor; 500 W. Madison Street; Chicago; IL; 60661; US Patent Application Number: 20040023884 Date filed: May 27, 2003 Abstract: The present invention provides peptides having an amino acid sequence that is the amino acid sequence of a human bactericidal/permeability-increasin- g protein
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(BPI) functional domain or a subsequence thereof, and variants of the sequence or subsequence thereof, having at least one of the BPI biological activities, such as heparin binding, heparin neutralization, LPS binding, LPS neutralization or bactericidal activity. The invention provides peptides and pharmaceutical compositions of such peptides for a variety of therapeutic uses. Excerpt(s): This is a continuation-in-part of U.S. patent application Ser. No. 08/209,762 filed Mar. 11, 1994, which is a continuation-in-part of U.S. patent application Ser. No. 08/183,222 filed Jan. 14, 1994, which is a continuation-in-part of U.S. patent application Ser. No. 08/093,202, filed Jul. 15, 1993, which is a continuation-in-part of U.S. patent application Ser. No. 08/030,644 filed Mar. 12, 1993. The present invention relates to peptides derived from or based on bactericidal/permeability-increasing protein and therapeutic uses of such peptides. The bactericidal effect of BPI has been shown to be highly specific to sensitive Gram-negative species. The precise mechanism by which BPI kills Gram-negative bacteria is not yet known, but it is known that BPI must first attach to the surface of susceptible Gram-negative bacteria This initial binding of BPI to the bacteria involves electrostatic interactions between BPI, which is a basic (i.e., positively charged) protein, and negatively charged sites on lipopolysaccharides (LPS). LPS is also known as "endotoxin" because of the potent inflammatory response that it stimulates. LPS induces the release of mediators by host inflammatory cells which may ultimately result in irreversible endotoxic shock. BPI binds to Lipid A, the most toxic and most biologically active component of LPS. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Branched polyethylene oxide terminated biomedical polymers and their use in biomedical devices Inventor(s): Anderson, James M.; (Cleveland, OH), Ebert, Michael J.; (Fridley, MN), Yang, Zhongping; (Woodbury, MN) Correspondence: Medtronic, INC.; 710 Medtronic Parkway NE; Ms-Lc340; Minneapolis; MN; 55432-5604; US Patent Application Number: 20030204230 Date filed: April 25, 2002 Abstract: A biomedical polymer has a substantially linear base polymer; and branched polyethylene oxide covalently bonded to the base polymer as surface active end groups. The branched polyethylene oxide has at least two, more particularly at least four, and still more particularly at least six branches. Suitable base polymers include epoxies, polyurethanes, polyurethane copolymers, fluoropolymers, polyolefins and silicone rubbers. Biologically active agents may be attached to the branched polyethylene oxide. Suitable biologically active agents include microbial peptide agents, detergents, nonsteroidal anti-inflammatory drugs, cations, amine-containing organosilicones, diphosphonates, fatty acids, fatty acid salts, heparin and glucocorticosteroids. The biological polymer may be used as a casing for a medical unit of an implantable medical device, such as a pacemaker. In this case, the casing at least partially encloses the medical unit. Excerpt(s): This application incorporates by reference the contents of U.S. Pat. No. 5,895,563 to Ward et al., issued Dec. 31, 1996. Some functional surface modifying endgroups (SMEs), such as hydrocarbons, fluorocarbons, silicones, linear PEOs and sulfonates, have been demonstrated in biomedical polymers to improve
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biocompatibility and biostability. These biomedical polymers may, for example, be used as a casing to enclose an implantable biomedical device (IMD). A small concentration of the surface modifying endgroups, which terminates the ends of a base polymer, modifies the surface properties of the base polymer without significantly modifying bulk properties. Low bulk concentrations of the SME can produce essentially complete monolayer coverage. The surface modifying endgroups (SMEs) migrate to the surface of the polymer. Thus, if the polymer is used as a casing for an implantable medical device, the end groups will migrate to the surface of the IMD. This surface develops spontaneously by surface-energy-reducing migrations of the SME to the air-facing surface. Interfacial energy continues to form the surface in response to a change in environment, e.g., following implantation into a patient and tissue contact. Surface modification is thought to reduce protein adsorption and platelet adhesion, possibly minimizing tissue encapsulation. However, current SMEs cannot provide a sufficiently think cover on the base polymer surfaces because linear molecules are used for the SMEs. It is believed that polymers having low SME coverage may be ineffective in improving long-term biocompatibility and biostability in implantable biomedical devices. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Coated surfaces for immobilizing negatively charged anticoagulating agents from blood fluid Inventor(s): Sandhu, Shivpal S.; (Reading, GB) Correspondence: Brad Pedersen; Patterson, Thuente, Skaar & Christensen, P.A.; 4800 Ids Center; 80 South 8th Street; Minneapolis; MN; 55402-2100; US Patent Application Number: 20030229376 Date filed: March 14, 2003 Abstract: A wound closure apparatus is provided which utilizes blood fluid by activating the clotting cascade of blood fluid outside the body within a substantially enclosed sterile container then introducing, the blood fluid to the wound site to complete clotting. An apparatus for providing ways of inhibiting anticoagulating agents, and slowing fibrin clot degradation are also disclosed. Kits for practicing the invention singularly or in combination with, and/or associated with preferred procedures are also disclosed. The invention provides a clotting cascade initiation apparatus (1) including a substantially enclosed sterile containment chamber within which an aliquot of blood fluid, either autologous or from donor sources can be received, and retained. In preferred embodiments, the sterile containment chamber further includes a heparin binding agent which will bind heparin and remove it from the blood fluid. In further embodiments, the containment chamber will also include a procoagulating agent, wherein a clotting cascade can be initiated when the blood fluid is accepted into the sterile containment chamber. Excerpt(s): This application is a continuation of pending U.S. application Ser. Nos. 10/291,965, filed Nov. 12, 2002, entitled, CLOTTING CASCADE INITIATING APPARATUS AND METHODS OF USE, and 10/194,403, filed Jul. 11, 2002, entitled, CLOTTING CASCADE INITIATING APPARATUS AND METHODS OF USE, which claims priority to U.S. application No. 09/585,488, filed Jun. 1, 2000, entitled, SYSTEM FOR REMOVAL OF ANTI-COAGULATING AGENTS FROM BLOOD FLUID, now U.S. Pat. No. 6,482,223, which claims priority to U.S. Provisional Application No. 60/136,837, filed Jun. 1, 1999, entitled, HEPARIN REVERSAL BLOOD DRAWING APPARATUS.
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The entire disclosures of the prior applications are considers as being part of the disclosure of the accompanying application and are hereby incorporated by reference. The present invention relates to a novel apparatus and method for surgical wound closure applications. Numerous medical applications exist where sealing of biological tissue is desired. U.S. Pat. No. 5,510,102 to Conchrum identifies a variety of applications including traumas of the liver, spleen, pancreas, lung, bone, etc., cardiovascular and vascular applications, such as microvascular anastomoses, vascular grafts, intraoperative bleeding and aortic repair; and the like. The described invention provides a means to remove the heparin from anticoagulated whole blood. A sample of blood intended for either diagnostic analysis or therapeutic use is drawn into a blood collection apparatus. The blood is exposed to a material that has an immobilized substrate that removes a negatively charged anticoagulating agent, preferably heparin, from the sample. Blood drawn into and across the immobilized biomaterial will be deheparinized, and therefore will be capable of clot formation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Disodium salts, monohydrates, and ethanol solvates for delivering active agents Inventor(s): Agarwal, Rajesh K.; (Yorktown Heights, NY), Bay, William E.; (Ridgefield, CT), Chaudhary, Kiran; (West Nyack, NY), Goldberg, Michael M.; (Englewood, NJ), Majuru, Shingai; (Brewster, NY), Russo, JoAnne P.; (Harrison, NY) Correspondence: Darby & Darby P.C.; 805 Third Avenue; New York; NY; 10022; US Patent Application Number: 20040106825 Date filed: July 7, 2003 Abstract: The inventors have discovered that the disodium salt of certain delivery agents has surprisingly greater efficacy for delivering active agents than the corresponding monosodium salt. Furthermore, the inventors have discovered that the disodium salts of these delivery agents form solvates with ethanol and hydrates with water. The delivery agents have the formula 1whereinR.sup.1, R.sup.2, R.sup.3, and R.sup.4 are indepedently hydrogen, halogen, C.sub.1-C.sub.4 alkyl, or C.sub.1-C.sub.4 alkoxy; andR.sup.5 is a substitued or unsubstituted C.sub.2-C.sub.16 alkylene, substituted or unsubstituted C.sub.2-C.sub.16 alkenylene, substituted or unsubstituted C.sub.1C.sub.12 alkyl(arylene), or substituted or unsubstituted aryl(C.sub.1-C.sub.12 alkylene). The hydrates and solvates of present invention also have surprisingly greater efficacy for delivering active agents, such as heparin and calcitonin, than their corresponding monosodium salts and free acids. The present invention provides an alcohol solvate, such as ethanol solvate, of a disodium salt of a delivery agent of the formula above. The invention also provides a hydrate of a disodium salt of a delivery agent of the formula above. Preferred delivery agents include, but are not limited to, N-(5-chlorosalicyloyl)-8aminocaprylic acid (5-CNAC), N-(10-[2-hydroxybenzoyl]amino)decanoic acid (SNAD), and sodium N-(8-[2-hydroxybenzoyl]amino)caprylate (SNAC). The invention also provides methods of preparing the disodium salt, ethanol solvate, and hydrate and compositions containing the disodium salt, ethanol solvate, and/or hydrate. Excerpt(s): This application claims the benefit of U.S. patent application Serial No. 60/127,754, filed Apr. 5, 1999; U.S. patent application Serial No. 60/186,143, filed Mar. 1, 2000; U.S. patent application Serial No. 60/186,142, filed Mar. 1, 2000; and U.S. patent application Serial No. 60/191,286, filed Mar. 21, 2000. The present invention relates to a disodium salt of a delivery agent, such as N-(5-chlorosalicyloyl)-8-aminocaprylic acid, N-(10-[2-hydroxybenzoyl]amino)decanoic acid, or N-(8-[2-hydroxybenzoyl]am-
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ino)caprylic acid, an ethanol solvate of the disodium salt, and a monohydrate of the disodium salt for delivering active agents and methods of preparing the same. U.S. Pat. Nos. 5,773,647 and 5,866,536 disclose compositions for the oral delivery of active agents, such as heparin and calcitonin, with modified amino acids, such as N-(5chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), N-(10-[2hydroxybenzoyl]amino)decanoic acid (SNAD), and N-(8-[2hydroxybenzoyl]amino)caprylic acid (SNAC). Many current commercial formulations containing an active agent, such as heparin and calcitonin, are delivered by routes other than the oral route. Formulations delivered orally are typically easier to administer than by other routes and improve patient compliance. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
DNA encoding human apoB48R: a monocyte-macrophage apolipoprotein B48 receptor gene and protein Inventor(s): Bradley, William A.; (Birmingham, AL), Gianturco, Sandra H.; (Birmingham, AL) Correspondence: Benjamin Aaron Adler, PH.D., J.D.; Adler & Associates; 8011 Candle Lane; Houston; TX; 77071; US Patent Application Number: 20030208060 Date filed: June 12, 2003 Abstract: The present invention provides an isolated DNA molecule that codes for a cellsurface binding protein in human monocytes and macrophages. In addition, an amino acid sequence derived from the nucleotide sequence is provided. The newly-identified cell-surface binding protein described herein is instrumental in the apoB-mediated cellular uptake of plasma chylomicrons and remnants and hypertriglyceridemic triglyceride-rich lipoproteins in an ApoE- and lipoprotein lipase- and heparin sulfate proteoglycan-independent pathway. The new human macrophage receptor has been cloned and uniquely, binds TGRLP via apolipoprotein B48, the marker of dietary TGRLP (apoB48R). This process rapidly converts macrophages and apoB48R-transfected Chinese hamster ovary cells in vitro into lipid-filled "foam cells," hallmarks of atherosclerotic lesions. The apoB48R cDNA (3744 bp) encodes a novel protein with no known homologs. Its.about.3.8 kb mRNA is expressed primarily by reticuloendothelial cells. Immunohistochemical studies indicate that foam cells of human atherosclerotic lesions express the apoB48R. Excerpt(s): This application is a continuation-in-part and claims the benefit of priority under 35 USC.sctn.120 of U.S. patent application Ser. No. 09/130,242, filed Sep. 8, 1998. The present invention relates generally to the fields of molecular biology, cardiovascular medicine and cellular nutrition. More specifically, the present invention relates to DNA encoding the human monocyte-macrophage and placental triglyceride-rich lipoprotein/apolipoprotein B (apoB) receptor gene(s) and protein(s). Hypertriglyceridemia is a common, heterogeneous disorder. When chylomicrons persist in the fasting state, lipid-filled monocyte-macrophage-derived foam cells can accumulate in the spleen, liver, bone marrow, atherosclerotic lesions, and skin (Fredrickson, 1978). Many, but not all, early studies (Carlson, 1972; Brunzell, 1976; Grundy, 1988; Schaefer, 1988; Austin, 1991) indicate elevated plasma triglycerides are a risk factor for coronary heart disease and myocardial infarction, sequelae of atherosclerosis. The possibility that triglyceride-rich lipoproteins (hepatic as well a s dietary) are involved in atherosclerosis has been strengthened recently. Both the Procam
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study and a follow-up of the Helsinki Heart Study implicate elevated triglycerides (and therefore triglyceride-rich lipoproteins) as an important risk factor in atherosclerosis (Assmann, 1992). Havel et al. demonstrated that plasma very low density lipoprotein and intermediate density lipoprotein cholesterol levels correlated with progression of coronary atherosclerosis disease, whereas low density lipoprotein cholesterol level did not (Phillips, 1993). Moreover, very low density lipoprotein-intermediate density lipoprotein particles enter the artery wall and are found in human atherosclerotic plaques (Rapp, 1994). Elevated postprandial chylomicron remnants of Sf<400 are significantly higher in subjects with coronary heart disease but with normal fasting lipid levels than in matched control subjects without this disease (Patsch, 1992; Weintraub, 1996). Thus, there is increasing biochemical as well as epidemiologic evidence that the major carriers of plasma triglycerides, very low density lipoproteins and plasma chylomicrons and their remnants, are atherogenic. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Formulation of amphiphilic heparin derivatives for enhancing mucosal absorption Inventor(s): Byun, Youngro; (Kwangju, KR), Lee, Yong-Kyu; (Kwangju, KR) Correspondence: Alan J. Howarth; P.O. Box 1909; Sandy; UT; 84091-1909; US Patent Application Number: 20040152663 Date filed: July 8, 2003 Abstract: Formulations for enhanced mucosal absorption of heparin are disclosed. In one preferred embodiment, an amphiphilic heparin derivative composed of heparin covalently bonded to a hydrophobic agent is dissolved in a water phase, the water phase is then dispersed in an organic phase such that an emulsion is formed, and then the emulsion is dried to obtain a powdered composition. In another embodiment, the amphiphilic heparin derivative is dissolved in water or a water/organic co-solvent, the water or co-solvent is then dispersed in an oil phase, and then the water or co-solvent is evaporated, resulting in the amphiphilic heparin derivative dispersed in the oil phase. In another embodiment, the amphiphilic heparin derivative is dissolved in an aqueous solvent, a surfactant is mixed with the aqueous solvent and nanoparticles of the amphiphilic heparin derivative are disrupted, resulting in nanoparticles having surfactant molecules associated with the hydrophobic agent on the outside of the nanoparticles. Compositions made according to these methods are also described. Excerpt(s): This application is a continuation of co-pending U.S. patent application Ser. No. 09/852,131, filed May 9, 2001, U.S. Pat. No. 6,589,943,entitled "Formulation of Amphiphilic Heparin Derivatives for Enhancing Mucosal Absorption," which is incorporated herein by reference in its entirety, including but not limited to those portions that specifically appear hereinafter, the incorporation by reference being made with the following exception: In the event that any portion of the above-referenced application is inconsistent with this application, this application supercedes said abovereferenced application. Not applicable. This invention relates to administration of heparin for treating patients in need of anticoagulation therapy. More particularly, this invention relates to formulations of heparin that enhance absorption of heparin through mucosal tissues. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Heparin compositions and methods of making and using the same Inventor(s): Koulik, Edouard; (Golden Valley, MN) Correspondence: Medtronic, INC.; 710 Medtronic Parkway NE; Ms-Lc340; Minneapolis; MN; 55432-5604; US Patent Application Number: 20040005470 Date filed: June 26, 2003 Abstract: Heparin-polyoxyalkylenepolyamine adducts, and methods of making and using such adducts are disclosed. Compositions including a quaternary ammonium heparin complex, a moisture curable polysiloxane, and an organic solvent are also disclosed, along with methods of making and using such compositions. Excerpt(s): The present invention relates to heparin compositions, methods of making such compositions, and compositions prepared therefrom. Development of materials that do not induce hostile response from the body tissues upon implantation or insertion in a human or animal body is an important target in the medical device field. In practice, many commonly used materials including plastics, ceramics, and metals have substantial biocompatibility problems. One important property for medical devices that contact blood after implantation or insertion in a human or animal body is thrombogenicity. Thrombogenicity is the ability of the device to induce formation of blood clots. For blood to clot, it is believed that thrombin must be generated in the blood. Several potent anticoagulants are known that are able to prevent formation of thrombin. The most widely used anticoagulant used during surgical procedures is heparin. When heparin is immobilized on the surface of a medical device, the ability of the surface to induce formation of clots decreases, or in other words, the surface becomes antithrombogenic. However, the antithrombogenicity of a heparinized surface tends to decrease as the surface heparin loses its potency to retard clot formation. Many heparinized surfaces tend to have poor stability in vivo. New heparin compositions and coatings are needed to improve the antithrombogenic stability of heparinized surfaces. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Heparin-like compounds, their preparation and use to prevent arterial thrombosis associated with vascular injury and interventions Inventor(s): Kovanen, Petri; (Espoo, FI), Lassila, Riitta; (Espoo, FI), Lindstedt, Ken; (Helsinki, FI) Correspondence: Teresa Stanek Rea; Burns, Doane, Swecker & Mathis, L.L.P.; P.O. Box 1404; Alexandria; VA; 22313-1404; US Patent Application Number: 20030212042 Date filed: April 18, 2003 Abstract: The present invention is related to heparin-like compounds characterized by their capacity of inhibiting collagen-induced platelet aggregation in flowing whole blood and their use for prophylactic treatment of arterial thrombosis associated with vascular or microvascular injury and interventions. Said properties are related to a high coupling density of negatively charged heparin or heparin-like glycosaminoglycan molecules, present in multiple heparin or heparin-like glycosaminoglycans as well as in proteoglycans containing said multiple heparin or heparin-like glycosaminoglycans or lower-molecular-weight heparin or heparin-like glycosaminoglycans connected directly
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or through spacer/linker molecules to globular core molecules. Heparin-like compounds, with said properties are obtainable from mammalian mast cells, by tissue extraction or cell cultivation. The heparin-like compounds of the present invention can also be produced by synthetical, semisynthetical and/or biotechnological methods and they are useful for manufacturing preparations, means and devices for local or topical application in prophylactic treatment of arterial thrombosis and its sequelae. Excerpt(s): The invention is related to heparin-like compounds characterized by their capacity of almost complete inhibition of collagen-induced platelet aggregation in flowing whole blood and a coupling density of negatively charged heparin or heparinlike glycosaminoglycan units that gives them the unique properties first displayed in native mast cell-derived heparin proteoglycans (HEP-PG) or heparin glycosaminoglycan (HEP-GAG) molecules-obtainable thereof. The present invention is also related to methods for preparing said heparin-like compounds and their use in prophylactic treatment of arterial thrombosis associated with vascular injuries and interventions. Heparin is a glycosaminoglycan, an acidic mucopolysaccharide composed of D-glucuronic acid and D-glucosamine with a high degree of N-sulphation. It is present in the form of proteoglycan in many mammalian tissues, such as the intestine, liver, lung, being localized in the connective tissue-type mast cells, which line for example the vascular and serosal system of mammals. The main pharmaceutical characteristic of heparin is its ability to enhance the activity of the natural anticoagulant, antithrombin III. Heparins exist naturally bound to proteins, forming so called heparin proteoglycans. Usually, the endogenous or native, naturally existing heparin proteoglycans contain 10-15 heparin glycosaminoglycan chains, each chain having a molecular weight in the range of 75.+-.25 kDa, and being bound to one core protein or polypeptide. Each native heparin glycosaminoglycan chain contains several separate heparin units consecutively placed end-to-end, which are cleaved by endoglycosidases in their natural environment. The natural or native conjugates are difficult to prepare in pure form. Thus, they have not been suggested for therapeutical or corresponding use. Heparin glycosaminoglycans belong to a larger group of negatively charged heteropolysaccharides, which generally are associated with proteins forming so called proteoglycans. Examples of other naturally existing glycosaminoglycans are for example chondroitin-4- and 6-sulphates, keratan sulphates, dermatan sulphates, hyaluronic acid, heparan sulphates and heparins. Of said heparin-like compounds existing in nature, only hyaluronic acid is generally not associated with a proteinaceous core molecule. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Intradermal delivery of substances Inventor(s): Pinkerton, Thomas C.; (Kalamazoo, MI) Correspondence: Harness, Dickey, & Pierce, P.L.C; 7700 Bonhomme, Ste 400; ST. Louis; MO; 63105; US Patent Application Number: 20040073160 Date filed: June 29, 2001 Abstract: A method for administration of a substance into the dermis of a mammal is disclosed. The method involves administration into the dermis by injection which results in improved systemic absorption relative to that obtained upon subcutaneous administration of the substance. The substance administered may be a growth hormone, a low molecular weight heparin or a dopamine receptor agonist.
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Excerpt(s): This application is a continuation-in-part of U.S. application Ser. No. 09/606,909 filed Jun. 29, 2000. The present invention relates to methods and devices for administration of substances into the intradermal layer of skin. The importance of efficiently and safely administering pharmaceutical substances such as diagnostic agents and drugs has long been recognized. Although an important consideration for all pharmaceutical substances, obtaining adequate bioavailability of large molecules such as proteins that have arisen out of the biotechnology industry has recently highlighted this need to obtain efficient and reproducible absorption (Cleland et al., Curr. Opin. Biotechnol. 12: 212-219, 2001). The use of conventional needles has long provided one approach for delivering pharmaceutical substances to humans and animals by administration through the skin. Considerable effort has been made to achieve reproducible and efficacious delivery through the skin while improving the ease of injection and reducing patient apprehension and/or pain associated with conventional needles. Furthermore, certain delivery systems eliminate needles entirely, and rely upon chemical mediators or external driving forces such as iontophoretic currents or electroporation or thermal poration or sonophoresis to breach the stratum corneum, the outermost layer of the skin, and deliver substances through the surface of the skin. However, such delivery systems do not reproducibly breach the skin barriers or deliver the pharmaceutical substance to a given depth below the surface of the skin and consequently, clinical results can be variable. Thus, mechanical breach of the stratum comeum such as with needles, is believed to provide the most reproducible method of administration of substances through the surface of the skin, and to provide control and reliability in placement of administered substances. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Large-scale recombinant adeno-associated virus (rAAV) production and purification Inventor(s): Qu, Quang; (Alameda, CA), Wright, John Fraser; (Mill Valley, CA) Correspondence: Knobbe Martens Olson & Bear Llp; 2040 Main Street; Fourteenth Floor; Irvine; CA; 92614; US Patent Application Number: 20030207439 Date filed: May 19, 2003 Abstract: Methods are provided for large-scale purification of recombinant AAV (rAAV) virions that were produced in the absence of infectious adenovirus. Preferably, the rAAV is produced in a host cell line via triple-transfection with an accessory function vector, an AAV vector, and an AAV helper vector. The methods include preparing a lysate from the host cell line and passing that lysate over various combination of ion exchange chromatography media and/or affinity chromatography media. The affinity chromatography medium is an AAV receptor or an antibody with binding affinity for AAV, e.g., heparin sulfate. A variety of cation exchange and anion exchange media are contemplated by the present invention. In certain embodiment, optional purification steps may be included, such as filtering the lysate through one or more filters, or treating the lysate with a nuclease. Excerpt(s): The present application is a continuation patent application of U.S. patent application Ser. No. 09/633,834, entitled Large-Scale Recombinant Adeno-Associated Virus (rAAV) Production and Purification, which was filed Aug. 7, 2000 on behalf of John Fraser Wright and Quang Qu. The invention relates to methods for producing and purifying recombinant adeno-associated virus (rAAV). More particularly, it relates to methods for producing commercial grade rAAV at large scale where rAAV was
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generated in the absence of infectious helper virus. The methods employ a plurality of column purification steps that yield purified rAAV. One embodiment of the invention is a two-column purification system comprising purification over an anion exchange column and over an affinity column. In another embodiment, a cation exchange column purification step is included. Gene delivery is a promising method for the treatment of acquired and inherited diseases. A number of viral-based systems for gene transfer purposes have been described, including adeno-associated virus (AAV)-based systems. AAV is a helper-dependent DNA parvovirus that belongs to the genus Dependovirus. AAV requires coinfection with an unrelated helper virus, e.g., adenovirus, herpes virus, or vaccinia, in order for a productive infection to occur. In the absence of a helper virus, AAV establishes a latent state by inserting its genome into a host cell chromosome. Subsequent infection by a helper virus rescues the integrated viral genome, which can then replicate to produce infectious viral progeny. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Low molecular weight heparin assay, system and reagent therefor Inventor(s): Mize, Patrick D.; (Durham, NC) Correspondence: Oblon, Spivak, Mcclelland, Maier & Neustadt, P.C.; 1940 Duke Street; Alexandria; VA; 22314; US Patent Application Number: 20040115753 Date filed: November 26, 2003 Abstract: A method, kit, system and reagent for measuring low molecular weight heparin in a whole blood sample is provided which involves the use of a Factor Xa activator, such as Russell's Viper Venom, as the coagulation assay initiator. Excerpt(s): The present invention relates to a dry chemistry format assay for measuring the low molecular weight heparin content of a whole blood sample, and a system and reagent for performing such an assay. Low molecular weight heparins (LMWHs) are a heterogeneous group of antithrombotic drugs produced from unfractionated heparin (UFH) using diverse chemical and enzymatic processes. LMWHs, like UFH, exhibit an anticoagulant effect by complexing with antithrombin (AT) to inactivate several of the coagulation enzymes preventing fibrin formation. Of these, Factor Xa and thrombin (IIa) are the most responsive to inhibition. LMWHs, introduced as antithrombotic drugs in the mid-1980s, are now established as the drug of choice for surgical thromboprophylaxis and are increasingly replacing UFH in the acute treatment of venous thromboembolic disorders. The low molecular weight heparin, enoxaparin, increasingly is used in patients with unstable angina (UA) and non-Q-wave myocardial infarction (NQMI) (J. Fareed et al, Past, present and future considerations on low molecular weight heparin differentiation: an epilogue. Semin Thromb Hemost, 25 Suppl 3:145-7 (1999), and J. Hirsh et al, Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest, Jan;119(1 Suppl):64S-94S (2001)), who transition to percutaneous coronary intervention (PCI) (Lovenox (enoxaparin sodium) injection package insert,.COPYRGT.1998, rev. 01/2001). Although the activated partial thromboplastin time (aPTT) and activated clotting time (ACT) are the most common methods used to monitor UFH, they are relatively insensitive to LMWHs, such as enoxaparin. While chromogenic anti-Xa assays are commonly used to monitor the concentration of LMWHs, such assays provide an indirect measure of drug concentration and results are not routinely available in a cardiac catheterization laboratory setting. The LMWHs have mean molecular weights
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between 4000 to 6000 daltons, and they have less ability to inactivate thrombin compared to UFH. Each LMWH is a specific mixture often demonstrating a unique antiXa/anti-IIa ratio and signature anticoagulant profile. The result is an anti-Xa/anti-IIa ratio of approximately 3 to 14:1 (depending on the brand of LMWH, dosage, and route of administration) compared to the 1:1 ratio observed with UFH.sup.(Lovenox P.I.). The LMWH, enoxaparin, has a mean molecular weight of approximately 4,500 daltons and, given at a dose of 1.5 mg/kg subcutaneously (SC), is characterized by a higher ratio of anti-Factor Xa to anti-Factor IIa activity (mean.+-.SD, 14.0+3.1) (based on areas under anti-Factor activity versus time curves) compared to the ratios observed for heparin (mean.+-.SD, 1.22.+-.0.13).sup.(Lovenox P.I.). This is an important distinction because the ability to prolong the APTT and ACT is proportional to anti-IIa activity. Chromogenic anti-Xa assays provide estimates of enoxaparin concentration only in dilute, supplemented plasma and are not suitable for point-of-care (POC) testing. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Medical device for delivering a therapeutic substance and method therefor Inventor(s): Berg, Eric P.; (Plymouth, MN), Dinh, Thomas Q.; (Minnetonka, MN) Correspondence: Medtronic Vascular, INC.; Legal Department; 3576 Unocal Place; Santa Rosa; CA; 95403; US Patent Application Number: 20040111150 Date filed: December 5, 2003 Abstract: A device useful for localized delivery of a therapeutic material is provided. The device includes a structure including a porous material; and a water-insoluble salt of a therapeutic material dispersed in the porous material. The water-insoluble salt is formed by contacting an aqueous solution of a therapeutic salt with a heavy metal water-soluble salt dispersed throughout a substantial portion of the porous material. The heavy metal water-soluble salt can be dispersed in the porous material so that the device can be sterilized and the therapeutic material can be loaded in the device in situ, for example, just prior to use. The therapeutic material is preferably a heparin or heparin derivative or analog which renders the material antithrombotic as an implantable or invasive device. Excerpt(s): This application is a continuation of U.S. application Ser. No. 09/769,423, filed Jan. 26, 2001, which is a continuation of U.S. application Ser. No. 08/877,532, filed Jun. 17, 1997, that issued as U.S. Pat. No. 6,203,536, the disclosures of each of which are hereby incorporated by reference herein in their entireties. This invention relates to a medical device employing a therapeutic substance as a component thereof. For example in an arterial site treated with percutaneous transluminal coronary angioplasty therapy for obstructive coronary artery disease a therapeutic antithrombogenic substance such as heparin may be included with a device and delivered locally in the coronary artery. Also provided is a method for making a medical device capable of localized application of therapeutic substances. Medical devices which serve as substitute blood vessels, synthetic and intraocular lenses, electrodes, catheters and the like in and on the body or as extracorporeal devices intended to be connected to the body to assist in surgery or dialysis are well known. For example, intravascular procedures can bring medical devices into contact with the patient's vasculature. In treating a narrowing or constriction of a duct or canal percutaneous transluminal coronary angioplasty (PTCA) is often used with the insertion and inflation of a balloon catheter into a stenotic vessel. Other intravascular invasive therapies include atherectomy (mechanical systems to
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remove plaque residing inside an artery), laser ablative therapy and the like. However, this use of mechanical repairs can have adverse consequences for the patient. For example, restenosis at the site of a prior invasive coronary artery disease therapy occurs in a majority of cases. Restenosis, defined angiograhpically, is the recurrence of a 50% or greater narrowing of a luminal diameter at the site of a prior coronary artery disease therapy, such as a balloon dilatation in the case of PTCA therapy. In particular, an intraluminal component of restenosis develops near the end of the healing process initiated by vascular injury, which then contributes to the narrowing of the luminal diameter. This phenomenon is sometimes referred to as "intimal hyperplasia." It is believed that a variety of biologic factors are involved in restenosis, such as the extent of the injury, platelets, inflammatory cells, growth factors, cytokines, endothelial cells, smooth muscle cells, and extracellular matrix production, to name a few. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
METHOD AND DEVICE FOR DETERMINING THE CONCENTRATION OF HEPARIN IN A SAMPLE OF FLUID Inventor(s): Caputo, Giuseppe; (Torino, IT), Castelli, Raffaele; (Mirandola, IT), Ciana, Leopoldo Della; (Ivrea, IT), Comoglio, Elena; (Torino, IT), Giannetti, Arnaldo; (Crescentino, IT) Correspondence: Terry L. Wiles; Popovich & Wiles, PA; Ids Center, Suite 1902; 80 South 8th Street; Minneapolis; MN; 55402; US Patent Application Number: 20040027557 Date filed: August 5, 2003 Abstract: A device for determining the concentration of heparin in a fluid sample comprising: a container for holding the fluid sample; a container for holding the dye solution; a mixer for mixing the fluid sample and the dye solution; an illumination source for illuminating a mixture comprising the fluid sample and the dye solution with electromagnetic radiation having a substantially continuous range of wavelengths in the visible range; a detector for detecting the absorption spectrum of the mixture within the substantially continuous range of wavelengths; a recorder for recording the absorption spectrum of the mixture within the substantially continuous range of wavelengths; and a calculator for calculating a spectral parameter. Excerpt(s): This application is a continuation of U.S. application Ser. No. 09/686,219, filed Oct. 11, 2000, the contents of which are hereby incorporated herein by reference. The present invention relates to a method of determining the concentration of heparin in fluid samples, and to a device for performing the method. Heparin is a heteropolysaccharide of the acid mucopolysaccharide type which has anticoagulant activity resulting from its ability to catalyze the reaction between antithrombin III and thrombin. On the basis of this activity, heparin is widely used as an anticoagulant in cardiovascular surgery, for example, during operations with extracorporeal circulation, and in other diagnostic and therapeutic applications. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Novel therapeutic use of low molecular weight heparins Inventor(s): Stutzmann, Jean-Marie; (Villecresnes, FR), Uzan, Andre; (Paris, FR) Correspondence: Ross J. Oehler; Aventis Pharmaceuticals INC.; Route 202-206; Mail Code: D303a; Bridgewater; NJ; 08807; US Patent Application Number: 20030236222 Date filed: August 20, 2003 Abstract: The invention concerns the use of low molecular weight heparin for preventing and/or treating motor neuron diseases. Excerpt(s): The present invention relates to the use of low molecular weight heparins in the prevention and/or treatment of motoneuron diseases. Standard heparin is a sulfated polysaccharide with a mean molecular weight of 12000-15000 daltons, isolated from the intestinal mucous membranes of cattle, sheep and pigs. Heparin is used clinically for the prevention and treatment of thromboembolic disorders, but sometimes causes hemorrhages. For the past ten or so years, heparin has been progressively replaced with low molecular weight heparins which no longer exhibit, or exhibit to a lesser degree, the drawback of causing bleeding, and which now require only one injection per day instead of 2 to 3 injections per day for standard heparin. These low molecular weight heparins are prepared, in particular, by fractionation or controlled depolymerization of heparin, or by chemical synthesis. They have an anti-Xa activity/anti-IIa activity ratio of greater than 2. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Prevention of indwelling device related infection: composition and methods Inventor(s): Polaschegg, Hans-Dietrich; (Kostenberg, AT) Correspondence: Mark J. Pandiscio; Pandiscio & Pandiscio, P.C.; 470 Totten Pond Road; Waltham; MA; 02451-1914; US Patent Application Number: 20040156908 Date filed: February 2, 2004 Abstract: Catheters used for medical treatment, e.g., hemodialysis are filled with a locking solution, usually heparin between treatments. To prevent infections, antimicrobial or antibiotic substances have been used as locking solution alone or in combination with antithrombotic substances. It has been found that these locking solutions are rapidly washed out from the catheter tip. The invention describes a thixotropic gel that can be used as locking solution. Beneficial substances, e.g., antimicrobial or antibiotic substances can be added to the gel. A preferred antimicrobial substance is taurolidin alone or in combination with salicylic acid or one of its salts. Excerpt(s): This invention relates to methods and compositions, which prevent biofilm formation on or near medical prosthetic devices in order to reduce patient infection related to indwelling devices. The invention further addresses the complete life cycle of medical applications of an indwelling device teaching means to reduce or prevent infection. A new sub-study branch has developed in Microbiology to study Biofilm (Costerton JW, Stewart PS, Greenberg EP. Bacterial Biofilms: A Common Cause of Persistent Infections. Science 1999;284: 1318-22) The Biofilm specialty has adopted new methods of imaging and quantification techniques to study this form of microbial populations. These new techniques helped elucidate the sequencing steps of Biofilm
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formation and show how most infections in patients with indwelling medical devices can be traced to the Biofilm adhering to the device. In the last years scientists have discovered that microbes in a Biofilm are considerably different from the microbes in the planktonic form, which were the only microbes studied previously. Devices that have the highest rate of nosocomial infection include various catheters including ports and peripheral inserted central catheters (PICC) lines used for administration of liquids to the venous system such as saline, electrolytes, medications, imaging enhancers, chemotherapy drugs, and parenteral nutritional products as well as hemodialysis and hemofiltration. Other types of catheter devices such as enteral feeding tubes, spinal catheters, various shunts, urinary catheters, peritoneal dialysis catheters, intratracheal tubes for assisted breathing as well as diagnostic monitoring arterial catheters also carry high risk of Biofilm formation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Process for the preparation in pure form of the protease activating blood clotting factor VII, its proenzyme or a mixture of both proteins by means of chromatography Inventor(s): Feussner, Annette; (Marburg, DE), Roemisch, Juergen; (Marburg, DE), Stoehr, Hans-Arnold; (Wetter, DE) Correspondence: Finnegan, Henderson, Farabow, Garrett & Dunner; Llp; 1300 I Street, NW; Washington; DC; 20005; US Patent Application Number: 20040063187 Date filed: October 1, 2003 Abstract: A process for the preparation in pure form of the protease activating blood clotting factor VII and/or its proenzyme by use of one or more affinity chromatography separation processes and/or fractional precipitation is described, in which the affinity chromatography separation process used is adsorption oncalcium phosphate/hydroxyapatite,a hydrophobic matrix,a chelate matrix,a matrix on which heparin or a substance related to heparin, such as heparan sulfate or dextran sulfate, is immobilized, and/ora matrix which is coated with an immobilized monoclonal or polyclonal antibody directed against the protein to be isolated, or its F(ab) or F(ab).sub.2 fragments.A pharmaceutical preparation and a reagent are moreover described which contain the said protease and its proenzyme. Excerpt(s): The invention relates to a process for the preparation in pure form of the protease activating blood clotting factor VII, its proenzyme or a mixture of both proteins, and of pharmaceutical preparations which contain the proteins mentioned individually or as a mixture. German patent application 19 903 693.4 has already disclosed a protease for the activation of blood clotting factor VII, a process for its production, for its detection and for its inactivation, and pharmaceutical preparations which contain this protease. This protease, first isolated from plasma, occurs there together with a nonactivated form, which is designated below as "proenzyme". The protease activates blood clotting factor VII and accelerates clotting, as was shown by numerous experiments. In the further investigation of the biological properties of this protein, identified as serine protease, it emerged that single-chain plasminogen activators, such as prourokinase, are also effectively activated. Moreover, inactivation of factors V and VIII in vitro was observed. In addition to the sequenced regions already described in German patent application 19 903 693.4, N-terminal sequencings of protease fractions were carried out. The following amino acid sequences characterize the FVII-activating protease: IYGGFKSTAGKHP; LLESLDPDXTPD; EFHEQSFRVEKI;
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SKFTXAXPXQFK; where X means not identified. The sequences of the protease mentioned elucidated up to now show that they agree 100% with sequences of the protease published by Choi-Miura (Choi-Miura et al. J. Biochem. 1996; 119: 1157 to 1165). The investigations until now have especially concentrated on the protease in its activated form. The inactive form of the protease present in the plasma as a proenzyme was only recently discovered by means of a protein band pattern in the SDS-PAGE after reduction of the sample. Since, on the activation of the protease, a cleavage at a site of the primary structure typical for serine proteases and thus activation takes place, two or more bands are visible on electrophoresis. On reduction of the chains which are connected by disulfide bridges, the individual bands become visible in accordance with their lower molecular weight, the proenzyme remaining as a large individual chain. This was also clear in more complex solutions after transfer of the proteins to membranes and subsequent Western blotting using suitable antibodies. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Process for the preparation of esters of heparin Inventor(s): De Ferra, Lorenzo; (Roma, IT), Montorsi, Mauro; (Modena, IT) Correspondence: Darby & Darby P.C.; Post Office Box 5257; New York; NY; 10150-5257; US Patent Application Number: 20030236221 Date filed: March 28, 2003 Abstract: The description relates to a process for the production of esters of heparin, wherein from 0.1 to 2 g of a halogenated reagent having the formula R--CH.sub.2--X, where R is a phenyl group which is non-substituted or substituted by a halogen atom or by a nitro group, and X is a halogen atom, preferably chlorine, are reacted with from 2 to 20 g of one of the quaternary ammonium salts of heparin in from 30 to 250 ml of N,Ndimethylformamide and/or N,N-dimethylacetamide.The process in question allows esters of heparin to be obtained at lower cost and within shorter times than the methods known in the art, minimising among other things the use of lachrymatory reagents, such as, for example, benzyl chloride. Excerpt(s): The present invention relates to a process for the preparation of esters of heparin, wherein carboxylic groups are esterified partially or totally with a R--CH.sub.2- radical, where R is preferably a non-substituted or substituted phenyl group, by reaction with a halogenated reagent having the formula R--CH.sub.2--X in N,Ndimethylformamide at a temperature of between 35.degree. and 90.degree. C. for a reaction time of between 1 and 20 hours. The present invention relates to a process for the preparation of esters of heparin which are useful as intermediates in the synthesis of heparin having a low molecular weight, in particular of Enoxaparin (Common International Denomination--CID), a principal active ingredient with anti-coagulant and anti-thrombotic action, whose preparation is described in European patent application EP-40144 and in American patent U.S. Pat. No. 5,389,618, both incorporated herein by reference. The therapeutic use of Enoxaparin is, in particular, described in detail in various scientific publications, such as, for example, Frydman et al., J. Clin. Pharmacol., 1988; 28:609-618; Planes et al., Haemostasis, 16:152-158, 1986; Dahan et al., 16:152-158, 1986; Huet et al., 16:152-158, 1986; Aiach et al., Thrombosis Res., 31:611-621, 1983; Neville et al., Journal of Pharmaceutical Sciences, Vol. 78, no. 2, February 1989; Neville et al., Journal of Pharmaceutical Sciences, Vol. 79, no. 4, April 1990.
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Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Purification of vascular endothelial growth factor-b Inventor(s): Fabri, Louis J.; (Richmond, AU), Mackenzie, Andrew W.; (Victoria, AU), Nash, Andrew D.; (Victoria, AU), Scotney, Pierre D.; (Victoria, AU), Scrofani, Sergio D.B.; (Victoria, AU) Correspondence: Edward W Grolz; Scully Scott Murphy & Presser; 400 Garden City Plaza; Garden City; NY; 11530; US Patent Application Number: 20040137588 Date filed: August 16, 2002 Abstract: The present invention provides a method for purifying recombinant peptides, polypeptides or proteins away from truncated or other full-length forms of these molecules. In particular the invention contemplates a method of purifying a vascular endothelial growth factor (VEGF) molecule by subjecting a biological sample containing the molecule to be purified to affinity chromatography under conditions sufficient for the full length molecules to bind and not the truncated or clipped forms. In the preferred embodiment there are two columns, the first is based on affinity for a poly his tag, the second column based on heparin binding affinity. Particularly preferred VEGF molecules are untagged VEGF-B.sub.167, hexa-His-tagged VEGF-B.sub.167, hexa-Histagged VEGF-B.sub.186 and hexa-His-tagged VEGF-B.sub.10-108. Excerpt(s): The present invention relates generally to a method of producing recombinant peptides, polypeptides and proteins. More particularly, the present invention provides a method of purifying recombinant peptides, polypeptides or proteins away from truncated or other non-full length forms of these molecules. Even more particularly, the present invention contemplates a method of purifying a vascular endothelial growth factor (VEGF) molecule or a derivative or homologue thereof including amino acid tagged forms or other peptide, polypeptide or protein by subjecting a preparation containing the molecule to be purified to affinity chromatography under chromatographic conditions sufficient for full length molecules but not truncated or non-full length molecules corresponding to said full length molecules to bind or otherwise associate by the affinity process. In a preferred embodiment, the purification involves optionally subjecting a preparation containing the molecule to be purified to an affinity column based on the properties of an exogenous amino acid sequence followed by a second affinity column based on properties inherent with the peptide, polypeptide or protein. The present invention is further directed to a peptide, polypeptide or protein such as a VEGF molecule or a derivative or homologue thereof purified by the methods of the present invention. Particularly preferred VEGF molecules are VEGF-B molecules including untagged VEGF-B.sub.167, hexa-His-tagged VEGF-B.sub.167, hexa-His-tagged VEGF-B.sub.186 and hexa-His-tagged VEGF-B.sub.10-108. Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in Australia or any other country. Bibliographic details of the publications referred to by anthor in this specification are collected at the end of the description. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Pyridoxine and pyridoxal analogues: new uses Inventor(s): Haque, Wasimul; (Edmonton, CA) Correspondence: Merchant & Gould PC; P.O. Box 2903; Minneapolis; MN; 55402-0903; US Patent Application Number: 20040010015 Date filed: April 10, 2003 Abstract: The invention provides pyridoxal and pyridoxine analogues, pharmaceutical compositions containing pyridoxine and pyridoxal analogues, and methods of administering pharmaceutical compositions containing a therapeutically effective amount of at least one of these analogues. In accordance with the present invention, the pyridoxal and pyridoxine analogues can be used in the treatment or prevention of of heparin induced thrombocytopenia (HIT, stroke, and ischemia, and in the treatment of symptoms thereof. The the pyridoxal and pyridoxine analogues can be used in neuroprotection. Excerpt(s): This application claims priority from U.S. provisional application No. 60/216,907 filed Jul. 7, 2000, and is a continuation-in-part of U.S. Pat. No. 6,417,204 filed Jul. 6, 2001, and is a continuation-in-part of U.S. patent application Ser. No. 10/147,263 filed May 15, 2002, which is pending. The present invention relates to pyridoxine and pyridoxal analogue compounds, pharmaceutical compositions containing the pyridoxine and pyridoxal analogue compounds, and methods of treatment using a therapeutically effective amount of the pyridoxine and pyridoxal analogue compounds. The pyridoxine or pyridoxal analogues can be used in the treatment of undesired stroke, ischemia, and heparin induced thrombocytopenia (HIT), or related diseases and symptoms thereof, as well as providing neuroprotection. PLP is tho biologically active form of vitamin B.sub.6 inside cells and in blood plasma. Mammals cannot synthesize PLP de novo and must rely on dietary sources of the precursors pyridoxine, pyridoxal, and pyridoxamine, which are metabolized to PLP. For instance, mammals produce PLP by phosphorylating pyridoxine by action of pyridoxal kinase and then oxidizing the phosphorylated product. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Reagent and test cartridge for determining clotting time Inventor(s): Bruegger, Berndt B.; (Camarillo, CA) Correspondence: Brinks Hofer Gilson & Lione; Nbc Tower; Suite 3600; P.O. Box 10395; Chicago; IL; 60610; US Patent Application Number: 20040077097 Date filed: September 18, 2003 Abstract: The invention is a method, reagent and test cartridge for the determination of the clotting time of a blood sample by means of a reagent containing tissue factor and a sulfatide. In an alternative embodiment, the reagent may contain tissue factor and at least one of the group consisting of a phosphatide and a sulfatide. This invention is preferably used to monitor the effectiveness of heparin therapy in patients that have been administered low to moderate heparin doses to achieve blood heparin levels from 0 to about 3 U/mL, and may also be used for determining clotting time at higher heparin levels of up to about 6 U/mL.
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Excerpt(s): This application is a continuation of U.S. patent application Ser. No. 09/645,786, filed Aug. 24, 2000, which is a non-provisional of provisional application serial No. 60/152,450, filed Sep. 3, 1999, both of which are incorporated by reference as if reproduced in full below. The present invention relates to the field of determining the clotting time of blood samples and more specifically relates to the determination of the clotting time of blood samples from patients receiving heparin treatment, particularly patients that have been administered low to moderate heparin doses, as well as that of patients that have been administered high heparin doses. The activated clotting time (ACT) assay is a blood test that monitors the effectiveness of heparin dosing. The levels of heparin that the ACT assay is monitoring are generally beyond the range of the activated partial thromboplastin time (APTT) assay. Some APTT assays can monitor plasma heparin levels as high as 1.5 U/mL (which is equivalent to a blood heparin level of about 0.75 U/mL), while the ACT assay can monitor blood heparin levels generally as high as 6 U/mL. The higher end of the blood heparin range (high range; HR) is often used in cardiac pulmonary bypass surgery, while blood levels under 3 U/mL (moderate to low range; LR) but above the effective range of the APTT assay, are used in situations such as cardiac catheterization, extracorporeal membrane oxygenation (ECMO), hemodialysis, and percutaneous transluminal coronary angioplasty (PTCA). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Rhamnan sulphate composition for treatment of endothelial dysfunction Inventor(s): Daniels, Bruce Alan; (Oklahoma City, OK) Correspondence: Ali Kamarei; 280 Colorado Avenue; Palo Alto; CA; 94301; US Patent Application Number: 20040116377 Date filed: December 16, 2002 Abstract: The invention described is a method and composition for inducing cell surface anti-thrombotic activity in endothelial cells comprising administering to a patient a therapeutically-effective amount of Rhamnan Sulphate. The dose of Rhamnan Sulphate is equivalent to between approximately 8,000 IU and 12,000 IU of heparin activity daily on variable schedule or optionally at single dosage of 7.5 mg/kg, that is repeated on a daily basis as needed, to lower the incidence of thrombus formation or to lower the incidence of hard clot formation. Excerpt(s): This invention relates to a pharmacological composition and method that provides for surface anti-thrombotic activity of endothelial cells and without exerting any appreciable amount of blood anticoagulation. This composition is preferably used for patients susceptible to or suffering from a cardiovascular disorder or disease, and more particularly, but not by way of limitation, to a formulation with enhanced absorption characteristics for preventing and treating atherosclerosis, arteriosclerosis, congestive heart failure, arterial stenosis, cardiac cell hypertrophy, thrombogenicity, myocardial infarction, cerebrovascular ischemia, peripheral vascular ischemia, angina pectoris, hypertension or endothelial dysfunction, without increasing the patient's risk of hemorrhaging, either internal or as a result of an external injury. Cardiovascular disorders and diseases resulting from cell surface thrombosis, and their associated complications are a principal cause of disabilities and deaths of individuals in the world. For example, in recent years more than 500,000 deaths have occurred annually in the United States alone as a result of coronary artery disease, and an additional 1,200,000 patients have been hospitalized for myocardial ischemia and infarction. There has been significant and extensive research for effective long term treatment for disorders and
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diseases of the heart and arteries, such as atherosclerosis, arteriosclerosis, congestive heart failure, angina pectoris, and other diseases associated with the cardiovascular system. However, present treatments for such disorders are short term treatments such as administration of vasodilators, angioplasty, and by-pass surgery. These treatments have serious shortcomings in long term effectiveness, thus they have met with general disapproval due to the risks associated with them. The use of vasodilator drugs and mechanical treatments for acute and chronic occlusive vascular diseases of the heart central and peripheral vascular systems have to date been ineffective for favorable longterm results and do not treat the underlying molecular processes causal for the diseases. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Sulfate transferase and dna encoding this enzyme Inventor(s): Habuchi, Hiroko; (Nagoya-shi, JP), Kimata, Koji; (Nagoya-shi, JP) Correspondence: Knobbe Martens Olson & Bear Llp; 2040 Main Street; Fourteenth Floor; Irvine; CA; 92614; US Patent Application Number: 20040053253 Date filed: December 30, 2002 Abstract: A glycosaminoglycan 6-O-sulfotransferase having an activity of transferring sulfate to a hydroxyl at position 6 of a glycosamine residue of a glycosaminoglycan, which has a ratio of relative activities to substrates satisfying completely desulfated Nacetylated (CDSNAc) heparin/completely desulfated N-resulfated (CDSNS) heparin.gtoreq.0.05 and a molecular weight as calculated from constituent amino acids of from 53,000 to 58,000 daltons. Excerpt(s): The present invention relates to a sulfotransferase and to DNA encoding it. More particularly, the present invention relates to a polypeptide of 6-O-sulfotransferase which selectively sulfates the hydroxyl at position 6 of a glucosamine residue contained in a glycosaminoglycan which is a sulfate acceptor, and to DNA encoding the polypeptide. Heparin and heparan sulfate are glycosaminoglycans having a repeating unit (4GlcA.beta.1/IdoA.alpha.1.fwdarw.4GlcNAc.alpha.1.fwdarw.) composed of two sugars, i.e., a hexuronic acid (HexA) residue (D-glucuronic acid (GlcA) or L-iduronic acid (IdoA) residue) and an N-acetylglucosamine (GlcNAc) residue as a basic skeleton (heparin skeleton), basically with a portion of hydroxyl at position 2 of the hexuronic acid residues and a portion of amino groups at position 2 or hydroxyl at position 6 of the N-acetylglucosamine residue being replaced with sulfates. Cloning of the gene of an enzyme which transfers sulfate to glycosaminoglycans (glycosaminoglycan sulfotransferase) has made it possible to readily obtain the enzyme in amounts sufficient enough to obtain information on the biosynthesis of glycosaminoglycans having sulfates (sulfated glycosaminoglycans). This will presumably provide a useful approach to investigation on the relationship between the structure and function of sulfated glycosaminoglycans. It has been known that the biosynthesis of sulfated glycosaminoglycans, in particular, biosynthesis of heparin and heparan sulfate, is achieved by a variety of sulfation processes (Kobata, H., Hakomori, S., Nagai, K., Glycotechnology (5), 57 (1994), published by Kodansha Scientific). This sulfation may involve various glycosaminoglycan sulfotransferases. As the glycosaminoglycan sulfotransferases which transfer sulfate to heparin or heparan sulfate, heparan sulfate N-sulfotransferase (hereinafter in some cases abbreviated as "HSNST") which catalyzes de-N-acetylation of N-acetylglucosamine residue and sulfate transfer; heparan sulfate 2O-sulfotransferase (hereinafter in some cases abbreviated as "HS2ST") which transfers
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sulfate to hydroxyl at position 2 of hexuronic acid residue; and heparan sulfate 6-Osulfotransferase (hereinafter in some cases abbreviated as "HS6ST") which transfers sulfate to hydroxyl at position 6 of N-sulfated glycosamine residue, have been isolated and for some of the sulfotransferases, cDNA cloning has already been performed. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Synthetic peptides having FGF receptor affinity Inventor(s): Ballinger, Marcus; (Burlingame, CA), Kavanaugh, Michael; (Danville, CA) Correspondence: Chiron Corporation; Intellectual Property - R440; P.O. Box 8097; Emeryville; CA; 94662-8097; US Patent Application Number: 20040054131 Date filed: November 21, 2002 Abstract: Peptidic compositions having FGF receptor affinity, as well as fusion proteins and oligomers of the same, are provided. The subject peptidic compounds are characterized by having little or no homology to naturally occurring bFGF. The subject fusion proteins include the peptidic composition linked to an oligomerization domain, either directly or through a linking group and optionally further include a heparin binding domain. The subject peptidic compositions, fusion proteins and oligomers thereof find use in a variety of applications, including both research and therapeutic applications, in which FGF receptor ligands are employed. Excerpt(s): This application claims benefit of priority to provisional patent applications Serial Nos. 60/102,667, filed Sep. 30, 1998, and 60/134,120, filed May 14, 1999, the contents of which are incorporated herein by reference in their entirety. The field of this invention is growth factors, particularly fibroblast growth factors. Basic fibroblast growth factors (bFGF)(also known as FGF2), so named because they contain a high number of basic amino acid residues (lysine, arginine and histidine) and therefore are cations at neutral pH, are potent mitogens for vascular endothelial cells in vitro and stimulate new capillary growth in vivo, i.e. they are angiogenic. Both human and bovine forms of basic FGF have been isolated, and the genes expressing these products have been cloned and sequenced. In addition, bFGF has been found to be expressed in a wide variety of tissue types, including pituitary, brain, adrenal gland, corpus luteum, retina, kidney, placenta, etc. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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TGF-beta gene overexpression preventing substances for the treatment of disorders connected with pathological overexpression of TGF-beta Inventor(s): Gambaro, Giovanni; (Venezia, IT), Schleicher, Erwin; (Muenchen, DE) Correspondence: Foley And Lardner; Suite 500; 3000 K Street NW; Washington; DC; 20007; US Patent Application Number: 20040009952 Date filed: December 27, 2002 Abstract: The present invention is directed to use of an agent which is able to prevent pathological overexpression of TGF-.beta. gene in vivo for the preparation of a medicament for the treatment of disorders connected with AP-1 mediated TGF-.beta.
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gene expression, except use of sulodexide, low molecular weight heparin derivatives obtained by chemical or enzymatic depolymerization, chemically modified heparin derivatives and low molecular weight dermatan sulfates obtained by chemical or enzymatic depolymerization for the treatment of diabetic nephropathy. Further, the invention provides convenient, fast in vitro methods to assess the value of agents useful for the said disorders. Excerpt(s): This invention relates to the inhibition of disease- or repair-induced overexpression of growth factors, particularly transforming growth factor.beta. (TGF.beta.). A variety of cytokines and growth factors have been suggested to play a role in the development of organ fibrosis however, the multifunctional cytokine TGF-.beta. appears to be a key prosclerotic factor. Three TGF-.beta. isoforms, termed TGF-.beta.1, TGF-.beta.2 and TGF-.beta.3, have been identified in mammals. These isoforms exhibit both overlapping and distinct activities, but TGF-.beta.1 seems to play the main role, due to both its activity and its presence. The TGF-.beta. family is a multifuncional cytokine family since it is involved e.g. in the differentiation in embryonic development, in the regulation of cell proliferation and it controls the production of extracellular matrix proteins by stimulating the de novo synthesis of the matrix components (collagen and proteoglycans) and by inhibiting matrix degradation. Furthermore, TGF-.beta. exerts immunosupressive and chemotactic activities and, by auto-/paracrine action, it may induce other cells to synthesize and secrete cytokines and growth factors including TGF-.beta. Studies using i) proteins that bind TGF-.beta. and neutralize its activity like TGF-.beta. antibodies or decorin (which specifically binds TGF-.beta.) or ii) isoform specific TGF-.beta. antisense oligonucleotides which inhibit the synthesis of the respective TGF-.beta. isoform or iii) target-directed overexpression of TGF-.beta.1 leading to excessive fibrosis/sclerosis of the organ indicate the importance specifically of TGF-.beta.1 in the fibrotic/sclerotic processes. In addition, in most human diseases associated with fibrosis/sclerosis, TGF-.beta.1 overexpression-has been found. Overexpression of TGF-.beta. in early stages of Duchenne muscular dystrophy has also been found to be critical for the development of muscle fibrosis in these patients. These data indicate the causal involvement of TGF-.beta.1 in the initiation and/or progression of fibrotic processes. TGF-.beta.1 is synthesized as a TGF-.beta.1 precursor protein consisting of 391 amino acids. After proteolytic cleavage of the C-terminus of the TGF.beta.1 (112 amino acids) the 25-kDa homodimer forms the bioactive protein. However, if the N-terminal remnant of the precursor, denoted as the TGF-.beta.1 latency associated peptide (LAP), is associated to mature TGF-.beta.1, it blocks bioactivity. In most organs the latent form of TGF-.beta.1 is composed of three distinct components; mature TGF-.beta. 1, LAP and latent TGF-.beta. 1 binding protein (LTBP). Although several mechanisms for the in vivo activation of TGF-.beta. have been proposed this issue remains to be clarified. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Unit dosage forms for the treatment of herpes simplex Inventor(s): Pearson, Don C.; (Lakewood, WA), Richardson, Kenneth T.; (Anchorage, AK) Correspondence: Townsend And Townsend And Crew, Llp; Two Embarcadero Center; Eighth Floor; San Francisco; CA; 94111-3834; US Patent Application Number: 20040018996 Date filed: July 25, 2003
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Abstract: The components of this invention are chosen because of their complementarity for the prevention or treatment of diseases caused by the herpes simplex virus. L-Lysine favorably increases the physiologic immunomodulation necessary for defense against this virus. Zinc improves and maintains a normal immune response. 2-Deoxy-2-Dglucose and heparin sodium alter the surface interaction between the herpes virus and the cell, preventing fusion and infectivity. N-Acetyl-L-cysteine increases glutathione levels thereby creating a thiol redox barrier to the virus at the cell membrane. Quercetin reduces intraoellular replication of the herpes virus and viral infectivity. Ascorbate, in concert with copper and D-.alpha.-tocopherol, provides an antioxidant defense against the herpes virus, which tends to lose latency during period of oxidative, free radical excess. Selenium and quercetin also participate in reducing various oxidative stresses. Together the components of this invention provide the potential for improved resistance to, improved recovery from, and a decreased frequency of recurrence of herpes simplex virus infection. Excerpt(s): This application is related to U.S. Provisional Patent Application No. 60/101,308, filed Sep. 21, 1998, and claims all benefits legally available therefrom. Provisional Patent Application No. 60/101,308 is hereby incorporated by reference for all purposes capable of being served thereby. This invention is in the field of pharmacology, and relates specifically to the pharmacological treatment of conditions associated with herpes simplex virus infections. No human virus is considered normal flora; although some viruses may be more or less symptomatic, unlike bacteria none can be considered non-pathogenic. And because the viral life cycle is played out within a host cell, the membrane and molecular function of the target eukaryocyte and the biological life cycle of the invasive virion are inextricably entwined. 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 heparin, 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 “heparin” (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 heparin. You can also use this procedure to view pending patent applications concerning heparin. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.
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CHAPTER 6. BOOKS ON HEPARIN Overview This chapter provides bibliographic book references relating to heparin. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on heparin include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.
Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “heparin” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on heparin: •
Review of Hemodialysis for Nurses and Dialysis Personnel. 6th ed Source: St. Louis, MO: Mosby. 1999. 371 p. Contact: Available from Harcourt Publishers. Foots Cray High Street, Sidcup, Kent DA14 5HP UK. 02083085700. Fax 02083085702. E-mail:
[email protected]. Website: www.harcourt-international.com. PRICE: $37.95 plus shipping and handling. ISBN: 0815120990. Summary: This text poses questions and then answers those questions with the aim of giving a good understanding of the basic principles, basic diseases, and basic problems in the treatment of kidney patients by dialysis. Twenty-three chapters cover the hemodialysis team, the basic chemistry of body fluids and electrolytes, renal physiology and the pathology of renal failure, principles of hemodialysis, dialyzers and dialysate, water treatment, dialyzer preparation and reprocessing, access to the bloodstream, patient and machine monitoring and assessment, anticoagulation and heparin
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administration, medication problems and dialysis, nutrition management, acute renal failure and dialysis, complications of chronic dialysis therapy, transplantation, peritoneal dialysis and home dialysis therapies, diabetes and hemodialysis, infection control and universal precautions, the psychosocial aspects of dialysis therapy, pediatric hemodialysis, end stage renal disease (ESRD) in the elderly, management of quality in dialysis care, and renal care and information technology. The text concludes with references and recommended readings, a listing of nephrology organizations and resources, a glossary of terms, a subject index, and three appendices: conversion factors used in hemodialysis, conversion table for pounds to kilograms of body weight, and the sodium and potassium content of selected foods. The text offers charts and drawings where appropriate. The authors focus on giving members of the dialysis team (including nurses, technicians, dietitians, pharmacologists, social workers, and patients) a strong foundation of basic information and an understanding on the necessary interdisciplinary approach to quality care in the dialysis field. 117 references.
Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “heparin” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “heparin” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “heparin” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
Cell-surface-associated Heparin Sulfate Proteoglycans by G. Mertens; ISBN: 9061866375; http://www.amazon.com/exec/obidos/ASIN/9061866375/icongroupinterna
•
Chemistry and biology of heparin; ISBN: 0444004459; http://www.amazon.com/exec/obidos/ASIN/0444004459/icongroupinterna
•
Low Molecular Weight Heparin by Trevor W. Barrowcliffe, et al; ISBN: 0471933244; http://www.amazon.com/exec/obidos/ASIN/0471933244/icongroupinterna
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Low Molecular Weight Heparin and Its Clinical Use by Meyer M. Samama (Other Contributor); ISBN: 3805542305; http://www.amazon.com/exec/obidos/ASIN/3805542305/icongroupinterna
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Low Molecular Weight Heparin Therapy by Monique Sarret, et al; ISBN: 0824782135; http://www.amazon.com/exec/obidos/ASIN/0824782135/icongroupinterna
•
Synthesis of oligosaccharides related to heparin and heparan sulphate and their binding to fibroblast growth factors (Chemical communications / Stockholm University) by Jacob Westman; ISBN: 9171533168; http://www.amazon.com/exec/obidos/ASIN/9171533168/icongroupinterna
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Chapters on Heparin In order to find chapters that specifically relate to heparin, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and heparin using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “heparin” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on heparin: •
Anticoagulation and Heparin Administration Source: in Gutch, C.F.; Stoner, M.H.; Corea, A.L. Review of Hemodialysis for Nurses and Dialysis Personnel. 6th ed. St. Louis, MO: Mosby. 1999. p. 134-141. Contact: Available from Harcourt Publishers. Foots Cray High Street, Sidcup, Kent DA14 5HP UK. 02083085700. Fax 02083085702. E-mail:
[email protected]. Website: www.harcourt-international.com. PRICE: $37.95 plus shipping and handling. ISBN: 0815120990. Summary: Blood, when it encounters any surface that is not the lining of a normal blood vessel, tends to clot. This mechanism is vital to preserving the life of the individual. Dialysis, the process of cleansing the blood of accumulated waste products, is a complex treatment during which considerations of clotting must be addressed. Blood will clot soon after entering the extracorporeal circuit of the hemodialysis system, rendering treatment impossible, unless the ability to clot is interrupted. This chapter on anticoagulation and heparin administration is from a nursing text that poses questions and then answers those questions with the aim of giving a good understanding of the basic principles, basic diseases, and basic problems in the treatment of kidney patients by dialysis. The authors of the chapter discuss several methods used to prevent coagulation of the extracorporeal (outside the body) circuit, each of which has advantages and drawbacks for the patient or the practitioner. The authors stress that dialysis care providers must be familiar with more than one method, in order to safely and effectively meet the needs of each individual hemodialysis patient. Heparin (an anticoagulant made from pork mucosa) effect is estimated by the increase in the length of time necessary for a clot to form. Heparin is given during dialysis by either intermittent infusion or continuous infusion. There is always a danger of bleeding when heparin is used; one must be particularly concerned about any patient who has had surgery within the preceding 24 to 48 hours or is scheduled for surgery immediately post dialysis, who has recently been injured, has pericarditis, or may have a hemorrhagic lesion of the gastrointestinal tract or uterus. Low dose or tight heparin treatment consists of monitoring the patient with frequent clotting times and administering only enough heparin to reduce clotting so it does not interfere with dialysis. The authors conclude by discussing other contributing factors that can prevent hemorrhage during hemodialysis. 2 figures. 1 table.
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CHAPTER 7. PERIODICALS AND NEWS ON HEPARIN Overview In this chapter, we suggest a number of news sources and present various periodicals that cover heparin.
News Services and Press Releases One of the simplest ways of tracking press releases on heparin 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 “heparin” (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 heparin. 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 “heparin” (or synonyms). The following was recently listed in this archive for heparin: •
Bivalirudin comparable to heparin in long-term outcomes after PCI Source: Reuters Industry Breifing Date: August 11, 2004
•
Enoxaparin an effective alternative to heparin for some acute coronary syndromes Source: Reuters Industry Breifing Date: July 06, 2004
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Unfractionated heparin comparable to nadroparin for thromboembolism Source: Reuters Medical News Date: June 03, 2004
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Angiomax efficacy matches heparin in 6-month review Source: Reuters Industry Breifing Date: September 15, 2003
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Tenecteplase with heparin recommended for prehospital treatment of acute MI Source: Reuters Medical News Date: July 07, 2003
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Subcutaneous heparin raises risk for thromboembolic complications Source: Reuters Industry Breifing Date: May 30, 2003
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MicroMed gets European approval of heparin coating for heart assist device Source: Reuters Industry Breifing Date: December 18, 2002
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Oral formulation of heparin achieves therapeutic anticoagulation levels Source: Reuters Medical News Date: December 10, 2002
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Emisphere reports promising data on heparin tablets, capsules Source: Reuters Industry Breifing Date: December 10, 2002
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Alteplase added to heparin improves outcome in pulmonary embolism Source: Reuters Industry Breifing Date: October 09, 2002
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Low MW heparin lowers risk of haemorrhagic transformation in ischaemic stroke Source: Reuters Medical News Date: August 20, 2002
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Unfractionated heparin appears safe in patients with severe head injuries Source: Reuters Industry Breifing Date: August 05, 2002
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Emisphere shares tumble on poor heparin study results Source: Reuters Industry Breifing Date: May 14, 2002
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Wyeth recalls heparin injection Source: Reuters Industry Breifing Date: May 01, 2002
•
Enoxaparin comparable to unfractionated heparin in improving blood flow after MI Source: Reuters Industry Breifing Date: March 04, 2002 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
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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 “heparin” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “heparin” (or synonyms). If you know the name of a company that is relevant to heparin, 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 “heparin” (or synonyms).
Academic Periodicals covering Heparin Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to heparin. In addition to these sources, you can search for articles covering heparin 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.”
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If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”
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CHAPTER 8. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.
U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for heparin. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a nonprofit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI Advice for the Patient can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with heparin. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The
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following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to heparin: Abciximab •
Systemic - U.S. Brands: ReoPro http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500417.html
Headache Medicines, Ergot Derivative-Containing •
Systemic - U.S. Brands: Cafergot; Cafertine; Cafetrate; D.H.E. 45; Ercaf; ErgoCaff; Ergomar; Ergostat; Gotamine; Migergot; Wigraine http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202216.html
Heparin •
Systemic - U.S. Brands: Calciparine; Liquaemin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202280.html
Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.
Mosby’s Drug Consult Mosby’s Drug Consult database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee.
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Researching Orphan Drugs Although the list of orphan drugs is revised on a daily basis, you can quickly research orphan drugs that might be applicable to heparin by using the database managed by the National Organization for Rare Disorders, Inc. (NORD), at http://www.rarediseases.org/. Scroll down the page, and on the left toolbar, click on “Orphan Drug Designation Database.” On this page (http://www.rarediseases.org/search/noddsearch.html), type “heparin” (or synonyms) into the search box, and click “Submit Query.” When you receive your results, note that not all of the drugs may be relevant, as some may have been withdrawn from orphan status. Write down or print out the name of each drug and the relevant contact information. From there, visit the Pharmacopeia Web site and type the name of each orphan drug into the search box at http://www.nlm.nih.gov/medlineplus/druginformation.html. You may need to contact the sponsor or NORD for further information. NORD conducts “early access programs for investigational new drugs (IND) under the Food and Drug Administration’s (FDA’s) approval ‘Treatment INDs’ programs which allow for a limited number of individuals to receive investigational drugs before FDA marketing approval.” If the orphan product about which you are seeking information is approved for marketing, information on side effects can be found on the product’s label. If the product is not approved, you may need to contact the sponsor. The following is a list of orphan drugs currently listed in the NORD Orphan Drug Designation Database for heparin: •
Recombinant human atithrombin III http://www.rarediseases.org/nord/search/nodd_full?code=1039
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Epoprostenol (trade name: Flolan) http://www.rarediseases.org/nord/search/nodd_full?code=405
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Ancrod (trade name: Arvin) http://www.rarediseases.org/nord/search/nodd_full?code=559
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Lepirudin (trade name: Refludan) http://www.rarediseases.org/nord/search/nodd_full?code=818
•
Ancrod http://www.rarediseases.org/nord/search/nodd_full?code=856
If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.
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APPENDICES
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APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.
NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute10: •
Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm
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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/
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National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
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National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25
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National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm
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National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
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National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
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National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/
10
These publications are typically written by one or more of the various NIH Institutes.
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National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm
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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
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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
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Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html
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Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm
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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.11 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:12 •
Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html
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HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
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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/
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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
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MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html
11
Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 12 See http://www.nlm.nih.gov/databases/databases.html.
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Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html
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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 Gateway13 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.14 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “heparin” (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 63987 334 394 131 210 65056
HSTAT15 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.16 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.17 Simply search by “heparin” (or synonyms) at the following Web site: http://text.nlm.nih.gov.
13
Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.
14
The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 15 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 16 17
The HSTAT URL is http://hstat.nlm.nih.gov/.
Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.
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Coffee Break: Tutorials for Biologists18 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.19 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.20 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.
Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •
CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.
•
Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
18 Adapted 19
from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.
The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 20 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.
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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on heparin 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 heparin. 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 heparin. 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 “heparin”:
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Hepatitis C http://www.nlm.nih.gov/medlineplus/hepatitisc.html Infant and Toddler Health http://www.nlm.nih.gov/medlineplus/infantandtoddlerhealth.html Occupational Health for Healthcare Providers http://www.nlm.nih.gov/medlineplus/occupationalhealthforhealthcareproviders. html Bleeding Disorders http://www.nlm.nih.gov/medlineplus/bleedingdisorders.html Cancer http://www.nlm.nih.gov/medlineplus/cancer.html Childhood Immunization http://www.nlm.nih.gov/medlineplus/childhoodimmunization.html Laboratory Tests http://www.nlm.nih.gov/medlineplus/laboratorytests.html Pulmonary Embolism http://www.nlm.nih.gov/medlineplus/pulmonaryembolism.html Thrombophlebitis http://www.nlm.nih.gov/medlineplus/thrombophlebitis.html You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on heparin. 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: •
Interstitial Cystitis and Heparin Source: Rockville, MD: Interstitial Cystitis Association. 2001. 1 p. Contact: Available from Interstitial Cystitis Association (ICA). 110 North Washington Street, Suite 340, Rockville, MD 20850. (301) 610-5300. Fax (301) 610-5308. E-mail:
[email protected]. Website: www.ichelp.org. PRICE: $1.00 for members; $1.25 for nonmembers; plus shipping and handling. Item number: RFP01. Summary: This fact sheet reviews the use of heparin for treating patients who have interstitial cystitis (IC). IC is characterized by a number of symptoms (urinary urgency,
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frequency, suprapubic pain, diminished bladder capacity) which can affect IC patients in varying combinations or in varying degrees of intensity. Heparin is a compound that has both antiinflammatory and surface protective actions. Heparin can mimic the activity of the bladder's mucous lining. It can be used as a primary treatment method or as a maintenance medication to supplement other types of treatment. The fact sheet outlines treatment using heparin and briefly considers clinical studies that support its use and compare it to the use of DMSO instillation. The side effects of instilled heparin are limited primarily to pain, irritation, or discomfort resulting from frequent catheterization. The fact sheet includes contact information for the Interstitial Cystitis Association (ICA). 3 references. (AA-M). 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 heparin. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats
•
Family Village: http://www.familyvillage.wisc.edu/specific.htm
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Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
•
Med Help International: http://www.medhelp.org/HealthTopics/A.html
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Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
•
Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/
•
WebMDHealth: 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 heparin. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with heparin.
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The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about heparin. 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 “heparin” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “heparin”. 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 “heparin” (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 “heparin” (or a synonym) into the search box, and click “Submit Query.”
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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.
Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.21
Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.
Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of
21
Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.
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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)22: •
Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/
•
Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)
•
Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm
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California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html
•
California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html
•
California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html
•
California: Gateway Health Library (Sutter Gould Medical Foundation)
•
California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/
•
California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp
•
California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html
•
California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/
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California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/
•
California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/
•
California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html
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California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/
•
Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/
•
Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/
•
Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/
22
Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.
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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/
•
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/
•
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
•
Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp
•
Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/
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Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html
•
Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm
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Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp
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Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/
•
Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html
•
Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/
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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/
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New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm
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New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm
•
New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/
•
New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html
•
New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/
•
New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html
•
New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/
•
Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm
•
Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp
•
Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/
•
Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/
•
Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml
•
Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html
•
Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html
•
Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml
•
Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp
•
Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm
•
Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/
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South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp
•
Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/
•
Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/
•
Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72
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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •
ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html
•
MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp
•
Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/
•
Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html
•
On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/
•
Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp
•
Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm
Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a).
Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •
Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical
•
MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html
•
Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/
•
Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine
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HEPARIN DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Ablate: In surgery, is to remove. [NIH] Ablation: The removal of an organ by surgery. [NIH] Abortion: 1. The premature expulsion from the uterus of the products of conception - of the embryo, or of a nonviable fetus. The four classic symptoms, usually present in each type of abortion, are uterine contractions, uterine haemorrhage, softening and dilatation of the cervix, and presentation or expulsion of all or part of the products of conception. 2. Premature stoppage of a natural or a pathological process. [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] Acetylglucosamine: The N-acetyl derivative of glucosamine. [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] Acuity: Clarity or clearness, especially of the vision. [EU] Acute renal: A condition in which the kidneys suddenly stop working. In most cases, kidneys can recover from almost complete loss of function. [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] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH]
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Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenosine Triphosphate: Adenosine 5'-(tetrahydrogen triphosphate). An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adhesions: Pathological processes consisting of the union of the opposing surfaces of a wound. [NIH] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH] 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] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adsorption: The condensation of gases, liquids, or dissolved substances on the surfaces of solids. It includes adsorptive phenomena of bacteria and viruses as well as of tissues treated with exogenous drugs and chemicals. [NIH] Adsorptive: It captures volatile compounds by binding them to agents such as activated carbon or adsorptive resins. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Affinity Chromatography: In affinity chromatography, a ligand attached to a column binds specifically to the molecule to be purified. [NIH] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the
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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] 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] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Aldehydes: Organic compounds containing a carbonyl group in the form -CHO. [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] Alkalinization: The process by which a substance becomes an alkali. An alkali is the opposite of an acid. [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] Allergens: Antigen-type substances (hypersensitivity, immediate). [NIH]
that
produce
immediate
hypersensitivity
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] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha 1-Antichymotrypsin: Glycoprotein found in alpha(1)-globulin region in human serum. It inhibits chymotrypsin-like proteinases in vivo and has cytotoxic killer-cell activity in vitro. The protein also has a role as an acute-phase protein and is active in the control of immunologic and inflammatory processes, and as a tumor marker. It is a member of the serpin superfamily. [NIH] Alpha 1-Antitrypsin: Plasma glycoprotein member of the serpin superfamily which inhibits trypsin, neutrophil elastase, and other proteolytic enzymes. Commonly referred to as alpha 1-proteinase inhibitor (A1PI), it exists in over 30 different biochemical variant forms known collectively as the PI (protease inhibitor) system. Hereditary A1PI deficiency is associated with pulmonary emphysema. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons,
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i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alpha-helices: One of the secondary element of protein. [NIH] Alpha-helix: One of the secondary element of protein. [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] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] Amino acid: Any organic compound containing an amino (-NH2 and a carboxyl (- COOH) group. The 20 a-amino acids listed in the accompanying table are the amino acids from which proteins are synthesized by formation of peptide bonds during ribosomal translation of messenger RNA; all except glycine, which is not optically active, have the L configuration. Other amino acids occurring in proteins, such as hydroxyproline in collagen, are formed by posttranslational enzymatic modification of amino acids residues in polypeptide chains. There are also several important amino acids, such as the neurotransmitter y-aminobutyric acid, that have no relation to proteins. Abbreviated AA. [EU] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acid Substitution: The naturally occurring or experimentally induced replacement of one or more amino acids in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties. [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] Amphetamine: A powerful central nervous system stimulant and sympathomimetic. Amphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulation of release of monamines, and inhibiting monoamine oxidase. Amphetamine is also a drug of abuse and a psychotomimetic. The l- and the d,l-forms are included here. The l-form has less central nervous system activity but stronger cardiovascular effects. The d-form is dextroamphetamine. [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] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile
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sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Analytes: A component of a test sample the presence of which has to be demonstrated. The term "analyte" includes where appropriate formed from the analyte during the analyses. [NIH]
Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anastomosis: A procedure to connect healthy sections of tubular structures in the body after the diseased portion has been surgically removed. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anemic: Hypoxia due to reduction of the oxygen-carrying capacity of the blood as a result of a decrease in the total hemoglobin or an alteration of the hemoglobin constituents. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angina: Chest pain that originates in the heart. [NIH] 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] Angioedema: A vascular reaction involving the deep dermis or subcutaneous or submucal tissues, representing localized edema caused by dilatation and increased permeability of the capillaries, and characterized by development of giant wheals. [EU] 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] Angiogenesis inhibitor: A substance that may prevent the formation of blood vessels. In anticancer therapy, an angiogenesis inhibitor prevents the growth of blood vessels from surrounding tissue to a solid tumor. [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
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new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anionic: Pertaining to or containing an anion. [EU] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]
Anode: Electrode held at a positive potential with respect to a cathode. [NIH] Anomalies: Birth defects; abnormalities. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Antiangiogenic: Having to do with reducing the growth of new blood vessels. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]
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] Antibodies, Anticardiolipin: Antiphospholipid antibodies found in association with systemic lupus erythematosus (lupus erythematosus, systemic), antiphospholipid syndrome, and in a variety of other diseases as well as in healthy individuals. The antibodies are detected by solid-phase immunoassay employing the purified phospholipid antigen cardiolipin. [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] Antidote: A remedy for counteracting a poison. [EU] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH] Anti-infective: An agent that so acts. [EU]
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Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] 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] Antiphospholipid Syndrome: The presence of antibodies directed against phospholipids (antibodies, antiphospholipid). The condition is associated with a variety of diseases, notably systemic lupus erythematosus and other connective tissue diseases, thrombopenia, and arterial or venous thromboses. In pregnancy it can cause abortion. Of the phospholipids, the cardiolipins show markedly elevated levels of anticardiolipin antibodies (antibodies, anticardiolipin). Present also are high levels of lupus anticoagulant (lupus coagulation inhibitor). [NIH] Antiplasmin: A member of the serpin superfamily found in human plasma that inhibits the lysis of fibrin clots which are induced by plasminogen activator. It is a glycoprotein, molecular weight approximately 70,000 that migrates in the alpha 2 region in immunoelectrophoresis. It is the principal plasmin inactivator in blood, rapidly forming a very stable complex with plasmin. [NIH] Antiproliferative: Counteracting a process of proliferation. [EU] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [EU] Antithrombins: An endogenous family of proteins belonging to the serpin superfamily that neutralizes the action of thrombin. Six naturally occuring antithrombins have been identified and are designated by Roman numerals I to VI. Of these, Antithrombin I and antithrombin III appear to be of major importance. [NIH] Antithrombotic: Preventing or interfering with the formation of thrombi; an agent that so acts. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Aorta: The main trunk of the systemic arteries. [NIH] Aortic Aneurysm: Aneurysm of the aorta. [NIH] Aortic Valve: The valve between the left ventricle and the ascending aorta which prevents backflow into the left ventricle. [NIH] Apheresis: Components plateletpheresis. [NIH]
being
separated
out,
as
leukapheresis,
plasmapheresis,
Aplasia: Lack of development of an organ or tissue, or of the cellular products from an organ or tissue. [EU] Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the
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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] Applicability: A list of the commodities to which the candidate method can be applied as presented or with minor modifications. [NIH] Aqueous: Having to do with water. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] 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 intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Arteriosus: Circle composed of anastomosing arteries derived from two long posterior ciliary and seven anterior ciliary arteries, located in the ciliary body about the root of the iris. [NIH]
Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Arthroplasty: Surgical reconstruction of a joint to relieve pain or restore motion. [NIH] Articular: Of or pertaining to a joint. [EU] 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
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channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Atherectomy: Endovascular procedure in which atheromatous plaque is excised by a cutting or rotating catheter. It differs from balloon and laser angioplasty procedures which enlarge vessels by dilation but frequently do not remove much plaque. If the plaque is removed by surgical excision under general anesthesia rather than by an endovascular procedure through a catheter, it is called endarterectomy. [NIH] Atherogenic: Causing the formation of plaque in the lining of the arteries. [NIH] Atmospheric Pressure: The pressure at any point in an atmosphere due solely to the weight of the atmospheric gases above the point concerned. [NIH] Atrial: Pertaining to an atrium. [EU] Atrial Fibrillation: Disorder of cardiac rhythm characterized by rapid, irregular atrial impulses and ineffective atrial contractions. [NIH] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Attenuated: Strain with weakened or reduced virulence. [NIH] Audiometry: The testing of the acuity of the sense of hearing to determine the thresholds of the lowest intensity levels at which an individual can hear a set of tones. The frequencies between 125 and 8000 Hz are used to test air conduction thresholds, and the frequencies between 250 and 4000 Hz are used to test bone conduction thresholds. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autologous bone marrow transplantation: A procedure in which bone marrow is removed from a person, stored, and then given back to the person after intensive treatment. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Axonal: Condition associated with metabolic derangement of the entire neuron and is manifest by degeneration of the distal portion of the nerve fiber. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Bacteraemia: The presence of bacteria in the blood. [EU] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Infections: Infections by bacteria, general or unspecified. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Balloon Dilatation: Nonoperative repair of occluded vessels, ducts, or valves by insertion of a balloon catheter. It is used, amoung other things, to treat varices, torn retinas, renal and biliary calculi, gastric, bronchial and rectal stenoses, and heart valves, and includes
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catheterization with Fogarty and Foley catheters. [NIH] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]
Benign tumor: A noncancerous growth that does not invade nearby tissue or spread to other parts of the body. [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] Beta-Thromboglobulin: A platelet-specific protein which is released when platelets aggregate. Elevated plasma levels have been reported after deep venous thrombosis, preeclampsia, myocardial infarction with mural thrombosis, and myeloproliferative disorders. Measurement of beta-thromboglobulin in biological fluids by radioimmunoassay is used for the diagnosis and assessment of progress of thromboembolic disorders. [NIH] 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] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding agent: A substance that makes a loose mixture stick together. For example, binding agents can be used to make solid pills from loose powders. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioassay: Determination of the relative effective strength of a substance (as a vitamin, hormone, or drug) by comparing its effect on a test organism with that of a standard preparation. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biogenic Amines: A group of naturally occurring amines derived by enzymatic decarboxylation of the natural amino acids. Many have powerful physiological effects (e.g., histamine, serotonin, epinephrine, tyramine). Those derived from aromatic amino acids, and also their synthetic analogs (e.g., amphetamine), are of use in pharmacology. [NIH] Biological Assay: A method of measuring the effects of a biologically active substance using
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an intermediate in vivo or in vitro tissue or cell model under controlled conditions. It includes virulence studies in animal fetuses in utero, mouse convulsion bioassay of insulin, quantitation of tumor-initiator systems in mouse skin, calculation of potentiating effects of a hormonal factor in an isolated strip of contracting stomach muscle, etc. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biological Transport: The movement of materials (including biochemical substances and drugs) across cell membranes and epithelial layers, usually by passive diffusion. [NIH] Bioluminescence: The emission of light by living organisms such as the firefly, certain mollusks, beetles, fish, bacteria, fungi and protozoa. [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] Biopolymers: Polymers, such as proteins, DNA, RNA, or polysaccharides formed by any living organism. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Bivalent: Pertaining to a group of 2 homologous or partly homologous chromosomes during the zygotene stage of prophase to the first metaphase in meiosis. [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] Bleeding Time: Duration of blood flow after skin puncture. This test is used as a measure of capillary and platelet function. [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,
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in the forearm. [NIH] Blood transfusion: The administration of blood or blood products into a blood vessel. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blood Viscosity: The internal resistance of the blood to shear forces. The in vitro measure of whole blood viscosity is of limited clinical utility because it bears little relationship to the actual viscosity within the circulation, but an increase in the viscosity of circulating blood can contribute to morbidity in patients suffering from disorders such as sickle cell anemia and polycythemia. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]
Blotting, Western: Identification of proteins or peptides that have been electrophoretically separated by blotting and transferred to strips of nitrocellulose paper. The blots are then detected by radiolabeled antibody probes. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Bone Conduction: Sound transmission through the bones of the skull to the inner ear. [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 metastases: Cancer that has spread from the original (primary) tumor to the bone. [NIH]
Bone Morphogenetic Proteins: Bone-growth regulatory factors that are members of the transforming growth factor-beta superfamily of proteins. They are synthesized as large precursor molecules which are cleaved by proteolytic enzymes. The active form can consist of a dimer of two identical proteins or a heterodimer of two related bone morphogenetic proteins. [NIH] Bone Resorption: Bone loss due to osteoclastic activity. [NIH] Bone scan: A technique to create images of bones on a computer screen or on film. A small amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [NIH] 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] 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] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Bronchiseptica: A small, gram-negative, motile bacillus. A normal inhabitant of the
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respiratory tract in man, dogs, and pigs, but is also associated with canine infectious tracheobronchitis and atrophic rhinitis in pigs. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Buccal mucosa: The inner lining of the cheeks and lips. [NIH] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Cachexia: General ill health, malnutrition, and weight loss, usually associated with chronic disease. [NIH] 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] Calcitonin: A peptide hormone that lowers calcium concentration in the blood. In humans, it is released by thyroid cells and acts to decrease the formation and absorptive activity of osteoclasts. Its role in regulating plasma calcium is much greater in children and in certain diseases than in normal adults. [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] Calcium Chloride: A salt used to replenish calcium levels, as an acid-producing diuretic, and as an antidote for magnesium poisoning. [NIH] Calculi: An abnormal concretion occurring mostly in the urinary and biliary tracts, usually composed of mineral salts. Also called stones. [NIH] Cannula: A tube for insertion into a duct or cavity; during insertion its lumen is usually occupied by a trocar. [EU] Canonical: A particular nucleotide sequence in which each position represents the base more often found when many actual sequences of a given class of genetic elements are compared. [NIH] 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 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] Capsid: The outer protein protective shell of a virus, which protects the viral nucleic acid. [NIH]
Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbogen: An inhalant of oxygen and carbon dioxide that increases the sensitivity of tumor
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cells to the effects of radiation therapy. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] 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] Cardiac arrest: A sudden stop of heart function. [NIH] Cardiac catheterization: A procedure in which a thin, hollow tube is inserted into a blood vessel. The tube is then advanced through the vessel into the heart, enabling a physician to study the heart and its pumping activity. [NIH] Cardiac Output: The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). [NIH] Cardiolipins: Acidic phospholipids composed of two molecules of phosphatidic acid covalently linked to a molecule of glycerol. They occur primarily in mitochondrial inner membranes and in bacterial plasma membranes. They are the main antigenic components of the Wassermann-type antigen that is used in nontreponemal syphilis serodiagnosis. [NIH] Cardiopulmonary: Having to do with the heart and lungs. [NIH] Cardiopulmonary Bypass: Diversion of the flow of blood from the entrance of the right atrium directly to the aorta (or femoral artery) via an oxygenator thus bypassing both the heart and lungs. [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 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] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for
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example, age, gender, ethnic origin). [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Catheter: A flexible tube used to deliver fluids into or withdraw fluids from the body. [NIH] Catheter Ablation: Removal of tissue with electrical current delivered via electrodes positioned at the distal end of a catheter. Energy sources are commonly direct current (DCshock) or alternating current at radiofrequencies (usually 750 kHz). The technique is used most often to ablate the AV junction and/or accessory pathways in order to interrupt AV conduction and produce AV block in the treatment of various tachyarrhythmias. [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] Cathode: An electrode, usually an incandescent filament of tungsten, which emits electrons in an X-ray tube. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [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 Communication: Any of several ways in which living cells of an organism communicate with one another, whether by direct contact between cells or by means of chemical signals carried by neurotransmitter substances, hormones, and cyclic AMP. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral
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proteins are embedded to varying degrees. [EU] Cell motility: The ability of a cell to move. [NIH] Cell Physiology: Characteristics and physiological processes of cells from cell division to cell death. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [NIH] Cellular adhesion: The close adherence (bonding) to adjoining cell surfaces. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] 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 Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] 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] 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] Chemokines: Class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. They can be divided into at least three structural branches: C (chemokines, C), CC (chemokines, CC), and CXC (chemokines, CXC), according to variations in a shared cysteine motif. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotaxis: The movement of cells or organisms toward or away from a substance in response to its concentration gradient. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chimera: An individual that contains cell populations derived from different zygotes. [NIH] Chimeric Proteins: Proteins in individuals that are derived from genetically different zygotes. [NIH] Chlorine: A greenish-yellow, diatomic gas that is a member of the halogen family of elements. It has the atomic symbol Cl, atomic number 17, and atomic weight 70.906. It is a powerful irritant that can cause fatal pulmonary edema. Chlorine is used in manufacturing,
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as a reagent in synthetic chemistry, for water purification, and in the production of chlorinated lime, which is used in fabric bleaching. [NIH] Cholera: An acute diarrheal disease endemic in India and Southeast Asia whose causative agent is vibrio cholerae. This condition can lead to severe dehydration in a matter of hours unless quickly treated. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] Chondrocytes: Polymorphic cells that form cartilage. [NIH] Chondroitin sulfate: The major glycosaminoglycan (a type of sugar molecule) in cartilage. [NIH]
Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Chymotrypsin: A serine endopeptidase secreted by the pancreas as its zymogen, chymotrypsinogen and carried in the pancreatic juice to the duodenum where it is activated by trypsin. It selectively cleaves aromatic amino acids on the carboxyl side. [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] Cirrhosis: A type of chronic, progressive liver disease. [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] C-kit receptor: A protein on the surface of some cells that binds to stem cell factor (a substance that causes certain types of cells to grow). Altered forms of this receptor may be associated with some types of cancer. [NIH] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [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]
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Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]
Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Clot Retraction: Retraction of a clot resulting from contraction of platelet pseudopods attached to fibrin strands that is dependent on the contractile protein thrombosthenin. Used as a measure of platelet function. [NIH] Coagulants: Exogenous substances used to promote blood coagulation. The endogenous blood coagulation factors are considered to be coagulants only when administered as drugs. [NIH]
Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Coenzymes: Substances that are necessary for the action or enhancement of action of an enzyme. Many vitamins are coenzymes. [NIH] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever (periodic disease). [NIH] Colectomy: An operation to remove the colon. An open colectomy is the removal of the colon through a surgical incision made in the wall of the abdomen. Laparoscopic-assisted colectomy uses a thin, lighted tube attached to a video camera. It allows the surgeon to remove the colon without a large incision. [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] Collagen disease: A term previously used to describe chronic diseases of the connective tissue (e.g., rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis), but now is thought to be more appropriate for diseases associated with defects in collagen, which is a component of the connective tissue. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The
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remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Colonic Neoplasms: Tumors or cancer of the colon. [NIH] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable compounds at once. [NIH] Communicable disease: A disease that can be transmitted by contact between persons. [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 1: The first complement component to act in the cytolysis reaction. It is a trimolecular complex held together with Ca ions and, when activated, has esterase activity which initiates the next step in the sequence. [NIH] Complement 1 Inactivators: Compounds which inhibit, antagonize, or inactivate complement 1. A well-known inhibitor is a serum glycoprotein believed to be alpha-2neuroaminoglycoprotein. It inhibits the activated (esterase) form of complement 1 as well as kinin-forming, coagulation, and fibrinolytic systems. Deficiency of this inactivator has been found in patients with hereditary angioneurotic edema. These compounds are members of the serpin superfamily. [NIH] 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
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as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Conduction: The transfer of sound waves, heat, nervous impulses, or electricity. [EU] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjugation: 1. The act of joining together or the state of being conjugated. 2. A sexual process seen in bacteria, ciliate protozoa, and certain fungi in which nuclear material is exchanged during the temporary fusion of two cells (conjugants). In bacterial genetics a form of sexual reproduction in which a donor bacterium (male) contributes some, or all, of its DNA (in the form of a replicated set) to a recipient (female) which then incorporates differing genetic information into its own chromosome by recombination and passes the recombined set on to its progeny by replication. In ciliate protozoa, two conjugants of separate mating types exchange micronuclear material and then separate, each now being a fertilized cell. In certain fungi, the process involves fusion of two gametes, resulting in union of their nuclei and formation of a zygote. 3. In chemistry, the joining together of two compounds to produce another compound, such as the combination of a toxic product with some substance in the body to form a detoxified product, which is then eliminated. [EU] 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] Connective Tissue Diseases: A heterogeneous group of disorders, some hereditary, others acquired, characterized by abnormal structure or function of one or more of the elements of connective tissue, i.e., collagen, elastin, or the mucopolysaccharides. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] 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] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Continuous infusion: The administration of a fluid into a blood vessel, usually over a
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prolonged period of time. [NIH] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] 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] Conus: A large, circular, white patch around the optic disk due to the exposing of the sclera as a result of degenerative change or congenital abnormality in the choroid and retina. [NIH] 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] Corneal Diseases: Diseases of the cornea. [NIH] Corneum: The superficial layer of the epidermis containing keratinized cells. [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 Arteriosclerosis: Thickening and loss of elasticity of the coronary arteries. [NIH] Coronary Circulation: The circulation of blood through the coronary vessels of the heart. [NIH]
Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] 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] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Coumarin: A fluorescent dye. [NIH] Cowpox: A mild, eruptive skin disease of milk cows caused by cowpox virus, with lesions occurring principally on the udder and teats. Human infection may occur while milking an infected animal. [NIH] Cowpox Virus: A species of orthopoxvirus that is the etiologic agent of cowpox. It is closely related to but antigenically different from vaccina virus. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU]
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Criterion: A standard by which something may be judged. [EU] Critical Care: Health care provided to a critically ill patient during a medical emergency or crisis. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [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] Cyclin: Molecule that regulates the cell cycle. [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]
Cystitis: Inflammation of the urinary bladder. [EU] 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] Cytoprotection: The process by which chemical compounds provide protection to cells against harmful agents. [NIH] Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Dalteparin: A drug that helps prevent the formation of blood clots; it belongs to the family of drugs called anticoagulants. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH] Decidua: The epithelial lining of the endometrium that is formed before the fertilized ovum reaches the uterus. The fertilized ovum embeds in the decidua. If the ovum is not fertilized, the decidua is shed during menstruation. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Delivery of Health Care: The concept concerned with all aspects of providing and distributing health services to a patient population. [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]
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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] Depressive Disorder: An affective disorder manifested by either a dysphoric mood or loss of interest or pleasure in usual activities. The mood disturbance is prominent and relatively persistent. [NIH] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] Dermis: A layer of vascular connective tissue underneath the epidermis. The surface of the dermis contains sensitive papillae. Embedded in or beneath the dermis are sweat glands, hair follicles, and sebaceous glands. [NIH] Detergents: Purifying or cleansing agents, usually salts of long-chain aliphatic bases or acids, that exert cleansing (oil-dissolving) and antimicrobial effects through a surface action that depends on possessing both hydrophilic and hydrophobic properties. [NIH] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Dextran Sulfate: Long-chain polymer of glucose containing 17-20% sulfur. It has been used as an anticoagulant and also has been shown to inhibit the binding of HIV-1 to CD4+ Tlymphocytes. It is commonly used as both an experimental and clinical laboratory reagent and has been investigated for use as an antiviral agent, in the treatment of hypolipidemia, and for the prevention of free radical damage, among other applications. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialysate: A cleansing liquid used in the two major forms of dialysis--hemodialysis and peritoneal dialysis. [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] Diamide: A sulfhydryl reagent which oxidizes sulfhydryl groups to the disulfide form. It is a radiation-sensitizing agent of anoxic bacterial and mammalian cells. [NIH] Diamines: Organic chemicals which have two amino groups in an aliphatic chain. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Diclofenac: A non-steroidal anti-inflammatory agent (NSAID) with antipyretic and analgesic actions. It is primarily available as the sodium salt, diclofenac sodium. [NIH] Diclofenac Sodium: The sodium form of diclofenac. It is used for its analgesic and antiinflammatory properties. [NIH] Dietary Fats: Fats present in food, especially in animal products such as meat, meat products, butter, ghee. They are present in lower amounts in nuts, seeds, and avocados. [NIH]
Diethylcarbamazine: An anthelmintic used primarily as the citrate in the treatment of filariasis, particularly infestations with Wucheria bancrofti or Loa loa. [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]
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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] Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer. [NIH] Dimethyl: A volatile metabolite of the amino acid methionine. [NIH] Diphosphonates: Organic compounds which contain P-C-P bonds, where P stands for phosphonates or phosphonic acids. These compounds affect calcium metabolism. They inhibit ectopic calcification and slow down bone resorption and bone turnover. Technetium complexes of diphosphonates have been used successfully as bone scanning agents. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Disaccharides: Sugars composed of two monosaccharides linked by glycoside bonds. [NIH] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Dissociative Disorders: Sudden temporary alterations in the normally integrative functions of consciousness. [NIH] 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] Diuretic: A drug that increases the production of urine. [NIH] Domesticated: Species in which the evolutionary process has been influenced by humans to meet their needs. [NIH] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dosage Forms: Completed forms of the pharmaceutical preparation in which prescribed doses of medication are included. They are designed to resist action by gastric fluids,
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prevent vomiting and nausea, reduce or alleviate the undesirable taste and smells associated with oral administration, achieve a high concentration of drug at target site, or produce a delayed or long-acting drug effect. They include capsules, liniments, ointments, pharmaceutical solutions, powders, tablets, etc. [NIH] Dose-limiting: Describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. [NIH] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] 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 Delivery Systems: Systems of administering drugs through controlled delivery so that an optimum amount reaches the target site. Drug delivery systems encompass the carrier, route, and target. [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] Duct: A tube through which body fluids pass. [NIH] Ductus Arteriosus: A fetal blood vessel connecting the pulmonary artery with the descending aorta. [NIH] Duodenum: The first part of the small intestine. [NIH] 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] 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 predispose to premature atherosclerosis. [NIH] Dyspareunia: Painful sexual intercourse. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Ectromelia: Gross hypo- or aplasia of one or more long bones of one or more limbs. The concept includes amelia, hemimelia, and phocomelia. [NIH] Ectromelia Virus: A species of orthopoxvirus infecting mice and causing a disease that involves internal organs and produces characteristic skin lesions. [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
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to describe cells in the immune system. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elastic: Susceptible of resisting and recovering from stretching, compression or distortion applied by a force. [EU] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Elastomers: A generic term for all substances having the properties of natural, reclaimed, vulcanized, or synthetic rubber, in that they stretch under tension, have a high tensile strength, retract rapidly, and recover their original dimensions fully. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrode: Component of the pacing system which is at the distal end of the lead. It is the interface with living cardiac tissue across which the stimulus is transmitted. [NIH] Electrolysis: Destruction by passage of a galvanic electric current, as in disintegration of a chemical compound in solution. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]
Electrophysiological: Pertaining to electrophysiology, that is a branch of physiology that is concerned with the electric phenomena associated with living bodies and involved in their functional activity. [EU] Ellagic Acid: A fused four ring compound occurring free or combined in galls. Isolated from the kino of Eucalyptus maculata Hook and E. Hemipholia F. Muell. Activates Factor XII of the blood clotting system which also causes kinin release; used in research and as a dye. [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] Embryo Transfer: Removal of a mammalian embryo from one environment and replacement in the same or a new environment. The embryo is usually in the pre-nidation phase, i.e., a blastocyst. The process includes embryo or blastocyst transplantation or transfer after in vitro fertilization and transfer of the inner cell mass of the blastocyst. It is not used for transfer of differentiated embryonic tissue, e.g., germ layer cells. [NIH] Embryogenesis: The process of embryo or embryoid formation, whether by sexual (zygotic) or asexual means. In asexual embryogenesis embryoids arise directly from the explant or on intermediary callus tissue. In some cases they arise from individual cells (somatic cell
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embryoge). [NIH] Emergency Treatment: First aid or other immediate intervention for accidents or medical conditions requiring immediate care and treatment before definitive medical and surgical management can be procured. [NIH] Emollient: Softening or soothing; called also malactic. [EU] 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] Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [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] 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] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endometrium: The layer of tissue that lines the uterus. [NIH] Endopeptidases: A subclass of peptide hydrolases. They are classified primarily by their catalytic mechanism. Specificity is used only for identification of individual enzymes. They comprise the serine endopeptidases, EC 3.4.21; cysteine endopeptidases, EC 3.4.22; aspartic endopeptidases, EC 3.4.23, metalloendopeptidases, EC 3.4.24; and a group of enzymes yet to be assigned to any of the above sub-classes, EC 3.4.99. EC 3.4.-. [NIH] Endostatin: A drug that is being studied for its ability to prevent the growth of new blood vessels into a solid tumor. Endostatin belongs to the family of drugs called angiogenesis inhibitors. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelins: 21-Amino-acid peptides produced by vascular endothelial cells and functioning as potent vasoconstrictors. The endothelin family consists of three members, endothelin-1, endothelin-2, and endothelin-3. All three peptides contain 21 amino acids, but vary in amino acid composition. The three peptides produce vasoconstrictor and pressor responses in various parts of the body. However, the quantitative profiles of the pharmacological activities are considerably different among the three isopeptides. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH]
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Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] 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] 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] Enoxaparin: A drug used to prevent blood clots. It belongs to the family of drugs called anticoagulants. [NIH] Enterocytes: Terminally differentiated cells comprising the majority of the external surface of the intestinal epithelium (see intestinal mucosa). Unlike goblet cells, they do not produce or secrete mucins, nor do they secrete cryptdins as do the paneth cells. [NIH] Enteropeptidase: A specialized proteolytic enzyme secreted by intestinal cells. It converts trypsinogen into its active form trypsin by removing the N-terminal peptide. EC 3.4.21.9. [NIH]
Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]
Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] 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] Enzyme-Linked Immunosorbent Assay: An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed. [NIH] Eosinophil: A polymorphonuclear leucocyte with large eosinophilic granules in its cytoplasm, which plays a role in hypersensitivity reactions. [NIH] Eosinophilic: A condition found primarily in grinding workers caused by a reaction of the pulmonary tissue, in particular the eosinophilic cells, to dust that has entered the lung. [NIH] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU]
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Epidermal Growth Factor: A 6 kD polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. epidermal growth factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and epithelial cells. [NIH] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] 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 covers the inner or outer surfaces of the body. [NIH] Epitopes: Sites on an antigen that interact with specific antibodies. [NIH] 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] Estradiol: The most potent mammalian estrogenic hormone. It is produced in the ovary, placenta, testis, and possibly the adrenal cortex. [NIH] Estrogen: One of the two female sex hormones. [NIH] Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [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]
Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ether: One of a class of organic compounds in which any two organic radicals are attached directly to a single oxygen atom. [NIH] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Excrete: To get rid of waste from the body. [NIH] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU]
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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] Extracorporeal: Situated or occurring outside the body. [EU] Extracorporeal Circulation: Diversion of blood flow through a circuit located outside the body but continuous with the bodily circulation. [NIH] Extracorporeal Membrane Oxygenation: Application of a life support system that circulates the blood through an oxygenating system, which may consist of a pump, a membrane oxygenator, and a heat exchanger. Examples of its use are to assist victims of smoke inhalation injury, respiratory failure, and cardiac failure. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Extrapyramidal: Outside of the pyramidal tracts. [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] Exudate: Material, such as fluid, cells, or cellular debris, which has escaped from blood vessels and has been deposited in tissues or on tissue surfaces, usually as a result of inflammation. An exudate, in contrast to a transudate, is characterized by a high content of protein, cells, or solid materials derived from cells. [EU] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]
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] Femoral Vein: The vein accompanying the femoral artery in the same sheath; it is a continuation of the popliteal vein and becomes the external iliac vein. [NIH]
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Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [NIH] Fertilization in Vitro: Fertilization of an egg outside the body when the egg is normally fertilized in the body. [NIH] Fetal Blood: Blood of the fetus. Exchange of nutrients and waste between the fetal and maternal blood occurs via the placenta. The cord blood is blood contained in the umbilical vessels at the time of delivery. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibrinolysis: The natural enzymatic dissolution of fibrin. [NIH] Fibrinolytic: Pertaining to, characterized by, or causing the dissolution of fibrin by enzymatic action [EU] Fibrinolytic Agents: Fibrinolysin or agents that convert plasminogen to fibrinolysin (plasmin). [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] Fibroid: A benign smooth muscle tumor, usually in the uterus or gastrointestinal tract. Also called leiomyoma. [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] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Fluorescein-5-isothiocyanate: Fluorescent probe capable of being conjugated to tissue and proteins. It is used as a label in fluorescent antibody staining procedures as well as protein-
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and amino acid-binding techniques. [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] Fluorocarbons: Liquid perfluorinated carbon compounds which may or may not contain a hetero atom such as nitrogen, oxygen or sulfur, but do not contain another halogen or hydrogen atom. This concept includes fluorocarbon emulsions and fluorocarbon blood substitutes. [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] Fold: A plication or doubling of various parts of the body. [NIH] Foramen: A natural hole of perforation, especially one in a bone. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fossa: A cavity, depression, or pit. [NIH] Fovea: The central part of the macula that provides the sharpest vision. [NIH] Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [NIH] Frameshift: A type of mutation which causes out-of-phase transcription of the base sequence; such mutations arise from the addition or delection of nucleotide(s) in numbers other than 3 or multiples of 3. [NIH] Frameshift Mutation: A type of mutation in which a number of nucleotides not divisible by three is deleted from or inserted into a coding sequence, thereby causing an alteration in the reading frame of the entire sequence downstream of the mutation. These mutations may be induced by certain types of mutagens or may occur spontaneously. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [NIH] 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] Gallate: Antioxidant present in tea. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a
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aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] Gangrene: Death and putrefaction of tissue usually due to a loss of blood supply. [NIH] Gangrenous: A circumscribed, deep-seated, suppurative inflammation of the subcutaneous tissue of the eyelid discharging pus from several points. [NIH] Gap Junctions: Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Bypass: Surgical procedure in which the stomach is transected high on the body. The resulting proximal remnant is joined to a loop of the jejunum in an end-to-side anastomosis. This procedure is used frequently in the treatment of morbid obesity. [NIH] Gastric Mucosa: Surface epithelium in the stomach that invaginates into the lamina propria, forming gastric pits. Tubular glands, characteristic of each region of the stomach (cardiac, gastric, and pyloric), empty into the gastric pits. The gastric mucosa is made up of several different kinds of cells. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]
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] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]
Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus,
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transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event. [NIH] Genetic 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] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] 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] Glioma: A cancer of the brain that comes from glial, or supportive, cells. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]
Glottis: The vocal apparatus of the larynx, consisting of the true vocal cords (plica vocalis) and the opening between them (rima glottidis). [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Clamp Technique: Maintenance of a constant blood glucose level by perfusion or infusion with glucose or insulin. It is used for the study of metabolic rates (e.g., in glucose, lipid, amino acid metabolism) at constant glucose concentration. [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] Glucuronides: Glycosides of glucuronic acid formed by the reaction of uridine diphosphate glucuronic acid with certain endogenous and exogenous substances. Their formation is important for the detoxification of drugs, steroid excretion and bilirubin metabolism to a more water-soluble compound that can be eliminated in the urine and bile. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]
Glycerophospholipids: Derivatives of phosphatidic acid in which the hydrophobic regions are composed of two fatty acids and a polar alcohol is joined to the C-3 position of glycerol through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. [NIH] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and
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used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycan: A type of long, unbranched polysaccharide molecule. Glycosaminoglycans are major structural components of cartilage and are also found in the cornea of the eye. [NIH] Glycoside: Any compound that contains a carbohydrate molecule (sugar), particularly any such natural product in plants, convertible, by hydrolytic cleavage, into sugar and a nonsugar component (aglycone), and named specifically for the sugar contained, as glucoside (glucose), pentoside (pentose), fructoside (fructose) etc. [EU] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction. [NIH] Goblet Cells: Cells of the epithelial lining that produce and secrete mucins. [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] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Gram-Negative Bacteria: Bacteria which lose crystal violet stain but are stained pink when treated by Gram's method. [NIH] Gram-positive: Retaining the stain or resisting decolorization by alcohol in Gram's method of staining, a primary characteristic of bacteria whose cell wall is composed of a thick layer of peptidologlycan with attached teichoic acids. [EU] Gram-Positive Bacteria: Bacteria which retain the crystal violet stain when treated by Gram's method. [NIH] Granule: A small pill made from sucrose. [EU] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanine: One of the four DNA bases. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and
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pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Guinea Pigs: A common name used for the family Caviidae. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research. [NIH]
Haematoma: A localized collection of blood, usually clotted, in an organ, space, or tissue, due to a break in the wall of a blood vessel. [EU] Haemodialysis: The removal of certain elements from the blood by virtue of the difference in the rates of their diffusion through a semipermeable membrane, e.g., by means of a haemodialyzer. [EU] Haemorrhage: The escape of blood from the vessels; bleeding. Small haemorrhages are classified according to size as petechiae (very small), purpura (up to 1 cm), and ecchymoses (larger). The massive accumulation of blood within a tissue is called a haematoma. [EU] Haemostasis: The arrest of bleeding, either by the physiological properties of vasoconstriction and coagulation or by surgical means. [EU] Hair follicles: Shafts or openings on the surface of the skin through which hair grows. [NIH] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] 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] Health Care Costs: The actual costs of providing services related to the delivery of health care, including the costs of procedures, therapies, and medications. It is differentiated from health expenditures, which refers to the amount of money paid for the services, and from fees, which refers to the amount charged, regardless of cost. [NIH] Health Expenditures: The amounts spent by individuals, groups, nations, or private or public organizations for total health care and/or its various components. These amounts may or may not be equivalent to the actual costs (health care costs) and may or may not be shared among the patient, insurers, and/or employers. [NIH] 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 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] Hematopoietic Stem Cell Transplantation: The transference of stem cells from one animal or human to another (allogeneic), or within the same individual (autologous). The source for the stem cells may be the bone marrow or peripheral blood. Stem cell transplantation has been used as an alternative to autologous bone marrow transplantation in the treatment of a variety of neoplasms. [NIH] Hemodiafiltration: The combination of hemodialysis and hemofiltration either simultaneously or sequentially. Convective transport (hemofiltration) may be better for removal of larger molecular weight substances and diffusive transport (hemodialysis) for smaller molecular weight solutes. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH]
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Hemodynamics: The movements of the blood and the forces involved in systemic or regional blood circulation. [NIH] Hemofiltration: Extracorporeal ultrafiltration technique without hemodialysis for treatment of fluid overload and electrolyte disturbances affecting renal, cardiac, or pulmonary function. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobin C: A commonly occurring abnormal hemoglobin in which lysine replaces a glutamic acid residue at the sixth position of the beta chains. It results in reduced plasticity of erythrocytes. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemorrhaging: A copious discharge of blood from the blood vessels. [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, Low-Molecular-Weight: Heparin fractions with a molecular weight usually between 4000 and 6000 kD. These low-molecular-weight fractions are effective antithrombotic agents. Their administration reduces the risk of hemorrhage, they have a longer half-life, and their platelet interactions are reduced in comparison to unfractionated heparin. They also provide an effective prophylaxis against postoperative major pulmonary embolism. [NIH] Heparin-binding: Protein that stimulates the proliferation of endothelial cells. [NIH] Hepatic: Refers to the liver. [NIH] Hepatic Veins: Veins which drain the liver. [NIH] Hepatic Veno-Occlusive Disease: Blockage of the small- or medium-sized hepatic veins due to nonthrombotic subendothelial edema which may progress to fibrosis. [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]
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Hepatoma: A liver tumor. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Herpes: Any inflammatory skin disease caused by a herpesvirus and characterized by the formation of clusters of small vesicles. When used alone, the term may refer to herpes simplex or to herpes zoster. [EU] Herpes virus: A member of the herpes family of viruses. [NIH] Herpes Zoster: Acute vesicular inflammation. [NIH] Heterodimer: 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]
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] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [NIH] Histones: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [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] 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] Horseradish Peroxidase: An enzyme isolated from horseradish which is able to act as an antigen. It is frequently used as a histochemical tracer for light and electron microscopy. Its antigenicity has permitted its use as a combined antigen and marker in experimental immunology. [NIH] Hyaluronidase: An enzyme that splits hyaluronic acid and thus lowers the viscosity of the
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acid and facilitates the spreading of fluids through tissues either advantageously or disadvantageously. [NIH] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [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] Hydrocortisone: The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. [NIH] Hydrogel: A network of cross-linked hydrophilic macromolecules used in biomedical applications. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Bonding: A low-energy attractive force between hydrogen and another element. It plays a major role in determining the properties of water, proteins, and other compounds. [NIH]
Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] 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] Hyperbaric: Characterized by greater than normal pressure or weight; applied to gases under greater than atmospheric pressure, as hyperbaric oxygen, or to a solution of greater specific gravity than another taken as a standard of reference. [EU] Hyperbaric oxygen: Oxygen that is at an atmospheric pressure higher than the pressure at sea level. Breathing hyperbaric oxygen to enhance the effectiveness of radiation therapy is being studied. [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [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] 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]
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Hyperreflexia: Exaggeration of reflexes. [EU] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypersensitivity, Immediate: Hypersensitivity reactions which occur within minutes of exposure to challenging antigen due to the release of histamine which follows the antigenantibody reaction and causes smooth muscle contraction and increased vascular permeability. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] 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] Hypothermia: Lower than normal body temperature, especially in warm-blooded animals; in man usually accidental or unintentional. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Hypoxic: Having too little oxygen. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Iduronic Acid: Component of dermatan sulfate. Differs in configuration from glucuronic acid only at the C-5 position. [NIH] Iliac Vein: A vein on either side of the body which is formed by the union of the external and internal iliac veins and passes upward to join with its fellow of the opposite side to form the inferior vena cava. [NIH] Imaging procedures: Methods of producing pictures of areas inside the body. [NIH] Immersion: The placing of a body or a part thereof into a liquid. [NIH] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]
Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH] Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunoblotting: Immunologic methods for isolating and quantitatively measuring immunoreactive substances. When used with immune reagents such as monoclonal
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antibodies, the process is known generically as western blot analysis (blotting, western). [NIH]
Immunocompromised: Having a weakened immune system caused by certain diseases or treatments. [NIH] Immunocompromised Host: A human or animal whose immunologic mechanism is deficient because of an immunodeficiency disorder or other disease or as the result of the administration of immunosuppressive drugs or radiation. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]
Infection Control: Programs of disease surveillance, generally within health care facilities, designed to investigate, prevent, and control the spread of infections and their causative microorganisms. [NIH]
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Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Inflammatory bowel disease: A general term that refers to the inflammation of the colon and rectum. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. [NIH]
Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Initiator: A chemically reactive substance which may cause cell changes if ingested, inhaled or absorbed into the body; the substance may thus initiate a carcinogenic process. [NIH] Innervation: 1. The distribution or supply of nerves to a part. 2. The supply of nervous energy or of nerve stimulus sent to a part. [EU] Inotropic: Affecting the force or energy of muscular contractions. [EU] Inpatients: Persons admitted to health facilities which provide board and room, for the purpose of observation, care, diagnosis or treatment. [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] Instillation: . [EU] 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] Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [NIH] Interleukin-8: A cytokine that activates neutrophils and attracts neutrophils and Tlymphocytes. It is released by several cell types including monocytes, macrophages, Tlymphocytes, fibroblasts, endothelial cells, and keratinocytes by an inflammatory stimulus. IL-8 is a member of the beta-thromboglobulin superfamily and structurally related to platelet factor 4. [NIH] Intermediate Filaments: Cytoplasmic filaments intermediate in diameter (about 10 nanometers) between the microfilaments and the microtubules. They may be composed of
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any of a number of different proteins and form a ring around the cell nucleus. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intracellular: Inside a cell. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intraocular: Within the eye. [EU] Intraperitoneal: IP. Within the peritoneal cavity (the area that contains the abdominal organs). [NIH] Intravascular: Within a vessel or vessels. [EU] Intravenous: IV. Into a vein. [NIH] Intravesical: Within the bladder. [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] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ion Exchange: Reversible chemical reaction between a solid, often an ION exchange resin, and a fluid whereby ions may be exchanged from one substance to another. This technique is used in water purification, in research, and in industry. [NIH] Ionophores: Chemical agents that increase the permeability of biological or artificial lipid membranes to specific ions. Most ionophores are relatively small organic molecules that act as mobile carriers within membranes or coalesce to form ion permeable channels across membranes. Many are antibiotics, and many act as uncoupling agents by short-circuiting the proton gradient across mitochondrial membranes. [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 (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.
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This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Ischemic stroke: A condition in which the blood supply to part of the brain is cut off. Also called "plug-type" strokes. Blocked arteries starve areas of the brain controlling sight, speech, sensation, and movement so that these functions are partially or completely lost. Ischemic stroke is the most common type of stroke, accounting for 80 percent of all strokes. Most ischemic strokes are caused by a blood clot called a thrombus, which blocks blood flow in the arteries feeding the brain, usually the carotid artery in the neck, the major vessel bringing blood to the brain. When it becomes blocked, the risk of stroke is very high. [NIH] Islet: Cell producing insulin in pancreas. [NIH] Isozymes: The multiple forms of a single enzyme. [NIH] Jejunum: That portion of the small intestine which extends from the duodenum to the ileum; called also intestinum jejunum. [EU] 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] 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] Keratin: A class of fibrous proteins or scleroproteins important both as structural proteins and as keys to the study of protein conformation. The family represents the principal constituent of epidermis, hair, nails, horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms an alpha-helix, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. [NIH] Keratinocytes: Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. [NIH] 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] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [NIH]
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Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Laceration: 1. The act of tearing. 2. A torn, ragged, mangled wound. [EU] Lactation: The period of the secretion of milk. [EU] 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] 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] 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] Lectins: Protein or glycoprotein substances, usually of plant origin, that bind to sugar moieties in cell walls or membranes and thereby change the physiology of the membrane to cause agglutination, mitosis, or other biochemical changes in the cell. [NIH] Leiomyoma: A benign tumor derived from smooth muscle tissue, also known as a fibroid tumor. They rarely occur outside of the uterus and the gastrointestinal tract but can occur in the skin and subcutaneous tissues, probably arising from the smooth muscle of small blood vessels in these tissues. [NIH] Length of Stay: The period of confinement of a patient to a hospital or other health facility. [NIH]
Lenses: Pieces of glass or other transparent materials used for magnification or increased visual acuity. [NIH] Lepirudin: A drug that inhibits blood clotting; it is being studied in cancer treatment. [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] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]
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] Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU]
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Ligands: A RNA simulation method developed by the MIT. [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] Lipaemia: The presence of an excess of fats or lipids in the blood. [NIH] Lipase: An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. (From Dorland, 27th ed) EC 3.1.1.3. [NIH] Lipid: Fat. [NIH] Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] Lipopolysaccharide: 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] Lipoprotein Lipase: An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. The enzyme hydrolyzes triacylglycerols in chylomicrons, very-low-density lipoproteins, low-density lipoproteins, and diacylglycerols. It occurs on capillary endothelial surfaces, especially in mammary, muscle, and adipose tissue. Genetic deficiency of the enzyme causes familial hyperlipoproteinemia Type I. (Dorland, 27th ed) EC 3.1.1.34. [NIH] Lithium: An element in the alkali metals family. It has the atomic symbol Li, atomic number 3, and atomic weight 6.94. Salts of lithium are used in treating manic-depressive disorders. [NIH]
Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another. [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] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside
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diameter) and used in transferring microorganisms. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] 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] Luciferase: Any one of several enzymes that catalyze the bioluminescent reaction in certain marine crustaceans, fish, bacteria, and insects. The enzyme is a flavoprotein; it oxidizes luciferins to an electronically excited compound that emits energy in the form of light. The color of light emitted varies with the organism. The firefly enzyme is a valuable reagent for measurement of ATP concentration. (Dorland, 27th ed) EC 1.13.12.-. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lutein Cells: The cells of the corpus luteum which are derived from the granulosa cells and the theca cells of the Graafian follicle. [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] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH]
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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] Manic: Affected with mania. [EU] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Mastitis: Inflammatory disease of the breast, or mammary gland. [NIH] Matrix metalloproteinase: A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis. [NIH] 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] 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] 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 Lipids: Lipids, predominantly phospholipids, cholesterol and small amounts of glycolipids found in membranes including cellular and intracellular membranes. These lipids may be arranged in bilayers in the membranes with integral proteins between the layers and peripheral proteins attached to the outside. Membrane lipids are required for active transport, several enzymatic activities and membrane formation. [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and
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lymphatic tissue. [NIH] Mesoderm: The middle germ layer of the embryo. [NIH] Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metalloporphyrins: Porphyrins which are combined with a metal ion. The metal is bound equally to all four nitrogen atoms of the pyrrole rings. They possess characteristic absorption spectra which can be utilized for identification or quantitative estimation of porphyrins and porphyrin-bound compounds. [NIH] Metaphase: The second phase of cell division, in which the chromosomes line up across the equatorial plane of the spindle prior to separation. [NIH] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Mice Minute Virus: The type species of parvovirus prevalent in mouse colonies and found as a contaminant of many transplanted tumors or leukemias. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] 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] Microfilaments: The smallest of the cytoskeletal filaments. They are composed chiefly of actin. [NIH] Micromanipulation: The performance of dissections, injections, surgery, etc., by the use of micromanipulators (attachments to a microscope that manipulate tiny instruments). [NIH] Micromanipulators: A high precision instrument used in microinjection or chromosome dissection activities. [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] Microspheres: Small uniformly-sized spherical particles frequently radioisotopes or various reagents acting as tags or markers. [NIH]
labeled
with
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Micturition: The passage of urine; urination. [EU] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Miscarriage: Spontaneous expulsion of the products of pregnancy before the middle of the second trimester. [NIH] Miscible: Susceptible of being mixed. [EU] 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] Mitotic: Cell resulting from mitosis. [NIH] Mitoxantrone: An anthracenedione-derived antineoplastic agent. [NIH] Mitral Valve: The valve between the left atrium and left ventricle of the heart. [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 mass: The sum of the atomic masses of all atoms in a molecule, based on a scale in which the atomic masses of hydrogen, carbon, nitrogen, and oxygen are 1, 12, 14, and 16, respectively. For example, the molecular mass of water, which has two atoms of hydrogen and one atom of oxygen, is 18 (i.e., 2 + 16). [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocyte: A type of white blood cell. [NIH] Mononuclear: A cell with one nucleus. [NIH] 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]
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Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] Multivalent: Pertaining to a group of 5 or more homologous or partly homologous chromosomes during the zygotene stage of prophase to first metaphasis in meiosis. [NIH] 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] 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] Myeloma: Cancer that arises in plasma cells, a type of white blood cell. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] 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 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] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense
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pain, food poisoning, and various enteroviruses. [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] 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] Nephrology: A subspecialty of internal medicine concerned with the anatomy, physiology, and pathology of the kidney. [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] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Junction: The synapse between a neuron and a muscle. [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] Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutralization: An act or process of neutralizing. [EU] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophil: A type of white blood cell. [NIH] 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] 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
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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] Nocturia: Excessive urination at night. [EU] 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] Normotensive: 1. Characterized by normal tone, tension, or pressure, as by normal blood pressure. 2. A person with normal blood pressure. [EU] Nosocomial: Pertaining to or originating in the hospital, said of an infection not present or incubating prior to admittance to the hospital, but generally occurring 72 hours after admittance; the term is usually used to refer to patient disease, but hospital personnel may also acquire nosocomial infection. [EU] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with nucleoproteins which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus. [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] Nucleoproteins: Proteins conjugated with nucleic acids. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [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] Oligo: Chemical and mineral elements that exist in minimal (oligo) quantities in the body, in foods, in the air, in soil; name applied to any element observed as a microconstituent of plant or animal tissue and of beneficial, harmful, or even doubtful significance. [NIH] Oligopeptides: Peptides composed of between two and twelve amino acids. [NIH] Oligosaccharides: Carbohydrates consisting of between two and ten monosaccharides
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connected by either an alpha- or beta-glycosidic link. They are found throughout nature in both the free and bound form. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [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] Ophthalmic: Pertaining to the eye. [EU] Ophthalmology: A surgical specialty concerned with the structure and function of the eye and the medical and surgical treatment of its defects and diseases. [NIH] Ophthalmoplegia: Paralysis of one or more of the ocular muscles due to disorders of the eye muscles, neuromuscular junction, supporting soft tissue, tendons, or innervation to the muscles. [NIH] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Orthopaedic: Pertaining to the correction of deformities of the musculoskeletal system; pertaining to orthopaedics. [EU] Osmosis: Tendency of fluids (e.g., water) to move from the less concentrated to the more concentrated side of a semipermeable membrane. [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] Osteoblasts: Bone-forming cells which secrete an extracellular matrix. Hydroxyapatite crystals are then deposited into the matrix to form bone. [NIH] Osteoclasts: A large multinuclear cell associated with the absorption and removal of bone. An odontoclast, also called cementoclast, is cytomorphologically the same as an osteoclast and is involved in cementum resorption. [NIH] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] Ovalbumin: An albumin obtained from the white of eggs. It is a member of the serpin superfamily. [NIH]
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Ovarian Follicle: Spheroidal cell aggregation in the ovary containing an ovum. It consists of an external fibro-vascular coat, an internal coat of nucleated cells, and a transparent, albuminous fluid in which the ovum is suspended. [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] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Ovum Implantation: Endometrial implantation of the blastocyst. [NIH] Oxidants: Oxidizing agents or electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (oxidation-reduction). In vivo, it appears that phagocyte-generated oxidants function as tumor promoters or cocarcinogens rather than as complete carcinogens perhaps because of the high levels of endogenous antioxidant defenses. It is also thought that oxidative damage in joints may trigger the autoimmune response that characterizes the persistence of the rheumatoid disease process. [NIH]
Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]
Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] Oxygenator: An apparatus by which oxygen is introduced into the blood during circulation outside the body, as during open heart surgery. [NIH] Pacemaker: An object or substance that influences the rate at which a certain phenomenon occurs; often used alone to indicate the natural cardiac pacemaker or an artificial cardiac pacemaker. In biochemistry, a substance whose rate of reaction sets the pace for a series of interrelated reactions. [EU] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Pancreatic Juice: The fluid containing digestive enzymes secreted by the pancreas in response to food in the duodenum. [NIH]
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Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Parenteral Nutrition: The administering of nutrients for assimilation and utilization by a patient who cannot maintain adequate nutrition by enteral feeding alone. Nutrients are administered by a route other than the alimentary canal (e.g., intravenously, subcutaneously). [NIH] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Partial Thromboplastin Time: Test of the intrinsic (factors VIII, IX, XI, and XII) and common (fibrinogen, prothrombin, factors V and X) pathways of coagulation in which a mixture of plasma and phospholipid platelet substitute (e.g., crude cephalins, soybean phosphatides) is recalcified and the time required for the appearance of fibrin strands measured. Activation may be provided by contact with the glass tube or exposure to activators (e.g., ellagic acid, particulate silicates such as diatomaceous earth or kaolin) before addition of the calcium chloride. It is used as a screening test and to monitor heparin therapy. [NIH] Particle: A tiny mass of material. [EU] Parturition: The act or process of given birth to a child. [EU] Parvovirus: A genus of the family Parvoviridae, subfamily Parvovirinae, infecting a variety of vertebrates including humans. Parvoviruses are responsible for a number of important diseases but also can be non-pathogenic in certain hosts. The type species is mice minute virus. [NIH] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]
Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Compliance: Voluntary cooperation of the patient in following a prescribed regimen. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]
Pelvic: Pertaining to the pelvis. [EU] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Penicillin: An antibiotic drug used to treat infection. [NIH] Pentosan polysulfate: A drug used to relieve pain or discomfort associated with chronic inflammation of the bladder. It is also being evaluated for its protective effects on the gastrointestinal tract in people undergoing radiation therapy. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of
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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] Perforation: 1. The act of boring or piercing through a part. 2. A hole made through a part or substance. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Pericarditis: Inflammation of the pericardium. [EU] 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 Nerves: The nerves outside of the brain and spinal cord, including the autonomic, cranial, and spinal nerves. Peripheral nerves contain non-neuronal cells and connective tissue as well as axons. The connective tissue layers include, from the outside to the inside, the epineurium, the perineurium, and the endoneurium. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH] Peritoneal Dialysis: Dialysis fluid being introduced into and removed from the peritoneal cavity as either a continuous or an intermittent procedure. [NIH] Peritoneum: Endothelial lining of the abdominal cavity, the parietal peritoneum covering the inside of the abdominal wall and the visceral peritoneum covering the bowel, the mesentery, and certain of the organs. The portion that covers the bowel becomes the serosal layer of the bowel wall. [NIH] Peritonitis: Inflammation of the peritoneum; a condition marked by exudations in the peritoneum of serum, fibrin, cells, and pus. It is attended by abdominal pain and tenderness, constipation, vomiting, and moderate fever. [EU] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Pertussis: An acute, highly contagious infection of the respiratory tract, most frequently affecting young children, usually caused by Bordetella pertussis; a similar illness has been associated with infection by B. parapertussis and B. bronchiseptica. It is characterized by a catarrhal stage, beginning after an incubation period of about two weeks, with slight fever, sneezing, running at the nose, and a dry cough. In a week or two the paroxysmal stage begins, with the characteristic paroxysmal cough, consisting of a deep inspiration, followed by a series of quick, short coughs, continuing until the air is expelled from the lungs; the close of the paroxysm is marked by a long-drawn, shrill, whooping inspiration, due to spasmodic closure of the glottis. This stage lasts three to four weeks, after which the convalescent stage begins, in which paroxysms grow less frequent and less violent, and
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finally cease. Called also whooping cough. [EU] Petechiae: Pinpoint, unraised, round red spots under the skin caused by bleeding. [NIH] Petrolatum: A colloidal system of semisolid hydrocarbons obtained from petroleum. It is used as an ointment base, topical protectant, and lubricant. [NIH] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Phallic: Pertaining to the phallus, or penis. [EU] 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] Pharmaceutical Solutions: Homogeneous liquid preparations that contain one or more chemical substances dissolved, i.e., molecularly dispersed, in a suitable solvent or mixture of mutually miscible solvents. For reasons of their ingredients, method of preparation, or use, they do not fall into another group of products. [NIH] Pharmacodynamics: The study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the correlation of actions and effects of drugs with their chemical structure; also, such effects on the actions of a particular drug or drugs. [EU] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Phenolphthalein: An acid-base indicator which is colorless in acid solution, but turns pink to red as the solution becomes alkaline. It is used medicinally as a cathartic. [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] Phenprocoumon: 3-(1-Phenylpropyl)-4-hydroxycoumarin. Long acting oral anticoagulant. It may cause diarrhea. [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] Phocomelia: Congenital deformity that leaves the child without legs. [NIH] Phorbol: Class of chemicals that promotes the development of tumors. [NIH] Phorbol Esters: Tumor-promoting compounds obtained from croton oil (Croton tiglium). Some of these are used in cell biological experiments as activators of protein kinase C. [NIH] 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] Phosphonic Acids: Inorganic or organic derivatives of phosphonic acid with the general formula ROP(OH)2. This includes phosphonates and phosphonic acid esters. The tautomeric form of this compound (P(OH)3) = phosphorous acids. [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]
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Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylates: Attached to a phosphate group. [NIH] Phosphorylating: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Physicochemical: Pertaining to physics and chemistry. [EU] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]
Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] 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;
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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] Plasminogen Inactivators: Important modulators of the activity of plasminogen activators. Four inhibitors, all belonging to the serpin family of proteins, have been implicated in plasminogen activation inhibition. They are PAI-1, PAI-2, protease-nexin, and protein C inhibitor (PAI-3). All inhibit both the tissue-type and urokinase-type plasminogen activators. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelet Count: A count of the number of platelets per unit volume in a sample of venous blood. [NIH] Platelet Factor 4: A high-molecular-weight proteoglycan-platelet factor complex which is released from blood platelets by thrombin. It acts as a mediator in the heparin-neutralizing capacity of the blood and plays a role in platelet aggregation. At high ionic strength (I=0.75), the complex dissociates into the active component (molecular weight 29,000) and the proteoglycan carrier (chondroitin 4-sulfate, molecular weight 350,000). The molecule exists in the form of a dimer consisting of 8 moles of platelet factor 4 and 2 moles of proteoglycan. [NIH]
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]
Pneumonia: Inflammation of the lungs. [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] Polyethylene: A vinyl polymer made from ethylene. It can be branched or linear. Branched or low-density polyethylene is tough and pliable but not to the same degree as linear polyethylene. Linear or high-density polyethylene has a greater hardness and tensile strength. Polyethylene is used in a variety of products, including implants and prostheses. [NIH]
Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand
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as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polyneuropathies: Diseases of multiple peripheral nerves. The various forms are categorized by the type of nerve affected (e.g., sensory, motor, or autonomic), by the distribution of nerve injury (e.g., distal vs. proximal), by nerve component primarily affected (e.g., demyelinating vs. axonal), by etiology, or by pattern of inheritance. [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] Polytetrafluoroethylene: Homopolymer of tetrafluoroethylene. Nonflammable, tough, inert plastic tubing or sheeting; used to line vessels, insulate, protect or lubricate apparatus; also as filter, coating for surgical implants or as prosthetic material. Synonyms: Fluoroflex; Fluoroplast; Ftoroplast; Halon; Polyfene; PTFE; Tetron. [NIH] Polyurethanes: A group of thermoplastic or thermosetting polymers containing polyisocyanate. They are used as elastomers, as coatings, as fibers and as foams. [NIH] Polyvinyl Alcohol: A polymer prepared from polyvinyl acetates by replacement of the acetate groups with hydroxyl groups. It is used as a pharmaceutic aid and ophthalmic lubricant as well as in the manufacture of surface coatings artificial sponges, cosmetics, and other products. [NIH] Popliteal: Compression of the nerve at the neck of the fibula. [NIH] Popliteal Vein: The vein formed by the union of the anterior and posterior tibial veins; it courses through the popliteal space and becomes the femoral vein. [NIH] Porphyrins: A group of compounds containing the porphin structure, four pyrrole rings connected by methine bridges in a cyclic configuration to which a variety of side chains are attached. The nature of the side chain is indicated by a prefix, as uroporphyrin, hematoporphyrin, etc. The porphyrins, in combination with iron, form the heme component in biologically significant compounds such as hemoglobin and myoglobin. [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] Postoperative: After surgery. [NIH]
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Postprandial: Occurring after dinner, or after a meal; postcibal. [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] Potentiating: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [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] Precipitation: The act or process of precipitating. [EU] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Pre-Eclampsia: Development of hypertension with proteinuria, edema, or both, due to pregnancy or the influence of a recent pregnancy. It occurs after the 20th week of gestation, but it may develop before this time in the presence of trophoblastic disease. [NIH] Pregnancy Outcome: Results of conception and ensuing pregnancy, including live birth, stillbirth, spontaneous abortion, induced abortion. The outcome may follow natural or artificial insemination or any of the various reproduction techniques, such as embryo transfer or fertilization in vitro. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Preoperative: Preceding an operation. [EU] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Prickle: Several layers of the epidermis where the individual cells are connected by cell bridges. [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] Proenzyme: 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] 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
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severity. [EU] Prolactin: Pituitary lactogenic hormone. A polypeptide hormone with a molecular weight of about 23,000. It is essential in the induction of lactation in mammals at parturition and is synergistic with estrogen. The hormone also brings about the release of progesterone from lutein cells, which renders the uterine mucosa suited for the embedding of the ovum should fertilization occur. [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] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] 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] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH] Prostaglandins D: Physiologically active prostaglandins found in many tissues and organs. They show pressor activity, are mediators of inflammation, and have potential antithrombotic effects. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Prostatectomy: Complete or partial surgical removal of the prostate. Three primary approaches are commonly employed: suprapubic - removal through an incision above the pubis and through the urinary bladder; retropubic - as for suprapubic but without entering the urinary bladder; and transurethral (transurethral resection of prostate). [NIH] Prostatitis: Inflammation of the prostate. [EU] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). [NIH] Protein 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
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peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein Kinase C: An enzyme that phosphorylates proteins on serine or threonine residues in the presence of physiological concentrations of calcium and membrane phospholipids. The additional presence of diacylglycerols markedly increases its sensitivity to both calcium and phospholipids. The sensitivity of the enzyme can also be increased by phorbol esters and it is believed that protein kinase C is the receptor protein of tumor-promoting phorbol esters. EC 2.7.1.-. [NIH] Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein. EC 2.7.1.37. [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]
Prothrombin Time: Measurement of clotting time of plasma recalcified in the presence of excess tissue thromboplastin. Factors measured are fibrinogen, prothrombin, and factors V, VII, and X. It is used for monitoring anticoagulant therapy with coumarins. [NIH] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH]
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Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]
Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulmonary Embolism: Embolism in the pulmonary artery or one of its branches. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]
Pupil: The aperture in the iris through which light passes. [NIH] Purifying: Respiratory equipment whose function is to remove contaminants from otherwise wholesome air. [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] Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] Putrefaction: The process of decomposition of animal and vegetable matter by living organisms. [NIH] Pyramidal Cells: Projection neurons in the cerebral cortex and the hippocampus. Pyramidal cells have a pyramid-shaped soma with the apex and an apical dendrite pointed toward the pial surface and other dendrites and an axon emerging from the base. The axons may have local collaterals but also project outside their cortical region. [NIH] Pyridoxal: 3-Hydroxy-5-(hydroxymethyl)-2-methyl-4- pyridinecarboxaldehyde. [NIH] Pyridoxal Kinase: An enzyme that catalyzes reversibly the phosphorylation of pyridoxal in the presence of ATP with the formation of pyridoxal 5-phosphate and ADP. Pyridoxine, pyridoxamine and various derivatives can also act as acceptors. EC 2.7.1.35. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Quality of Health Care: The levels of excellence which characterize the health service or health care provided based on accepted standards of quality. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quaternary: 1. Fourth in order. 2. Containing four elements or groups. [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]
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Quiescent: Marked by a state of inactivity or repose. [EU] 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] Radioactivity: The quality of emitting or the emission of corpuscular or electromagnetic radiations consequent to nuclear disintegration, a natural property of all chemical elements of atomic number above 83, and possible of induction in all other known elements. [EU] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] 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] Reaction Time: The time from the onset of a stimulus until the organism responds. [NIH] 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] 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, Chemokine: Cell surface glycoproteins that bind to chemokines and thus mediate the migration of pro-inflammatory molecules. The receptors are members of the seven-transmembrane G protein-coupled receptor family. Like the chemokines themselves, the receptors can be divided into at least three structural branches: CR, CCR, and CXCR, according to variations in a shared cysteine motif. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectal: By or having to do with the rectum. The rectum is the last 8 to 10 inches of the large intestine and ends at the anus. [NIH]
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Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractory: Not readily yielding to treatment. [EU] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] 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] Rehydration: The restoration of water or of fluid content to a body or to substance which has become dehydrated. [EU] Reliability: Used technically, in a statistical sense, of consistency of a test with itself, i. e. the extent to which we can assume that it will yield the same result if repeated a second time. [NIH]
Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [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] Repopulation: The replacement of functional cells, usually by proliferation, following or during irradiation. [NIH] Reproduction Techniques: Methods pertaining to the generation of new individuals. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respiratory distress syndrome: A lung disease that occurs primarily in premature infants; the newborn must struggle for each breath and blueing of its skin reflects the baby's inability to get enough oxygen. [NIH] Respiratory failure: Inability of the lungs to conduct gas exchange. [NIH]
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Resuscitation: The restoration to life or consciousness of one apparently dead; it includes such measures as artificial respiration and cardiac massage. [EU] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinal Ganglion Cells: Cells of the innermost nuclear layer of the retina, the ganglion cell layer, which project axons through the optic nerve to the brain. They are quite variable in size and in the shapes of their dendritic arbors, which are generally confined to the inner plexiform layer. [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] Retropubic: A potential space between the urinary bladder and the symphisis and body of the pubis. [NIH] Retropubic prostatectomy: Surgery to remove the prostate through an incision made in the abdominal wall. [NIH] Retrospective: Looking back at events that have already taken place. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Reversion: A return to the original condition, e. g. the reappearance of the normal or wild type in previously mutated cells, tissues, or organisms. [NIH] Rewarming: Application of heat to correct hypothermia, accidental or induced. [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] Rhinitis: Inflammation of the mucous membrane of the nose. [NIH] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series of complex reactions in response to visible light resulting in the transmission of nerve impulses to the brain. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Risk patient: Patient who is at risk, because of his/her behaviour or because of the type of
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person he/she is. [EU] Rod: A reception for vision, located in the retina. [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] Ryanodine: Insecticidal alkaloid isolated from Ryania speciosa; proposed as a myocardial depressant. [NIH] Salicylic: A tuberculosis drug. [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] 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] 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] Sebaceous: Gland that secretes sebum. [NIH] Sebaceous gland: Gland that secretes sebum. [NIH] Second Messenger Systems: Systems in which an intracellular signal is generated in response to an intercellular primary messenger such as a hormone or neurotransmitter. They are intermediate signals in cellular processes such as metabolism, secretion, contraction, phototransduction, and cell growth. Examples of second messenger systems are the adenyl cyclase-cyclic AMP system, the phosphatidylinositol diphosphate-inositol triphosphate system, and the cyclic GMP system. [NIH] 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
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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] Sedimentation: The act of causing the deposit of sediment, especially by the use of a centrifugal machine. [EU] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] 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] Sensor: A device designed to respond to physical stimuli such as temperature, light, magnetism or movement and transmit resulting impulses for interpretation, recording, movement, or operating control. [NIH] Septal: An abscess occurring at the root of the tooth on the proximal surface. [NIH] Septicaemia: A term originally used to denote a putrefactive process in the body, but now usually referring to infection with pyogenic micro-organisms; a genus of Diptera; the severe type of infection in which the blood stream is invaded by large numbers of the causal. [NIH] Septum: A dividing wall or partition; a general term for such a structure. The term is often used alone to refer to the septal area or to the septum pellucidum. [EU] Septum Pellucidum: A triangular double membrane separating the anterior horns of the lateral ventricles of the brain. It is situated in the median plane and bounded by the corpus callosum and the body and columns of the fornix. [NIH] Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Sequester: A portion of dead bone which has become detached from the healthy bone tissue, as occurs in necrosis. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serine Endopeptidases: Any member of the group of endopeptidases containing at the active site a serine residue involved in catalysis. EC 3.4.21. [NIH] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serotypes: A cause of haemorrhagic septicaemia (in cattle, sheep and pigs), fowl cholera of birds, pasteurellosis of rabbits, and gangrenous mastitis of ewes. It is also commonly found
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in atrophic rhinitis of pigs. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serpins: A family of serine proteinase inhibitors which are similar in amino acid sequence and mechanism of inhibition, but differ in their specificity toward proteolytic enzymes. This family includes alpha 1-antitrypsin, angiotensinogen, ovalbumin, antiplasmin, alpha 1antichymotrypsin, thyroxine-binding protein, complement 1 inactivators, antithrombin III, heparin cofactor II, plasminogen inactivators, gene Y protein, placental plasminogen activator inhibitor, and barley Z protein. Some members of the serpin family may be substrates rather than inhibitors of serine endopeptidases, and some serpins occur in plants where their function is not known. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Shedding: Release of infectious particles (e. g., bacteria, viruses) into the environment, for example by sneezing, by fecal excretion, or from an open lesion. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]
Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skin test: A test for an immune response to a compound by placing it on or under the skin. [NIH]
Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smallpox: A generalized virus infection with a vesicular rash. [NIH] Smoke Inhalation Injury: Pulmonary injury following the breathing in of toxic smoke from burning materials such as plastics, synthetics, building materials, etc. This injury is the most frequent cause of death in burn patients. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]
Sneezing: Sudden, forceful, involuntary expulsion of air from the nose and mouth caused by irritation to the mucous membranes of the upper respiratory tract. [NIH] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Social Work: The use of community resources, individual case work, or group work to promote the adaptive capacities of individuals in relation to their social and economic environments. It includes social service agencies. [NIH]
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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] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Sound wave: An alteration of properties of an elastic medium, such as pressure, particle displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] Spasm: An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. [NIH] Spasmodic: Of the nature of a spasm. [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] Spectroscopic: The recognition of elements through their emission spectra. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] 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] Spinous: Like a spine or thorn in shape; having spines. [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] Spontaneous Abortion: The non-induced birth of an embryo or of fetus prior to the stage of viability at about 20 weeks of gestation. [NIH] Squamous: Scaly, or platelike. [EU]
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Stabilization: The creation of a stable state. [EU] Statistically significant: Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. [NIH] Steady state: Dynamic equilibrium. [EU] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stem Cell Factor: Hematopoietic growth factor and the ligand of the c-kit receptor CD117 (proto-oncogene protein C-kit). It is expressed during embryogenesis and provides a key signal in multiple aspects of mast-cell differentiation and function. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stenosis: Narrowing or stricture of a duct or canal. [EU] 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] Sterile: Unable to produce children. [NIH] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stillbirth: The birth of a dead fetus or baby. [NIH] Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Streptomyces: A genus of bacteria that form a nonfragmented aerial mycelium. Many species have been identified with some being pathogenic. This genus is responsible for producing a majority of the antibiotics of practical value. [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 Fibers: Bundles of actin filaments (microfilaments) and myosin-II that span across the cell attaching to the cell membrane at focal adhesions and to the network of intermediate filaments that surrounds the nucleus. [NIH] Stricture: The abnormal narrowing of a body opening. Also called stenosis. [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.
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These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [NIH] Structure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Other factors contributing to structure-activity relationship include chemical reactivity, electronic effects, resonance, and inductive effects. [NIH] 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] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Submaxillary: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]
Substrate: A substance upon which an enzyme acts. [EU] Subtilisin: A serine endopeptidase isolated from Bacillus subtilis. It hydrolyzes proteins with broad specificity for peptide bonds, and a preference for a large uncharged residue in P1. It also hydrolyzes peptide amides. (From Enzyme Nomenclature, 1992) EC 3.4.21.62. [NIH]
Sulfates: Inorganic salts of sulfuric acid. [NIH] Sulfotransferases: Enzymes which transfer sulfate groups to various acceptor molecules. They are involved in posttranslational sulfation of proteins and sulfate conjugation of exogenous chemicals and bile acids. EC 2.8.2. [NIH] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Sulfuric acid: A strong acid that, when concentrated is extemely corrosive to the skin and mucous membranes. It is used in making fertilizers, dyes, electroplating, and industrial explosives. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH]
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Suramin: A polyanionic compound with an unknown mechanism of action. It is used parenterally in the treatment of African trypanosomiasis and it has been used clinically with diethylcarbamazine to kill the adult Onchocerca. (From AMA Drug Evaluations Annual, 1992, p1643) It has also been shown to have potent antineoplastic properties. [NIH] Surfactant: A fat-containing protein in the respiratory passages which reduces the surface tension of pulmonary fluids and contributes to the elastic properties of pulmonary tissue. [NIH]
Sweat: The fluid excreted by the sweat glands. It consists of water containing sodium chloride, phosphate, urea, ammonia, and other waste products. [NIH] Sweat Glands: Sweat-producing structures that are embedded in the dermis. Each gland consists of a single tube, a coiled body, and a superficial duct. [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] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but, according to the general view, there is no direct contiguity. [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] Synaptic Transmission: The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors. These activated receptors modulate ion channels and/or secondmessenger systems to influence the postsynaptic cell. Electrical transmission is less common in the nervous system, and, as in other tissues, is mediated by gap junctions. [NIH] Synaptic Vesicles: Membrane-bound compartments which contain transmitter molecules. Synaptic vesicles are concentrated at presynaptic terminals. They actively sequester transmitter molecules from the cytoplasm. In at least some synapses, transmitter release occurs by fusion of these vesicles with the presynaptic membrane, followed by exocytosis of their contents. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Synovial: Of pertaining to, or secreting synovia. [EU] Synthetic retinoid: A substance related to vitamin A that is produced in a laboratory. [NIH] Systemic: Affecting the entire body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU]
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Teichoic Acids: Bacterial polysaccharides that are rich in phosphodiester linkages. They are the major components of the cell walls and membranes of many bacteria. [NIH] 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] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Tetani: Causal agent of tetanus. [NIH] Tetanic: Having the characteristics of, or relating to tetanus. [NIH] Tetanus: A disease caused by tetanospasmin, a powerful protein toxin produced by Clostridium tetani. Tetanus usually occurs after an acute injury, such as a puncture wound or laceration. Generalized tetanus, the most common form, is characterized by tetanic muscular contractions and hyperreflexia. Localized tetanus presents itself as a mild condition with manifestations restricted to muscles near the wound. It may progress to the generalized form. [NIH] Tetanus Toxin: The toxin elaborated by Clostridium tetani. It is a protein with a molecular weight of about 150,000, probably consisting of two fragments, tetanolysin being the hemolytic and tetanospasmin the neurotoxic principle. The toxin causes disruption of the inhibitory mechanisms of the CNS, thus permitting uncontrolled nervous activity, leading to fatal convulsions. [NIH] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] 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] Thoracic: Having to do with the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thrombocytopenia: A decrease in the number of blood platelets. [NIH] Thrombolytic: 1. Dissolving or splitting up a thrombus. 2. A thrombolytic agent. [EU] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]
Thrombopenia: Reduction in the number of platelets in the blood. [NIH] Thrombophilia: A disorder of hemostasis in which there is a tendency for the occurrence of thrombosis. [NIH]
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Thrombophlebitis: Inflammation of a vein associated with thrombus formation. [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] 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] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Plasminogen Activator: A proteolytic enzyme in the serine protease family found in many tissues which converts plasminogen to plasmin. It has fibrin-binding activity and is immunologically different from urinary plasminogen activator. The primary sequence, composed of 527 amino acids, is identical in both the naturally occurring and synthetic proteases. EC 3.4.21.68. [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] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU]
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Tracer: A substance (such as a radioisotope) used in imaging procedures. [NIH] Traction: The act of pulling. [NIH] Transdermal: Entering through the dermis, or skin, as in administration of a drug applied to the skin in ointment or patch form. [EU] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Treatment Failure: A measure of the quality of health care by assessment of unsuccessful results of management and procedures used in combating disease, in individual cases or series. [NIH] 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] Trophoblast: The outer layer of cells of the blastocyst which works its way into the endometrium during ovum implantation and grows rapidly, later combining with mesoderm. [NIH] Tropism: Directed movements and orientations found in plants, such as the turning of the sunflower to face the sun. [NIH] Tropomyosin: A protein found in the thin filaments of muscle fibers. It inhibits contraction of the muscle unless its position is modified by troponin. [NIH]
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Troponin: One of the minor protein components of skeletal muscle. Its function is to serve as the calcium-binding component in the troponin-tropomyosin B-actin-myosin complex by conferring calcium sensitivity to the cross-linked actin and myosin filaments. [NIH] Trypanosomiasis: Infection with protozoa of the genus Trypanosoma. [NIH] Trypsin: A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tubulin: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from sperm flagella, cilia, and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to colchicine, vincristine, and vinblastine. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tumor-derived: Taken from an individual's own tumor tissue; may be used in the development of a vaccine that enhances the body's ability to build an immune response to the tumor. [NIH] Tumorigenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH]
Tunica: A rather vague term to denote the lining coat of hollow organs, tubes, or cavities. [NIH]
Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [NIH] Typhimurium: Microbial assay which measures his-his+ reversion by chemicals which cause base substitutions or frameshift mutations in the genome of this organism. [NIH] Tyramine: An indirect sympathomimetic. Tyramine does not directly activate adrenergic receptors, but it can serve as a substrate for adrenergic uptake systems and monoamine oxidase so it prolongs the actions of adrenergic transmitters. It also provokes transmitter release from adrenergic terminals. Tyramine may be a neurotransmitter in some invertebrate nervous systems. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ulcerative colitis: Chronic inflammation of the colon that produces ulcers in its lining. This condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and mucus from the bowel. [NIH]
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Ultrafiltration: The separation of particles from a suspension by passage through a filter with very fine pores. In ultrafiltration the separation is accomplished by convective transport; in dialysis separation relies instead upon differential diffusion. Ultrafiltration occurs naturally and is a laboratory procedure. Artificial ultrafiltration of the blood is referred to as hemofiltration or hemodiafiltration (if combined with hemodialysis). [NIH] Umbilical Arteries: Either of a pair of arteries originating from the internal iliac artery and passing through the umbilical cord to carry blood from the fetus to the placenta. [NIH] Umbilical Cord: The flexible structure, giving passage to the umbilical arteries and vein, which connects the embryo or fetus to the placenta. [NIH] Uncoupling Agents: Chemical agents that uncouple oxidation from phosphorylation in the metabolic cycle so that ATP synthesis does not occur. Included here are those ionophores that disrupt electron transfer by short-circuiting the proton gradient across mitochondrial membranes. [NIH] Universal Precautions: Prudent standard preventive measures to be taken by professional and other health personnel in contact with persons afflicted with a communicable disease, to avoid contracting the disease by contagion or infection. Precautions are especially applicable in the diagnosis and care of AIDS patients. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Ureters: Tubes that carry urine from the kidneys to the bladder. [NIH] Urethane: Antineoplastic agent that is also used as a veterinary anesthetic. It has also been used as an intermediate in organic synthesis. Urethane is suspected to be a carcinogen. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]
Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary Plasminogen Activator: A proteolytic enzyme that converts plasminogen to plasmin where the preferential cleavage is between arginine and valine. It was isolated originally from human urine, but is found in most tissues of most vertebrates. EC 3.4.21.73. [NIH]
Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urinary urgency: Inability to delay urination. [NIH] Urinate: To release urine from the bladder to the outside. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urothelium: The epithelial lining of the urinary tract. [NIH] Urticaria: A vascular reaction of the skin characterized by erythema and wheal formation due to localized increase of vascular permeability. The causative mechanism may be allergy, infection, or stress. [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] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccines: Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi,
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protozoa, or rickettsiae), antigenic proteins derived from them, or synthetic constructs, administered for the prevention, amelioration, or treatment of infectious and other diseases. [NIH]
Vaccinia: The cutaneous and occasional systemic reactions associated with vaccination using smallpox (variola) vaccine. [NIH] Vaccinia Virus: The type species of Orthopoxvirus, related to cowpox virus, but whose true origin is unknown. It has been used as a live vaccine against smallpox. It is also used as a vector for inserting foreign DNA into animals. Rabbitpox virus is a subspecies of vaccinia virus. [NIH] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Valves: Flap-like structures that control the direction of blood flow through the heart. [NIH] Varices: Stretched veins such as those that form in the esophagus from cirrhosis. [NIH] Variola: A generalized virus infection with a vesicular rash. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] Vascular Resistance: An expression of the resistance offered by the systemic arterioles, and to a lesser extent by the capillaries, to the flow of blood. [NIH] Vasoactive: Exerting an effect upon the calibre of blood vessels. [EU] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic 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] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Vena: A vessel conducting blood from the capillary bed to the heart. [NIH] 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] Venter: Belly. [NIH] Ventral: 1. Pertaining to the belly or to any venter. 2. Denoting a position more toward the belly surface than some other object of reference; same as anterior in human anatomy. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH]
300
Heparin
Vertebral: Of or pertaining to a vertebra. [EU] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Vial: A small bottle. [EU] Vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. [NIH] Vinca Alkaloids: A class of alkaloids from the genus of apocyanaceous woody herbs including periwinkles. They are some of the most useful antineoplastic agents. [NIH] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Vinorelbine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Proteins: Proteins found in any species of virus. [NIH] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] Virion: The infective system of a virus, composed of the viral genome, a protein core, and a protein coat called a capsid, which may be naked or enclosed in a lipoprotein envelope called the peplos. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] Visual Acuity: Acuteness or clearness of vision, especially of form vision, which is dependent mainly on the sharpness of the retinal focus. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Void: To urinate, empty the bladder. [NIH]
Dictionary 301
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]
Whooping Cough: A respiratory infection caused by Bordetella pertussis and characterized by paroxysmal coughing ending in a prolonged crowing intake of breath. [NIH] Whooping Cough: A respiratory infection caused by Bordetella pertussis and characterized by paroxysmal coughing ending in a prolonged crowing intake of breath. [NIH] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xanthine: An urinary calculus. [NIH] Xanthine Dehydrogenase: An enzyme that catalyzes the oxidation of xanthine in the presence of NAD+ to form urate and NADH. It acts also on a variety of other purines and aldehydes. EC 1.1.1.204. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] 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]
303
INDEX A Abdominal, 18, 219, 220, 261, 273, 275, 286, 297 Abdominal Pain, 219, 275, 297 Aberrant, 17, 54, 219 Ablate, 219, 233 Ablation, 65, 219 Abortion, 219, 225, 280 Abscess, 219, 288 Acceptor, 183, 219, 264, 273, 292, 296 Acetylcholine, 116, 219, 270, 271 Acetylglucosamine, 183, 219 Acrylonitrile, 219, 287 Actin, 42, 219, 267, 269, 291, 297 Acuity, 219, 227 Acute renal, 188, 219, 255 Acyl, 10, 219 Adaptability, 219, 233, 234 Adaptation, 67, 219 Adenine, 219, 220, 283 Adenocarcinoma, 47, 113, 220 Adenosine, 20, 220, 276 Adenosine Triphosphate, 20, 220, 276 Adenovirus, 153, 173, 174, 220 Adhesions, 99, 220, 291 Adipocytes, 220, 238, 263 Adipose Tissue, 30, 220, 264 Adjustment, 219, 220 Adrenal Cortex, 220, 239, 247, 257, 280 Adrenergic, 220, 242, 247, 293, 297 Adsorption, 41, 101, 156, 167, 178, 220 Adsorptive, 220 Adverse Effect, 17, 220, 289 Afferent, 220, 263 Affinity Chromatography, 64, 156, 173, 178, 180, 220 Agar, 220, 277 Age of Onset, 221, 297 Agonist, 142, 172, 221, 242 Airway, 8, 221 Albumin, 85, 221, 272, 277 Aldehydes, 221, 301 Algorithms, 221, 229 Alimentary, 4, 95, 221, 274 Alkaline, 221, 222, 231, 276 Alkalinization, 42, 221 Alkaloid, 221, 236, 287 Allergens, 8, 221
Allogeneic, 221, 254 Allograft, 11, 221 Allylamine, 221, 222 Alopecia, 79, 221 Alpha 1-Antichymotrypsin, 221, 289 Alpha 1-Antitrypsin, 221, 289 Alpha Particles, 221, 284 Alpha-helices, 53, 222 Alpha-helix, 53, 222, 262 Alternative medicine, 193, 222 Amine, 146, 166, 222, 256 Amino Acid Sequence, 157, 165, 169, 178, 180, 222, 224, 251, 289 Amino Acid Substitution, 65, 222 Ammonia, 222, 293 Amphetamine, 222, 228 Amplification, 29, 66, 222 Amputation, 5, 222 Amyloid, 62, 75, 222 Anaesthesia, 91, 222, 259 Anal, 101, 223, 249, 264 Analgesic, 156, 223, 241 Analog, 52, 56, 152, 175, 223, 250 Analogous, 10, 223, 278, 296 Analytes, 45, 223 Anaphylatoxins, 223, 237 Anastomosis, 107, 223, 251 Anatomical, 223, 227, 238, 287 Anemia, 223, 230 Anemic, 126, 223 Anesthesia, 20, 95, 97, 106, 108, 221, 223, 227, 245 Aneurysm, 57, 223, 225 Angina, 71, 72, 78, 132, 174, 182, 223 Angina Pectoris, 182, 223 Angioedema, 93, 223 Angiogenesis, 9, 21, 24, 28, 33, 40, 116, 223, 245, 266 Angiogenesis inhibitor, 223, 245 Angiotensinogen, 223, 289 Animal model, 10, 25, 30, 39, 57, 223 Anionic, 58, 140, 224 Anions, 45, 221, 224, 261, 292 Annealing, 224, 279 Anode, 224 Anomalies, 154, 224 Antagonism, 122, 123, 224 Antiangiogenic, 9, 37, 224
304
Heparin
Antibacterial, 224, 290 Antibiotic, 145, 177, 224, 274, 290, 294 Antibodies, Anticardiolipin, 224, 225 Antidote, 19, 51, 58, 96, 224, 231 Antigen, 22, 28, 37, 63, 220, 221, 224, 232, 237, 241, 246, 247, 256, 258, 259, 260, 266 Antigen-Antibody Complex, 224, 237 Antigen-presenting cell, 224, 241 Anti-infective, 224, 257 Anti-inflammatory, 10, 16, 42, 145, 166, 225, 226, 241, 252 Anti-Inflammatory Agents, 225, 226 Antimetabolite, 225, 250 Antimicrobial, 69, 71, 108, 177, 225, 241 Antineoplastic, 225, 250, 268, 293, 298, 300 Antioxidant, 25, 186, 225, 250, 273 Antiphospholipid Syndrome, 84, 117, 123, 224, 225 Antiplasmin, 225, 289 Antiproliferative, 20, 27, 49, 59, 70, 225 Antipyretic, 225, 241 Antithrombins, 37, 225 Antithrombotic, 37, 51, 61, 70, 84, 102, 174, 175, 177, 225, 255, 256, 281 Antiviral, 225, 241, 275 Anus, 223, 225, 237, 284 Aorta, 225, 232, 243, 254, 299 Aortic Aneurysm, 18, 225 Aortic Valve, 113, 225 Apheresis, 74, 163, 225 Aplasia, 225, 243 Apolipoproteins, 225, 264 Apoptosis, 8, 42, 91, 126, 225 Applicability, 145, 226 Aqueous, 143, 170, 175, 226, 240, 245, 257 Arachidonic Acid, 226, 281 Arginine, 19, 66, 157, 184, 223, 226, 256, 270, 297, 298 Arterioles, 226, 230, 231, 267, 269, 299 Arteriolosclerosis, 226 Arteriosclerosis, 26, 182, 226, 258 Arteriosus, 226, 283 Arthroplasty, 79, 102, 105, 112, 226 Articular, 93, 226 Aspirin, 89, 106, 112, 129, 226 Assay, 6, 12, 25, 29, 43, 62, 68, 76, 122, 123, 151, 152, 164, 174, 182, 226, 258, 297 Astrocytes, 226, 255 Atherectomy, 175, 227, 245 Atherogenic, 32, 170, 227 Atmospheric Pressure, 227, 257 Atrial, 61, 82, 108, 111, 154, 227
Atrial Fibrillation, 61, 82, 111, 227 Atrium, 154, 227, 232, 268, 299 Attenuated, 67, 227, 298 Audiometry, 4, 227 Autologous, 128, 167, 227, 254 Autologous bone marrow transplantation, 227, 254 Autonomic, 219, 227, 271, 275, 279 Axonal, 162, 227, 279 Axons, 227, 272, 275, 283, 286 B Bacteraemia, 89, 227 Bacterial Infections, 50, 227 Bacterial Physiology, 219, 227 Bactericidal, 165, 166, 227, 247 Bacteriophage, 227, 277, 296 Bacterium, 227, 238, 255 Balloon Dilatation, 176, 227 Basement Membrane, 131, 228, 248, 263 Basophils, 228, 263 Benign, 226, 228, 249, 250, 263, 270 Benign tumor, 228, 263 Beta-pleated, 222, 228 Beta-sheet, 10, 26, 228 Beta-Thromboglobulin, 228, 260 Bile, 29, 155, 228, 252, 264, 291, 292 Bile Acids, 155, 228, 291, 292 Bile Acids and Salts, 228 Biliary, 227, 228, 231 Bilirubin, 221, 228, 252 Binding agent, 167, 228 Binding Sites, 7, 11, 14, 34, 62, 64, 83, 228 Bioassay, 47, 228, 229 Bioavailability, 173, 228 Biogenic Amines, 31, 228 Biological Assay, 12, 228 Biological therapy, 229, 253 Biological Transport, 229, 241 Bioluminescence, 40, 229 Biomarkers, 13, 44, 229 Biopolymers, 27, 31, 229 Biopsy, 21, 74, 95, 229, 275 Biosynthesis, 13, 63, 183, 226, 229, 281, 288 Biotechnology, 60, 67, 128, 173, 193, 203, 229 Bivalent, 73, 229 Bladder, 20, 39, 47, 59, 209, 229, 238, 240, 261, 274, 281, 286, 298, 300 Blastocyst, 229, 238, 244, 273, 277, 296 Bleeding Time, 117, 229 Blood Coagulation, 22, 29, 50, 55, 61, 80, 109, 122, 152, 229, 231, 236, 294, 295
305
Blood Coagulation Factors, 229, 236 Blood Glucose, 229, 252, 255, 260 Blood Platelets, 161, 229, 278, 288, 294 Blood pressure, 23, 229, 232, 258, 268, 271, 283, 290 Blood transfusion, 4, 140, 230 Blood vessel, 4, 5, 23, 32, 57, 58, 141, 147, 154, 163, 175, 189, 223, 224, 229, 230, 232, 233, 234, 235, 238, 245, 248, 254, 255, 262, 263, 265, 266, 275, 289, 290, 291, 295, 299 Blood Viscosity, 75, 230 Blot, 230, 259 Blotting, Western, 230, 259 Body Fluids, 187, 229, 230, 231, 243, 290, 297 Bone Conduction, 227, 230 Bone Marrow, 25, 32, 95, 169, 227, 230, 251, 254, 258, 265, 290, 291 Bone metastases, 26, 47, 230 Bone Morphogenetic Proteins, 144, 230 Bone Resorption, 230, 242 Bone scan, 230, 242 Bowel, 4, 223, 230, 260, 261, 275, 291, 297 Bradykinin, 8, 230, 262, 271, 277 Brain Stem, 230, 234 Bronchi, 230, 247 Bronchial, 16, 227, 230, 256 Bronchiseptica, 230, 275 Buccal, 155, 231, 256, 265 Buccal mucosa, 155, 231 C Cachexia, 30, 231 Calcification, 45, 141, 226, 231, 242 Calcitonin, 168, 169, 231 Calcium, 6, 61, 98, 123, 130, 156, 158, 165, 231, 237, 242, 266, 267, 269, 274, 282, 297 Calcium Chloride, 165, 231, 274 Calculi, 227, 231 Cannula, 140, 231 Canonical, 10, 231 Capillary, 32, 149, 184, 229, 230, 231, 264, 287, 299 Capillary Permeability, 230, 231 Capsid, 16, 231, 300 Capsules, 192, 231, 243, 251 Carbogen, 3, 231 Carbohydrate, 86, 146, 148, 232, 252, 253, 279 Carbon Dioxide, 3, 231, 232, 240, 249, 277, 285, 299 Carcinogen, 13, 232, 298
Carcinogenesis, 13, 126, 232 Carcinogenic, 232, 260, 272, 281, 291, 297 Carcinoma, 47, 85, 87, 101, 232 Cardiac arrest, 131, 232 Cardiac catheterization, 113, 142, 151, 174, 182, 232 Cardiac Output, 23, 232 Cardiolipins, 225, 232 Cardiopulmonary, 65, 81, 83, 91, 97, 106, 108, 110, 126, 130, 140, 150, 232 Cardiopulmonary Bypass, 65, 81, 83, 91, 97, 106, 108, 110, 126, 130, 140, 150, 232 Cardiorespiratory, 68, 232 Cardiovascular disease, 5, 22, 32, 58, 142, 232 Cardiovascular System, 147, 183, 232 Carotene, 232, 286 Carrier Proteins, 232, 277 Case report, 74, 83, 107, 109, 110, 232, 235 Catabolism, 14, 233 Catecholamine, 233, 242 Catheter, 40, 75, 108, 113, 141, 154, 163, 175, 177, 178, 227, 233, 245, 261 Catheter Ablation, 113, 233 Catheterization, 101, 209, 228, 233, 261, 269 Cathode, 224, 233, 244 Cations, 58, 124, 166, 184, 233, 261 Caudal, 233, 279 Causal, 183, 185, 233, 288, 294 Cause of Death, 5, 17, 58, 142, 233, 289 Cell, 6, 7, 8, 9, 11, 13, 14, 15, 16, 21, 23, 24, 26, 27, 29, 30, 31, 32, 33, 34, 35, 41, 43, 46, 47, 48, 49, 51, 52, 54, 55, 57, 59, 60, 62, 64, 67, 74, 79, 83, 85, 90, 94, 122, 123, 127, 128, 131, 144, 149, 155, 159, 169, 172, 173, 174, 182, 185, 186, 188, 219, 221, 223, 224, 225, 226, 227, 229, 230, 232, 233, 234, 235, 237, 238, 240, 243, 244, 245, 246, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 260, 261, 262, 263, 266, 267, 268, 269, 270, 271, 272, 273, 276, 277, 278, 280, 281, 284, 285, 286, 287, 288, 291, 292, 293, 294, 296, 297, 299, 300, 301 Cell Adhesion, 34, 35, 94, 131, 144, 149, 233, 260 Cell Adhesion Molecules, 149, 233 Cell Communication, 59, 233 Cell Cycle, 6, 30, 48, 233, 240 Cell Death, 225, 233, 234, 270 Cell Differentiation, 233, 291
306
Heparin
Cell Division, 31, 227, 233, 234, 253, 266, 267, 268, 277, 281, 288 Cell membrane, 186, 229, 232, 233, 251, 276, 291 Cell motility, 234, 255 Cell Physiology, 59, 234 Cell proliferation, 9, 14, 24, 27, 33, 48, 49, 57, 59, 62, 64, 155, 159, 185, 226, 234 Cell Survival, 122, 234, 253 Cell Transplantation, 234, 254 Cellular adhesion, 85, 234 Centrifugation, 16, 234 Cerebellar, 14, 234 Cerebellum, 14, 234 Cerebral, 74, 85, 111, 131, 160, 230, 234, 247, 283 Cerebral Cortex, 234, 283 Cerebrovascular, 142, 182, 232, 234 Cerebrum, 234 Character, 223, 234 Chemokines, 6, 24, 234, 284 Chemotactic Factors, 234, 237 Chemotaxis, 6, 234 Chemotherapy, 13, 178, 234 Chimera, 21, 234 Chimeric Proteins, 52, 234 Chlorine, 179, 234 Cholera, 235, 288 Cholesterol, 53, 56, 133, 170, 228, 235, 239, 243, 257, 264, 265, 266, 291 Cholesterol Esters, 235, 264 Chondrocytes, 235, 249 Chondroitin sulfate, 50, 64, 75, 119, 127, 235 Choroid, 235, 239, 286 Chromatin, 226, 235 Chromosomal, 222, 235, 256, 277 Chromosome, 174, 235, 238, 264, 267, 288 Chronic Disease, 231, 235, 236 Chylomicrons, 169, 235, 264 Chymotrypsin, 64, 221, 235 Circulatory system, 141, 235 Cirrhosis, 71, 235, 299 CIS, 235, 286 C-kit receptor, 235, 291 Clamp, 21, 235 Clinical Medicine, 235, 280 Clinical study, 235, 239 Clinical trial, 5, 10, 19, 25, 42, 105, 110, 203, 235, 236, 243, 282, 284 Clone, 7, 236 Cloning, 183, 229, 236
Clot Retraction, 236, 277 Coagulants, 55, 236 Codon, 60, 236, 251 Coenzymes, 236, 270 Cofactor, 22, 26, 31, 38, 64, 65, 88, 98, 114, 116, 130, 131, 142, 146, 236, 282, 289, 294, 295 Colchicine, 236, 297 Colectomy, 4, 236 Colitis, 236 Collagen disease, 236, 257 Collapse, 68, 147, 236 Colloidal, 24, 221, 236, 244, 276 Colon, 4, 87, 236, 237, 260, 263, 297 Colonic Neoplasms, 72, 237 Combinatorial, 13, 237 Communicable disease, 237, 298 Complement, 26, 52, 55, 62, 78, 80, 94, 98, 124, 223, 237, 251, 260, 277, 289 Complement 1, 237, 289 Complement 1 Inactivators, 237, 289 Complement Activation, 52, 98, 223, 237 Complementary and alternative medicine, 121, 135, 237 Complementary medicine, 121, 237 Compliance, 23, 57, 143, 238 Computational Biology, 203, 238 Conception, 219, 238, 249, 280 Concomitant, 145, 146, 238 Conduction, 162, 227, 233, 238 Cones, 238, 286 Congestive heart failure, 182, 238 Conjugated, 123, 145, 228, 238, 249, 271 Conjugation, 146, 155, 238, 292 Connective Tissue Cells, 238 Connective Tissue Diseases, 225, 238 Consciousness, 223, 238, 242, 286 Constipation, 238, 275 Constriction, 175, 238, 262, 299 Constriction, Pathologic, 238, 299 Contamination, 16, 146, 238 Continuous infusion, 189, 238 Contraindications, ii, 239 Controlled clinical trial, 122, 239 Conus, 239, 283 Convulsion, 229, 239 Coordination, 41, 234, 239 Cornea, 38, 239, 253, 287, 291 Corneal Diseases, 39, 239 Corneum, 173, 239, 247 Coronary Arteriosclerosis, 239, 269 Coronary Circulation, 223, 239
307
Coronary heart disease, 169, 232, 239 Coronary Thrombosis, 239, 267, 269 Corpus, 184, 239, 265, 280, 288, 300 Corpus Luteum, 184, 239, 265, 280 Cortex, 116, 239, 256 Cortical, 239, 247, 283 Cortisol, 56, 221, 239 Coumarin, 152, 239 Cowpox, 239, 299 Cowpox Virus, 239, 299 Cranial, 234, 239, 272, 275 Criterion, 20, 240 Critical Care, 70, 85, 107, 110, 113, 240 Crossing-over, 240, 284 Curative, 240, 270, 294 Cutaneous, 12, 123, 240, 265, 299 Cyclic, 132, 233, 240, 253, 271, 279, 287 Cyclin, 27, 240 Cysteine, 186, 234, 240, 245, 284, 292 Cystine, 240 Cystitis, 20, 39, 59, 70, 208, 240 Cytokine, 8, 15, 16, 22, 25, 48, 99, 149, 185, 240, 260 Cytomegalovirus, 62, 240 Cytoplasm, 226, 228, 233, 240, 246, 293 Cytoprotection, 25, 240 Cytoskeleton, 7, 240, 260 D Dalteparin, 95, 105, 117, 240 De novo, 181, 185, 240 Decarboxylation, 228, 240, 256 Decidua, 16, 240, 277 Deletion, 21, 226, 240 Delivery of Health Care, 240, 254 Denaturation, 240, 279 Dendrites, 240, 241, 270, 283 Dendritic, 28, 78, 241, 266, 286 Dendritic cell, 28, 241 Density, 14, 53, 56, 67, 92, 170, 171, 172, 234, 241, 243, 264, 272, 278, 290 Depressive Disorder, 241, 264 Deprivation, 85, 241 Dermis, 172, 223, 241, 293, 296 Detergents, 166, 241 Deuterium, 241, 257 Dextran Sulfate, 65, 156, 178, 241 Diagnostic procedure, 29, 139, 193, 241 Dialysate, 187, 241 Dialyzer, 163, 187, 241, 254 Diamide, 11, 241 Diamines, 31, 241 Diarrhea, 241, 276
Diastolic, 241, 258 Diclofenac, 156, 241 Diclofenac Sodium, 241 Dietary Fats, 241, 264 Diethylcarbamazine, 241, 293 Diffusion, 144, 163, 229, 231, 241, 254, 298 Digestion, 221, 228, 230, 241, 261, 264, 291, 299 Dilation, 227, 230, 242 Dimerization, 24, 66, 242 Dimethyl, 27, 242 Diphosphonates, 166, 242 Direct, iii, 13, 14, 52, 69, 70, 79, 88, 106, 112, 123, 149, 195, 233, 235, 242, 265, 285, 293 Disaccharides, 24, 56, 242 Discrete, 100, 242 Discrimination, 122, 242 Disinfectant, 242, 247 Dissociation, 34, 144, 145, 220, 242 Dissociative Disorders, 242 Distal, 154, 227, 233, 242, 244, 279 Diuretic, 231, 242 Domesticated, 242, 254 Dopamine, 172, 222, 242, 270, 276 Dorsal, 242, 279 Dosage Forms, 155, 185, 242 Dose-limiting, 142, 243 Double-blind, 122, 243 Drive, ii, vi, 22, 30, 51, 60, 115, 243 Drug Delivery Systems, 40, 243 Drug Interactions, 142, 196, 243 Drug Tolerance, 243, 295 Duct, 175, 231, 233, 243, 247, 287, 291, 293 Ductus Arteriosus, 154, 243 Duodenum, 228, 235, 243, 262, 273, 291 Dyes, 222, 228, 243, 292 Dyslipidemia, 23, 243 Dyspareunia, 243, 247 Dystrophy, 185, 243 E Ectromelia, 52, 243 Ectromelia Virus, 53, 243 Edema, 160, 223, 237, 243, 255, 269, 280 Effector, 8, 219, 237, 243 Effector cell, 243 Efficacy, 8, 11, 19, 20, 40, 51, 63, 76, 81, 96, 103, 106, 108, 137, 168, 174, 192, 244 Elastic, 244, 290, 293 Elasticity, 34, 226, 239, 244 Elastin, 126, 236, 238, 244, 248 Elastomers, 244, 279
308
Heparin
Elective, 97, 102, 105, 244 Electrode, 45, 224, 233, 244 Electrolysis, 224, 233, 244 Electrolyte, 244, 255, 262, 280, 290 Electrons, 225, 233, 244, 261, 273, 284 Electrophoresis, 32, 157, 179, 244 Electrophysiological, 162, 244 Ellagic Acid, 244, 274 Embolus, 244, 259 Embryo, 16, 49, 219, 229, 233, 244, 259, 267, 278, 280, 290, 298 Embryo Transfer, 244, 280 Embryogenesis, 244, 291 Emergency Treatment, 74, 245 Emollient, 245, 252, 271 Emulsion, 170, 245, 249 Encapsulated, 145, 147, 245 Endarterectomy, 227, 245 Endocarditis, 113, 245 Endocardium, 245 Endocytosis, 6, 56, 245 Endogenous, 12, 21, 28, 29, 47, 56, 82, 172, 225, 229, 236, 242, 245, 252, 273 Endometrium, 240, 245, 296 Endopeptidases, 245, 281, 288 Endostatin, 9, 245 Endothelial cell, 8, 15, 21, 22, 24, 25, 32, 40, 41, 43, 57, 61, 64, 65, 67, 81, 100, 105, 144, 176, 182, 184, 245, 249, 255, 260, 294 Endothelins, 122, 245 Endothelium, 23, 148, 245, 246, 270, 278 Endothelium, Lymphatic, 245, 246 Endothelium, Vascular, 245, 246 Endothelium-derived, 246, 270 Endotoxic, 166, 246, 264 Endotoxins, 237, 246 Energy balance, 246, 263 Enhancers, 178, 246 Enoxaparin, 62, 68, 69, 70, 77, 81, 82, 102, 104, 106, 110, 174, 179, 191, 192, 246 Enterocytes, 55, 246 Enteropeptidase, 246, 297 Environmental Health, 202, 204, 246 Enzymatic, 28, 33, 39, 174, 185, 222, 228, 231, 232, 237, 246, 249, 256, 266, 279, 286 Enzyme Inhibitors, 246, 277 Enzyme-Linked Immunosorbent Assay, 79, 246 Eosinophil, 17, 246 Eosinophilic, 246
Epidermal, 12, 15, 20, 38, 47, 59, 70, 86, 92, 100, 103, 104, 110, 113, 127, 144, 246, 247, 262, 266 Epidermal Growth Factor, 12, 15, 20, 38, 47, 59, 70, 92, 100, 103, 104, 110, 113, 144, 247 Epidermis, 239, 241, 246, 247, 262, 280, 283 Epigastric, 247, 273 Epinephrine, 220, 228, 242, 247, 270, 271, 297 Epithelial, 8, 16, 25, 26, 38, 55, 59, 113, 127, 148, 220, 229, 240, 247, 253, 255, 263, 298 Epithelial Cells, 8, 16, 25, 39, 59, 113, 247, 255, 263 Epithelium, 8, 39, 40, 46, 47, 59, 228, 245, 246, 247, 251, 261 Epitopes, 55, 247 Erythema, 247, 298 Erythrocytes, 223, 230, 247, 255, 285 Estradiol, 21, 141, 247 Estrogen, 21, 247, 281 Estrogen receptor, 21, 247 Estrogen Replacement Therapy, 21, 247 Ethanol, 168, 169, 247 Ether, 140, 247 Excitatory, 18, 247, 252 Excrete, 247, 262 Exhaustion, 224, 247 Exocrine, 247, 273 Exogenous, 8, 12, 21, 28, 56, 180, 220, 236, 245, 247, 252, 292, 297 Extracellular Matrix, 16, 26, 32, 34, 41, 46, 64, 123, 131, 176, 185, 238, 248, 249, 260, 266, 272 Extracellular Matrix Proteins, 123, 185, 248, 266 Extracellular Space, 248 Extracorporeal, 94, 98, 103, 108, 110, 130, 140, 151, 175, 176, 182, 189, 248, 255 Extracorporeal Circulation, 103, 130, 176, 248 Extracorporeal Membrane Oxygenation, 151, 182, 248 Extraction, 29, 172, 248 Extrapyramidal, 242, 248 Extravascular, 22, 248 Extremity, 5, 248 Exudate, 164, 248 Eye Infections, 220, 248 F Family Planning, 203, 248
309
Fat, 21, 30, 57, 220, 226, 228, 230, 232, 239, 244, 248, 263, 264, 286, 290, 293, 296 Fatigue, 248, 254 Feces, 29, 238, 248, 291 Femoral, 154, 232, 248, 279 Femoral Artery, 232, 248 Femoral Vein, 154, 248, 279 Femur, 248, 249 Fertilization in Vitro, 249, 280 Fetal Blood, 243, 249 Fetus, 219, 249, 277, 280, 290, 291, 298 Fibrinogen, 32, 43, 55, 74, 249, 274, 277, 282, 294 Fibrinolysis, 33, 46, 80, 109, 117, 122, 249 Fibrinolytic, 43, 55, 82, 142, 237, 249 Fibrinolytic Agents, 82, 249 Fibroblast Growth Factor, 4, 12, 20, 25, 47, 52, 64, 66, 67, 79, 105, 124, 144, 184, 188, 249 Fibroblasts, 57, 83, 126, 238, 249, 260 Fibroid, 249, 263 Fibronectin, 34, 42, 85, 93, 108, 128, 129, 131, 249 Fibrosis, 16, 185, 221, 249, 255, 287 Fixation, 154, 249 Fluorescein-5-isothiocyanate, 69, 249 Fluorescence, 17, 26, 33, 34, 53, 250 Fluorocarbons, 166, 250 Fluorouracil, 122, 250 Foam Cells, 32, 169, 250 Fold, 18, 26, 158, 250 Foramen, 154, 250, 275 Forearm, 230, 250 Fossa, 234, 250 Fovea, 249, 250 Fractionation, 63, 85, 177, 250 Frameshift, 250, 297 Frameshift Mutation, 250, 297 Free Radicals, 225, 242, 250, 269 Fungi, 229, 238, 248, 250, 267, 298, 301 G Gadolinium, 40, 250 Gallate, 128, 250 Ganglia, 219, 250, 270 Ganglion, 250, 286 Gangrene, 112, 113, 251 Gangrenous, 251, 288 Gap Junctions, 251, 293 Gas, 222, 232, 234, 241, 251, 257, 270, 271, 285, 299 Gastric, 89, 110, 227, 242, 247, 251, 256 Gastric Bypass, 89, 251
Gastric Mucosa, 110, 251 Gastrin, 86, 251, 256 Gastrointestinal, 86, 155, 189, 230, 247, 249, 251, 263, 274, 288, 291, 292, 297 Gastrointestinal tract, 155, 189, 247, 249, 251, 263, 274, 288, 291, 297 Gelatin, 251, 252, 294 Gene Expression, 9, 127, 185, 251 Gene Therapy, 46, 153, 220, 251 Genetic Code, 251, 271 Genetic Engineering, 229, 236, 251 Genetic Markers, 50, 252 Genetic testing, 252, 279 Genetics, 9, 238, 252 Genotype, 44, 252, 276 Germ Cells, 252, 266, 273, 290, 294 Gestation, 252, 277, 280, 290 Gland, 184, 220, 252, 256, 265, 266, 273, 277, 281, 287, 288, 291, 292, 293, 295 Glioma, 75, 252 Glomerular, 252, 262, 285 Glottis, 252, 275 Glucocorticoid, 31, 252, 257 Glucose, 21, 23, 30, 146, 186, 229, 241, 252, 253, 255, 260, 287 Glucose Clamp Technique, 21, 252 Glucuronic Acid, 155, 157, 172, 183, 252, 258 Glucuronides, 252 Glutamate, 18, 63, 252 Glycerol, 143, 232, 252, 276 Glycerophospholipids, 252, 276 Glycine, 222, 228, 252, 270, 288 Glycosaminoglycan, 22, 33, 35, 36, 87, 146, 149, 152, 171, 172, 183, 235, 253 Glycoside, 242, 253, 287 Glycosidic, 253, 272 Glycosylation, 31, 253 Goblet Cells, 246, 253 Gonadal, 253, 291 Governing Board, 253, 280 Gp120, 253, 275 Grade, 52, 173, 253 Graft, 5, 11, 18, 57, 65, 88, 98, 140, 143, 253, 269 Graft Survival, 11, 253 Grafting, 18, 73, 81, 253, 259 Gram-negative, 56, 166, 230, 246, 253 Gram-Negative Bacteria, 56, 246, 253 Gram-positive, 56, 253 Gram-Positive Bacteria, 56, 253 Granule, 14, 253
310
Heparin
Guanine, 129, 253, 283 Guanylate Cyclase, 253, 271 Guinea Pigs, 27, 63, 254 H Haematoma, 254 Haemodialysis, 92, 94, 102, 254 Haemorrhage, 74, 95, 219, 254 Haemostasis, 13, 70, 79, 80, 82, 84, 101, 102, 109, 121, 122, 125, 127, 130, 179, 254 Hair follicles, 241, 254 Half-Life, 145, 254, 255 Haptens, 220, 254 Health Care Costs, 144, 254 Health Expenditures, 254 Heart attack, 49, 232, 254 Heart failure, 183, 254 Heart Valves, 69, 70, 227, 254 Hematopoietic Stem Cell Transplantation, 95, 254 Hemodiafiltration, 254, 298 Hemodynamics, 23, 57, 255 Hemofiltration, 178, 254, 255, 298 Hemoglobin, 223, 247, 255, 279 Hemoglobin C, 223, 255 Hemoglobinopathies, 251, 255 Hemolytic, 65, 100, 255, 294 Hemorrhage, 58, 72, 142, 189, 255, 269, 283, 291 Hemorrhaging, 182, 255 Hemostasis, 22, 27, 29, 32, 33, 36, 43, 75, 90, 92, 142, 161, 255, 260, 288, 294 Heparan Sulfate Proteoglycan, 14, 26, 33, 35, 46, 51, 52, 255 Hepatic, 56, 63, 95, 107, 131, 169, 221, 255 Hepatic Veins, 255 Hepatic Veno-Occlusive Disease, 95, 255 Hepatocyte, 56, 145, 255 Hepatocyte Growth Factor, 145, 255 Hepatoma, 91, 256 Hereditary, 93, 221, 237, 238, 256 Heredity, 251, 252, 256 Herpes, 54, 62, 94, 174, 185, 186, 256 Herpes virus, 174, 186, 256 Herpes Zoster, 256 Heterodimer, 230, 256 Heterogeneity, 27, 127, 220, 256 Hippocampus, 256, 283 Hirudin, 26, 75, 90, 97, 108, 127, 256 Histamine, 63, 100, 223, 228, 256, 258 Histidine, 65, 90, 184, 256 Histones, 126, 235, 256 Homeostasis, 15, 48, 56, 256
Homodimer, 185, 256 Homogeneous, 45, 226, 256, 276 Homologous, 48, 53, 229, 240, 251, 256, 269, 288, 293 Hormonal, 229, 247, 256 Hormone, 16, 56, 172, 228, 231, 239, 247, 251, 256, 260, 263, 280, 281, 286, 287, 295 Horseradish Peroxidase, 246, 256 Hyaluronidase, 156, 256 Hybrid, 54, 236, 257 Hybridomas, 257, 260 Hydrocortisone, 116, 145, 257 Hydrogel, 12, 41, 156, 257 Hydrogen, 31, 168, 219, 222, 232, 240, 241, 248, 250, 257, 264, 268, 270, 271, 273, 282, 292 Hydrogen Bonding, 257, 271 Hydrogen Peroxide, 31, 257, 264, 292 Hydrolysis, 257, 279, 282, 297 Hydrophobic, 41, 153, 155, 156, 165, 170, 178, 241, 252, 257, 264 Hydroxylysine, 236, 257 Hydroxyproline, 222, 236, 257 Hyperbaric, 125, 257 Hyperbaric oxygen, 125, 257 Hypercholesterolemia, 243, 257 Hyperlipidemia, 243, 257 Hyperlipoproteinemia, 66, 257, 258, 264 Hyperplasia, 5, 176, 257 Hyperreflexia, 258, 294 Hypersensitivity, 221, 246, 258, 286 Hypersensitivity, Immediate, 221, 258 Hypertension, 23, 27, 142, 182, 226, 232, 258, 280 Hypertriglyceridemia, 169, 243, 258 Hypertrophy, 49, 182, 257, 258 Hypothermia, 110, 127, 258, 286 Hypoxia, 27, 223, 258 Hypoxic, 27, 258 I Idiopathic, 3, 128, 258 Iduronic Acid, 183, 258 Iliac Vein, 248, 258 Imaging procedures, 258, 296 Immersion, 140, 258 Immune function, 32, 258 Immune response, 6, 8, 15, 37, 43, 49, 57, 186, 224, 254, 258, 259, 289, 292, 297, 298, 300 Immune Sera, 258 Immune system, 224, 229, 244, 258, 259, 265, 276, 301
311
Immunization, 37, 208, 258 Immunoassay, 45, 224, 246, 258 Immunoblotting, 24, 258 Immunocompromised, 44, 259 Immunocompromised Host, 44, 259 Immunodeficiency, 51, 65, 259 Immunogenic, 28, 259, 264 Immunoglobulin, 130, 224, 259, 268 Immunologic, 221, 234, 258, 259 Immunology, 6, 9, 92, 93, 107, 128, 162, 220, 256, 259 Immunosuppressant, 250, 259 Immunosuppressive, 8, 252, 259 Implantation, 5, 31, 57, 76, 89, 143, 147, 167, 171, 238, 259, 273 In situ, 151, 175, 182, 259 Incision, 236, 259, 261, 281, 286 Incubation, 259, 275 Incubation period, 259, 275 Induction, 8, 24, 64, 91, 93, 259, 281, 284 Infarction, 42, 72, 133, 182, 259, 285 Infection Control, 188, 259 Inflammatory bowel disease, 4, 260 Infusion, 3, 4, 10, 21, 23, 76, 93, 189, 252, 260, 269, 296 Inhalation, 3, 260, 278 Initiation, 65, 76, 97, 167, 185, 260 Initiator, 174, 229, 260 Innervation, 260, 272 Inotropic, 242, 260 Inpatients, 3, 106, 111, 117, 260 Insight, 8, 9, 10, 14, 17, 22, 29, 35, 260 Instillation, 209, 260 Insulin, 21, 23, 157, 229, 252, 260, 262, 297 Insulin-dependent diabetes mellitus, 260 Integrins, 9, 85, 122, 260 Interleukin-6, 30, 260 Interleukin-8, 144, 260 Intermediate Filaments, 260, 291 Intermittent, 104, 105, 189, 261, 275 Interstitial, 20, 33, 39, 59, 70, 208, 248, 261, 262, 285 Intestinal, 4, 25, 55, 160, 177, 232, 246, 261 Intestine, 4, 25, 149, 172, 228, 230, 261, 263 Intracellular, 6, 30, 39, 149, 259, 260, 261, 266, 271, 280, 287 Intramuscular, 261, 274 Intraocular, 72, 175, 261 Intraperitoneal, 93, 99, 261 Intravascular, 22, 24, 30, 50, 117, 175, 261 Intravenous, 3, 19, 71, 80, 81, 84, 93, 96, 107, 111, 132, 155, 260, 261, 274
Intravesical, 39, 261 Intrinsic, 34, 152, 158, 165, 220, 228, 261, 274 Intubation, 233, 261 Invasive, 18, 49, 56, 82, 88, 106, 110, 128, 175, 186, 261, 265 Involuntary, 239, 261, 269, 289, 290 Ion Channels, 227, 261, 293 Ion Exchange, 173, 261 Ionophores, 45, 261, 298 Ions, 114, 158, 237, 242, 244, 257, 261, 282 Iris, 226, 239, 261, 283 Irradiation, 261, 285 Ischemia, 20, 25, 71, 100, 181, 182, 262, 269, 285 Ischemic stroke, 61, 85, 262 Islet, 10, 262 Isozymes, 31, 262 J Jejunum, 251, 262 K Kallidin, 230, 262 Kb, 169, 202, 262 Keratin, 262 Keratinocytes, 6, 78, 104, 260, 262 Kidney Failure, 163, 262 Kidney Failure, Acute, 262 Kidney Failure, Chronic, 262 Kinetic, 17, 18, 31, 34, 37, 38, 55, 94, 263 L Labile, 237, 263 Laceration, 263, 294 Lactation, 90, 263, 281 Laminin, 94, 123, 128, 228, 248, 263 Large Intestine, 261, 263, 284, 285, 289 Latency, 185, 186, 263 Latent, 174, 185, 263 Lectins, 151, 263 Leiomyoma, 88, 249, 263 Length of Stay, 111, 263 Lenses, 175, 263, 285 Lepirudin, 80, 94, 97, 98, 110, 197, 263 Leptin, 93, 263 Lesion, 49, 189, 263, 264, 289, 297 Lethal, 227, 263 Leucocyte, 246, 263 Leukapheresis, 225, 263 Leukemia, 54, 251, 263 Leukocytes, 22, 25, 62, 69, 148, 228, 230, 234, 263, 297 Life cycle, 6, 51, 177, 186, 250, 263 Ligament, 263, 281
312
Heparin
Ligands, 7, 24, 33, 42, 47, 52, 55, 184, 233, 260, 264 Linkage, 57, 252, 264 Lipaemia, 83, 264 Lipase, 56, 264 Lipid, 21, 30, 32, 53, 56, 130, 131, 166, 169, 225, 226, 231, 250, 252, 260, 261, 264, 273, 296 Lipid A, 56, 166, 264 Lipid Peroxidation, 264, 273 Lipophilic, 45, 264 Lipopolysaccharide, 128, 129, 253, 264 Lipoprotein Lipase, 32, 62, 63, 64, 83, 85, 86, 99, 104, 169, 264 Lithium, 125, 264 Liver Transplantation, 107, 264 Localization, 21, 22, 40, 59, 94, 264 Localized, 18, 19, 153, 172, 175, 219, 223, 245, 249, 254, 259, 263, 264, 277, 294, 297, 298 Longitudinal study, 68, 264 Loop, 10, 26, 36, 38, 130, 251, 264 Low-density lipoprotein, 74, 108, 243, 264, 265 Lucida, 263, 265 Luciferase, 40, 265 Lupus, 83, 84, 122, 224, 225, 265, 293 Lutein Cells, 265, 281 Lymph, 48, 235, 245, 246, 265, 292 Lymph node, 48, 265 Lymphatic, 246, 259, 265, 267, 290, 295 Lymphatic system, 265, 290, 295 Lymphocyte, 100, 224, 265, 266 Lymphoid, 148, 224, 263, 265 Lysine, 53, 158, 184, 186, 255, 256, 257, 265, 297 Lytic, 9, 265, 288 M Macrophage, 169, 265 Magnetic Resonance Imaging, 40, 265 Malignancy, 95, 106, 265 Malignant, 46, 47, 220, 225, 226, 265, 270, 287 Malnutrition, 221, 231, 266 Mammary, 83, 264, 266 Mammogram, 231, 266, 267 Manic, 264, 266 Manifest, 22, 227, 266 Mastitis, 132, 266, 288 Matrix metalloproteinase, 93, 129, 131, 266 Medial, 226, 266
Mediate, 9, 18, 20, 54, 99, 148, 233, 242, 266, 284 Mediator, 50, 266, 278, 288 Medicament, 160, 184, 266 MEDLINE, 203, 266 Meiosis, 229, 266, 269, 293 Melanin, 261, 266, 276, 297 Melanocytes, 266 Melanoma, 82, 266 Membrane, 15, 35, 45, 51, 54, 56, 101, 102, 122, 158, 163, 186, 226, 233, 235, 237, 241, 245, 248, 253, 254, 261, 263, 266, 269, 272, 276, 282, 286, 288, 293, 296, 300 Membrane Lipids, 266, 276 Menstruation, 133, 240, 266 Mental, iv, 4, 202, 204, 234, 242, 248, 266, 282, 298 Mental Health, iv, 4, 202, 204, 266, 282 Mental Processes, 242, 266, 282 Mesenchymal, 247, 266 Mesoderm, 267, 296 Meta-Analysis, 61, 96, 102, 267 Metabolite, 242, 267 Metalloporphyrins, 45, 267 Metaphase, 229, 267 Metastasis, 46, 47, 52, 82, 101, 148, 233, 266, 267 Metastatic, 26, 267, 288 Methionine, 242, 267, 292 MI, 42, 65, 89, 157, 172, 192, 217, 267 Mice Minute Virus, 267, 274 Microbe, 267, 295 Microbiology, 9, 54, 108, 177, 219, 267 Microcalcifications, 231, 267 Microcirculation, 267, 278 Microfilaments, 260, 267, 291 Micromanipulation, 41, 267 Micromanipulators, 267 Microorganism, 236, 267, 300 Microspheres, 12, 116, 124, 267 Micturition, 40, 268 Migration, 23, 33, 34, 35, 39, 42, 48, 105, 268, 284 Miscarriage, 107, 133, 268 Miscible, 143, 268, 276 Mitochondrial Swelling, 268, 270 Mitosis, 226, 263, 268 Mitotic, 14, 268, 300 Mitoxantrone, 159, 268 Mitral Valve, 83, 268 Mobility, 26, 268 Modeling, 5, 9, 17, 44, 268
313
Modification, 45, 146, 149, 167, 222, 251, 268, 283 Molecular mass, 110, 268 Monitor, 15, 23, 39, 53, 86, 151, 152, 165, 174, 181, 182, 268, 271, 274 Monoclonal, 32, 37, 43, 56, 156, 162, 178, 257, 258, 262, 268, 284 Monoclonal antibodies, 32, 43, 56, 259, 268 Monocyte, 15, 32, 91, 129, 169, 268 Mononuclear, 22, 268, 297 Morphological, 10, 244, 266, 268 Morphology, 163, 268 Motility, 85, 88, 113, 268, 288 Mucins, 246, 253, 269 Mucosa, 4, 189, 246, 251, 265, 269, 281, 292 Mucus, 269, 297 Multivalent, 24, 269 Muscular Dystrophies, 243, 269 Mutagenesis, 9, 15, 21, 22, 26, 37, 50, 64, 100, 269 Mutagens, 250, 269 Myeloma, 56, 269 Myocardial infarction, 5, 42, 55, 72, 76, 77, 78, 102, 169, 174, 182, 228, 239, 267, 269 Myocardial Ischemia, 182, 223, 269 Myocardial Reperfusion, 269, 285 Myocardial Reperfusion Injury, 269, 285 Myocardium, 42, 60, 223, 267, 269 Myosin, 269, 291, 297 N Nausea, 133, 243, 269, 298 Necrosis, 42, 113, 149, 226, 259, 267, 269, 270, 285, 288 Neoplasm, 270, 287 Neoplastic, 257, 270 Nephrology, 77, 87, 92, 101, 102, 108, 131, 188, 270 Nephropathy, 185, 270 Nerve, 123, 145, 162, 220, 223, 227, 240, 250, 260, 266, 270, 272, 279, 280, 286, 287, 291, 296 Nervous System, 60, 219, 220, 222, 250, 266, 270, 272, 288, 292, 293, 297 Neural, 15, 220, 222, 270 Neuromuscular, 219, 270, 272 Neuromuscular Junction, 219, 270, 272 Neuronal, 60, 100, 270, 275 Neurons, 18, 60, 240, 247, 250, 270, 283, 293 Neuropathy, 162, 270 Neurotoxic, 270, 294
Neurotransmitter, 219, 220, 222, 230, 233, 242, 252, 253, 256, 261, 270, 271, 287, 292, 293, 297 Neutralization, 19, 53, 157, 166, 270 Neutrons, 221, 261, 270, 284 Neutrophil, 42, 49, 61, 81, 125, 221, 270 Niacin, 99, 270, 297 Nitric Oxide, 15, 25, 127, 129, 270 Nitrogen, 221, 222, 248, 249, 250, 262, 267, 268, 271, 297 Nocturia, 39, 271 Norepinephrine, 220, 242, 270, 271 Normotensive, 23, 271 Nosocomial, 178, 271 Nuclear, 66, 238, 244, 250, 270, 271, 284, 286 Nuclear Proteins, 66, 271 Nuclei, 48, 222, 238, 244, 251, 252, 256, 265, 268, 270, 271, 272, 282 Nucleic acid, 31, 67, 153, 231, 251, 269, 271, 283 Nucleic Acid Hybridization, 67, 271 Nucleoproteins, 271 Nucleus, 226, 228, 235, 240, 241, 261, 266, 268, 270, 271, 281, 282, 291 O Ocular, 271, 272 Ointments, 243, 271 Oligo, 150, 271 Oligopeptides, 41, 271 Oligosaccharides, 24, 28, 41, 83, 188, 271 Oliguria, 262, 272 Oncogene, 255, 272, 291 Oncogenic, 260, 272 Opacity, 241, 272 Ophthalmic, 272, 279 Ophthalmology, 122, 249, 272 Ophthalmoplegia, 162, 272 Opsin, 272, 286 Optic Nerve, 272, 286, 287 Organelles, 234, 240, 266, 272 Orthopaedic, 102, 145, 272 Osmosis, 272 Osmotic, 103, 116, 221, 268, 272 Osteoblasts, 46, 47, 272 Osteoclasts, 231, 272 Osteoporosis, 247, 272 Outpatient, 77, 103, 272 Ovalbumin, 272, 289 Ovarian Follicle, 239, 273 Ovary, 169, 239, 247, 273, 278, 292 Overexpress, 41, 52, 273
314
Heparin
Ovum, 239, 240, 252, 263, 273, 280, 281, 296, 301 Ovum Implantation, 273, 296 Oxidants, 23, 273 Oxidation, 31, 150, 219, 225, 240, 264, 273, 298, 301 Oxidation-Reduction, 273 Oxidative Stress, 23, 186, 273 Oxygenation, 94, 273 Oxygenator, 140, 232, 248, 273 P Pacemaker, 166, 273 Palliative, 273, 294 Pancreas, 168, 219, 229, 235, 260, 262, 264, 273, 297 Pancreatic, 52, 235, 273 Pancreatic cancer, 52, 273 Pancreatic Juice, 235, 273 Parenteral, 178, 274 Parenteral Nutrition, 178, 274 Paroxysmal, 223, 274, 275, 301 Partial remission, 274, 285 Partial Thromboplastin Time, 89, 106, 151, 152, 174, 182, 274 Particle, 16, 41, 274, 290, 296 Parturition, 274, 281 Parvovirus, 174, 267, 274 Patch, 18, 71, 239, 274, 296 Pathogenesis, 4, 7, 9, 28, 29, 43, 49, 51, 53, 59, 90, 99, 274 Pathologic, 148, 226, 229, 239, 258, 274 Pathologic Processes, 226, 274 Pathologies, 32, 48, 148, 274 Pathophysiology, 20, 22, 49, 80, 101, 103, 274 Patient Compliance, 169, 274 Patient Education, 208, 212, 214, 217, 274 Pelvic, 20, 39, 70, 274, 281 Pelvis, 274, 298 Penicillin, 224, 274 Pentosan polysulfate, 40, 274 Peptide T, 59, 275 Percutaneous, 19, 69, 72, 73, 75, 76, 95, 101, 102, 110, 124, 141, 151, 174, 175, 182, 275 Perforation, 250, 275 Perfusion, 74, 75, 83, 252, 258, 275 Pericarditis, 189, 275 Perioperative, 77, 275 Peripheral blood, 57, 254, 275 Peripheral Nerves, 162, 275, 279 Peritoneal, 93, 178, 188, 241, 261, 275
Peritoneal Cavity, 261, 275 Peritoneal Dialysis, 93, 178, 188, 241, 275 Peritoneum, 275 Peritonitis, 100, 275 Peroxide, 31, 275 Pertussis, 63, 275, 301 Petechiae, 254, 276 Petrolatum, 245, 276 Phagocyte, 273, 276 Phallic, 249, 276 Pharmaceutical Preparations, 156, 178, 247, 251, 276 Pharmaceutical Solutions, 243, 276 Pharmacodynamics, 129, 276 Pharmacokinetic, 44, 58, 60, 276 Pharmacologic, 35, 43, 44, 46, 57, 102, 223, 254, 276, 295 Phenolphthalein, 245, 276 Phenotype, 24, 44, 48, 276 Phenprocoumon, 80, 276 Phenyl, 16, 179, 276 Phenylalanine, 276, 297 Phocomelia, 243, 276 Phorbol, 276, 282 Phorbol Esters, 276, 282 Phospholipids, 158, 164, 225, 232, 248, 264, 266, 276, 282 Phosphonic Acids, 242, 276 Phosphorus, 231, 276, 277 Phosphorylated, 5, 181, 277 Phosphorylates, 277, 282 Phosphorylating, 181, 277 Phosphorylation, 48, 79, 83, 277, 283, 298 Physicochemical, 60, 277 Physiologic, 9, 21, 42, 152, 186, 221, 229, 254, 266, 277, 284 Physiology, 5, 34, 86, 126, 128, 187, 244, 263, 270, 277 Pigment, 228, 266, 277 Pilot study, 105, 277 Pituitary Gland, 249, 277 Placenta, 184, 247, 249, 277, 280, 298 Plants, 221, 232, 252, 253, 268, 271, 277, 278, 287, 289, 295, 296 Plaque, 7, 176, 227, 277 Plasma cells, 224, 269, 277 Plasma protein, 36, 42, 151, 163, 221, 246, 277, 282 Plasmapheresis, 83, 163, 225, 277 Plasmid, 16, 277, 299 Plasmin, 58, 225, 249, 277, 278, 295, 298
315
Plasminogen, 58, 67, 131, 157, 178, 225, 249, 277, 278, 289, 295, 298 Plasminogen Activators, 157, 178, 277, 278 Plasminogen Inactivators, 278, 289 Platelet Activation, 7, 28, 80, 123, 124, 278 Platelet Aggregation, 62, 127, 142, 171, 172, 223, 271, 278 Platelet Count, 91, 130, 278 Platelet Factor 4, 28, 37, 61, 65, 79, 85, 91, 104, 260, 278 Plateletpheresis, 225, 278 Platelets, 7, 36, 76, 126, 148, 176, 228, 271, 278, 294, 295 Platinum, 13, 264, 278 Pneumonia, 239, 278 Poisoning, 231, 270, 278 Pollen, 278, 283 Polyethylene, 12, 40, 143, 166, 278 Polymerase, 29, 125, 278, 279 Polymerase Chain Reaction, 125, 279 Polymers, 12, 27, 41, 144, 166, 229, 279, 282, 292 Polymorphism, 53, 279 Polyneuropathies, 162, 279 Polypeptide, 9, 172, 180, 183, 222, 236, 247, 249, 277, 279, 280, 281, 282, 301 Polysaccharide, 130, 146, 150, 151, 155, 159, 160, 177, 224, 253, 279, 282 Polytetrafluoroethylene, 140, 279 Polyurethanes, 12, 45, 166, 279 Polyvinyl Alcohol, 154, 279 Popliteal, 248, 279 Popliteal Vein, 248, 279 Porphyrins, 267, 279 Posterior, 72, 223, 226, 234, 235, 242, 261, 273, 279, 287 Postmenopausal, 247, 272, 279 Postoperative, 74, 97, 129, 255, 279 Postprandial, 83, 170, 280 Postsynaptic, 280, 293 Potassium, 111, 119, 188, 280 Potentiate, 11, 146, 280 Potentiating, 146, 229, 280 Practice Guidelines, 204, 280 Precipitation, 74, 108, 156, 178, 280 Preclinical, 16, 27, 280 Pre-Eclampsia, 97, 105, 228, 280 Pregnancy Outcome, 74, 92, 280 Prenatal, 244, 280 Preoperative, 73, 97, 280 Presynaptic, 60, 270, 280, 293 Prickle, 262, 280
Probe, 15, 249, 280 Proenzyme, 156, 158, 178, 280 Progeny, 174, 238, 280 Progesterone, 16, 280, 281, 291 Progression, 7, 22, 25, 30, 38, 48, 65, 170, 185, 223, 280 Progressive, 42, 226, 233, 235, 243, 247, 262, 269, 270, 278, 280, 285 Prolactin, 16, 281 Proline, 236, 257, 281 Promoter, 60, 86, 281 Prophase, 229, 269, 281, 293 Prophylaxis, 10, 78, 88, 95, 97, 104, 112, 158, 255, 281, 298 Prospective study, 71, 264, 281 Prostaglandins, 116, 226, 281 Prostaglandins A, 116, 281 Prostaglandins D, 281 Prostate, 25, 46, 47, 88, 133, 229, 281, 286, 297 Prostatectomy, 281 Prostatitis, 20, 281 Protease, 8, 10, 22, 33, 48, 146, 156, 158, 178, 221, 278, 281, 295 Protease Inhibitors, 146, 281 Protein C, 7, 27, 53, 70, 185, 221, 222, 225, 227, 236, 262, 264, 281, 297, 300 Protein Conformation, 222, 262, 281 Protein Kinase C, 127, 282 Protein Kinases, 48, 282 Protein S, 7, 180, 229, 251, 282, 294 Proteinuria, 280, 282 Proteoglycan, 8, 35, 55, 75, 127, 169, 172, 278, 282 Proteolytic, 15, 185, 221, 230, 237, 246, 249, 277, 278, 282, 289, 295, 298 Prothrombin, 50, 147, 152, 158, 164, 165, 274, 282, 294 Prothrombin Time, 152, 164, 165, 282 Protocol, 121, 282 Protons, 221, 257, 282, 284 Protozoa, 229, 238, 267, 282, 297, 299 Psychiatry, 162, 249, 282 Psychology, 116, 242, 282 Public Health, 30, 204, 282 Public Policy, 203, 283 Publishing, 61, 283 Pulmonary Artery, 27, 229, 243, 283, 299 Pulmonary Edema, 234, 262, 283 Pulmonary Embolism, 96, 98, 109, 142, 155, 192, 208, 255, 283 Pulmonary hypertension, 27, 283
316
Heparin
Pulse, 268, 283 Pupil, 239, 242, 283 Purifying, 173, 180, 241, 283 Purines, 283, 288, 301 Purpura, 254, 283 Putrefaction, 251, 283 Pyramidal Cells, 18, 283 Pyridoxal, 181, 283 Pyridoxal Kinase, 181, 283 Pyrimidines, 283, 288 Q Quality of Health Care, 283, 296 Quality of Life, 19, 283 Quaternary, 30, 35, 171, 179, 281, 283 Quercetin, 186, 283 Quiescent, 31, 284 R Race, 268, 284 Radiation, 117, 176, 223, 232, 241, 250, 257, 259, 261, 274, 284, 301 Radiation therapy, 232, 250, 257, 261, 274, 284 Radioactive, 230, 254, 257, 259, 262, 268, 271, 272, 284, 297 Radioactivity, 6, 284 Radioisotope, 284, 296 Radiological, 275, 284 Randomized, 4, 23, 72, 74, 81, 82, 96, 104, 105, 106, 112, 116, 122, 244, 284 Reaction Time, 179, 284 Reactive Oxygen Species, 23, 25, 284 Reagent, 122, 151, 152, 156, 164, 165, 174, 178, 179, 181, 235, 241, 265, 284 Receptors, Chemokine, 24, 284 Recombinant, 14, 18, 34, 36, 43, 48, 131, 164, 173, 180, 197, 284, 299 Recombination, 48, 238, 251, 252, 284 Rectal, 4, 227, 284 Rectum, 225, 237, 251, 260, 263, 281, 284, 285 Recurrence, 105, 176, 186, 285 Red blood cells, 247, 255, 285, 287 Refer, 1, 231, 237, 249, 250, 256, 264, 270, 271, 285, 288, 295 Refraction, 285, 290 Refractory, 4, 285 Regeneration, 12, 249, 285 Regimen, 96, 102, 244, 274, 285 Regurgitation, 254, 285 Rehydration, 143, 285 Reliability, 19, 29, 173, 285 Remission, 4, 285
Renal failure, 129, 187, 285 Reperfusion, 25, 42, 100, 102, 148, 269, 285 Reperfusion Injury, 42, 100, 148, 285 Repopulation, 57, 285 Reproduction Techniques, 280, 285 Respiration, 232, 268, 285, 286 Respiratory distress syndrome, 146, 285 Respiratory failure, 248, 285 Resuscitation, 131, 286 Retina, 60, 184, 235, 238, 239, 272, 286, 287, 300 Retinal, 60, 272, 286, 300 Retinal Ganglion Cells, 60, 272, 286 Retinoid, 286 Retinol, 286 Retropubic, 88, 281, 286 Retropubic prostatectomy, 88, 286 Retrospective, 106, 107, 286 Retroviral vector, 251, 286 Reversion, 286, 297 Rewarming, 110, 286 Rheumatism, 93, 99, 286 Rheumatoid, 99, 129, 133, 236, 273, 286 Rheumatoid arthritis, 99, 236, 286 Rhinitis, 231, 286, 289 Rhodopsin, 272, 286 Ribose, 220, 286 Risk factor, 37, 50, 56, 169, 281, 286 Risk patient, 78, 82, 286 Rod, 227, 235, 287 Rubber, 140, 219, 244, 287 Rutin, 283, 287 Ryanodine, 61, 287 S Salicylic, 177, 287 Saline, 137, 163, 178, 287 Salivary, 240, 273, 287, 292 Salivary glands, 240, 287 Saphenous, 5, 65, 287 Saphenous Vein, 5, 65, 287 Saponins, 287, 291 Sarcoma, 9, 287 Sclera, 235, 239, 287 Sclerosis, 185, 226, 236, 287 Sclerotic, 185, 287 Screening, 13, 25, 29, 152, 236, 274, 287 Sebaceous, 241, 287 Sebaceous gland, 241, 287 Second Messenger Systems, 287 Secondary tumor, 267, 287 Secretion, 34, 47, 247, 256, 260, 263, 269, 287, 288, 299
317
Secretory, 8, 16, 33, 35, 64, 87, 288, 293 Sedimentation, 234, 288, 297 Segregation, 284, 288 Semen, 281, 288 Sensor, 45, 288 Septal, 108, 154, 288 Septicaemia, 288 Septum, 154, 288 Septum Pellucidum, 288 Sequence Homology, 275, 288 Sequencing, 61, 66, 177, 279, 288 Sequester, 19, 144, 145, 288, 293 Serine, 10, 17, 22, 33, 48, 55, 146, 157, 178, 235, 245, 282, 288, 289, 292, 295, 297 Serine Endopeptidases, 245, 288, 289 Serologic, 258, 288 Serotonin, 228, 270, 288, 297 Serotypes, 16, 288 Serous, 245, 289 Serpins, 38, 146, 289 Shedding, 38, 289 Shock, 5, 55, 166, 233, 257, 289, 296 Side effect, 17, 19, 142, 195, 197, 209, 220, 229, 243, 289, 295 Signs and Symptoms, 285, 289 Skeletal, 145, 235, 269, 289, 290, 297 Skeleton, 183, 219, 249, 289 Skin test, 78, 289 Skull, 230, 289, 294 Small intestine, 235, 243, 256, 261, 262, 289, 297 Smallpox, 52, 289, 299 Smoke Inhalation Injury, 248, 289 Smooth muscle, 6, 9, 15, 21, 23, 27, 49, 57, 62, 64, 88, 90, 155, 176, 221, 223, 238, 249, 250, 256, 258, 263, 289, 290, 292 Sneezing, 275, 289 Social Environment, 283, 289 Social Work, 188, 289 Sodium, 84, 94, 119, 123, 125, 145, 155, 168, 174, 186, 188, 241, 290, 293 Soft tissue, 143, 230, 272, 289, 290 Solid tumor, 223, 245, 290 Solvent, 140, 143, 170, 171, 247, 252, 272, 276, 290 Soma, 18, 283, 290 Somatic, 18, 244, 266, 268, 290 Sound wave, 238, 290 Spasm, 5, 290 Spasmodic, 275, 290 Specialist, 210, 242, 290
Specificity, 20, 26, 31, 36, 37, 67, 129, 220, 245, 289, 290, 292 Spectroscopic, 17, 42, 53, 290 Spectrum, 4, 29, 44, 149, 176, 290 Sperm, 235, 278, 290, 297 Spinal cord, 104, 226, 230, 235, 250, 270, 275, 290 Spinous, 247, 262, 290 Spleen, 149, 168, 169, 240, 265, 290 Spontaneous Abortion, 133, 280, 290 Squamous, 85, 290 Stabilization, 33, 291 Statistically significant, 4, 291 Steady state, 31, 291 Steel, 235, 291 Stem Cell Factor, 64, 235, 291 Stem Cells, 254, 291 Stenosis, 5, 107, 141, 182, 291 Stent, 18, 76, 106, 107, 147, 159, 291 Sterile, 146, 167, 291 Steroid, 4, 56, 228, 239, 252, 287, 291 Stillbirth, 280, 291 Stimulus, 243, 244, 260, 261, 263, 284, 291, 294 Stomach, 219, 229, 251, 256, 269, 275, 289, 290, 291 Stool, 237, 263, 291 Strand, 36, 278, 291 Streptomyces, 8, 291, 294 Stress, 7, 23, 42, 48, 56, 103, 116, 143, 189, 233, 239, 269, 273, 286, 287, 291, 298 Stress Fibers, 42, 291 Stricture, 48, 291 Stroke, 23, 38, 42, 49, 55, 85, 107, 111, 133, 181, 192, 202, 232, 262, 291 Stroma, 16, 22, 25, 46, 261, 291 Stromal, 25, 46, 291 Stromal Cells, 26, 46, 291 Structure-Activity Relationship, 28, 292 Styrene, 287, 292 Subacute, 106, 259, 292 Subclinical, 259, 292 Subcutaneous, 31, 84, 93, 107, 132, 155, 172, 192, 220, 223, 243, 251, 263, 274, 292 Submaxillary, 247, 292 Subspecies, 290, 292, 299 Substance P, 267, 288, 292 Substrate, 10, 29, 30, 31, 36, 150, 153, 156, 168, 246, 292, 297 Subtilisin, 8, 292 Sulfates, 42, 78, 183, 185, 292 Sulfotransferases, 183, 292
318
Heparin
Sulfur, 141, 241, 248, 250, 267, 292 Sulfuric acid, 292 Superoxide, 86, 292 Superoxide Dismutase, 86, 292 Suppression, 71, 292 Suramin, 117, 293 Surfactant, 41, 170, 293 Sweat, 241, 293 Sweat Glands, 241, 293 Sympathomimetic, 222, 242, 247, 271, 293, 297 Symphysis, 281, 293 Symptomatic, 105, 112, 186, 293 Synapse, 220, 270, 280, 293, 296 Synaptic, 18, 60, 270, 293 Synaptic Transmission, 18, 293 Synaptic Vesicles, 293 Synergistic, 12, 281, 293 Synovial, 129, 293 Synthetic retinoid, 78, 293 Systemic lupus erythematosus, 224, 225, 236, 293 Systolic, 23, 258, 293 T Teichoic Acids, 253, 294 Temporal, 32, 256, 294 Testis, 247, 294 Tetani, 294 Tetanic, 294 Tetanus, 60, 294 Tetanus Toxin, 60, 294 Tetracycline, 60, 135, 294 Therapeutics, 4, 36, 95, 106, 196, 294 Thermal, 173, 242, 270, 279, 294 Thigh, 105, 248, 294 Thoracic, 73, 75, 80, 90, 93, 103, 126, 130, 140, 294 Threonine, 48, 275, 282, 288, 294 Threshold, 4, 258, 294 Thrombocytes, 278, 294 Thrombolytic, 58, 142, 278, 294 Thrombomodulin, 11, 38, 42, 50, 55, 281, 294 Thrombopenia, 225, 294 Thrombophilia, 105, 109, 294 Thrombophlebitis, 208, 295 Thromboplastin, 152, 158, 164, 282, 295 Thromboses, 43, 142, 225, 295 Thrombus, 45, 58, 68, 108, 141, 182, 239, 259, 262, 269, 278, 294, 295, 299 Thymus, 258, 265, 295 Thyroid, 231, 295, 297
Thyroxine, 221, 276, 289, 295 Tissue Plasminogen Activator, 46, 55, 63, 295 Tolerance, 23, 219, 295 Tone, 271, 295 Tooth Preparation, 219, 295 Topical, 156, 172, 247, 257, 276, 295 Torsion, 259, 295 Toxic, iv, 19, 53, 163, 166, 238, 270, 289, 292, 295 Toxicity, 19, 40, 60, 96, 157, 243, 295 Toxicology, 16, 42, 71, 204, 295 Toxin, 163, 246, 294, 295 Tracer, 40, 41, 256, 296 Traction, 235, 296 Transdermal, 93, 296 Transduction, 6, 13, 16, 24, 28, 33, 39, 79, 296 Transfection, 153, 173, 229, 251, 296 Transfer Factor, 258, 296 Transferases, 253, 296 Transfusion, 88, 296 Translation, 222, 296 Translational, 48, 296 Translocation, 48, 296 Transmitter, 219, 226, 242, 261, 266, 271, 293, 296, 297 Transplantation, 10, 73, 83, 92, 95, 101, 102, 108, 131, 188, 244, 258, 262, 296 Trauma, 48, 55, 104, 110, 140, 270, 296 Treatment Failure, 77, 96, 296 Trees, 287, 296 Triglyceride, 32, 53, 169, 257, 258, 296 Trophoblast, 9, 16, 24, 48, 229, 296 Tropism, 9, 296 Tropomyosin, 296, 297 Troponin, 76, 296, 297 Trypanosomiasis, 293, 297 Trypsin, 32, 221, 235, 246, 280, 297 Tryptophan, 236, 288, 297 Tuberculosis, 265, 287, 297 Tubulin, 162, 297 Tumor marker, 221, 229, 297 Tumor Necrosis Factor, 65, 148, 297 Tumor-derived, 9, 297 Tumorigenic, 52, 297 Tunica, 245, 269, 297 Type 2 diabetes, 86, 297 Typhimurium, 56, 297 Tyramine, 228, 297 Tyrosine, 24, 48, 52, 62, 79, 242, 297
319
U Ulcer, 149, 297 Ulcerative colitis, 4, 80, 95, 113, 260, 297 Ultrafiltration, 163, 255, 298 Umbilical Arteries, 298 Umbilical Cord, 109, 298 Uncoupling Agents, 261, 298 Universal Precautions, 188, 298 Uremia, 262, 285, 298 Ureters, 298 Urethane, 11, 298 Urethra, 281, 298 Urinary, 20, 39, 47, 178, 208, 231, 240, 272, 281, 286, 295, 298, 301 Urinary Plasminogen Activator, 295, 298 Urinary tract, 47, 298 Urinary urgency, 208, 298 Urinate, 298, 300 Urine, 23, 59, 229, 242, 247, 252, 262, 268, 272, 282, 298 Urothelium, 20, 40, 47, 298 Urticaria, 128, 298 Uterus, 189, 219, 239, 240, 245, 249, 263, 266, 280, 298 V Vaccination, 298, 299 Vaccines, 298, 300 Vaccinia, 52, 174, 299 Vaccinia Virus, 52, 299 Vacuoles, 245, 272, 299 Valves, 45, 141, 227, 299 Varices, 227, 299 Variola, 52, 299 Vascular endothelial growth factor, 111, 112, 180, 299 Vascular Resistance, 23, 299 Vasoactive, 59, 299 Vasoconstriction, 161, 247, 254, 299 Vasodilator, 183, 230, 242, 256, 269, 299 Vasomotor, 247, 299 Vector, 16, 31, 46, 60, 173, 296, 299 Vein, 5, 25, 58, 67, 68, 76, 107, 132, 155, 223, 248, 258, 261, 271, 279, 287, 295, 298, 299 Vena, 154, 258, 299 Venous blood, 278, 299 Venous Thrombosis, 10, 77, 78, 84, 127, 142, 228, 299 Venter, 299 Ventral, 116, 299 Ventricle, 154, 225, 256, 268, 283, 293, 299 Ventricular, 45, 154, 269, 299
Venules, 230, 231, 246, 267, 299 Vertebrae, 290, 299 Vertebral, 47, 300 Vesicular, 256, 289, 299, 300 Veterinary Medicine, 203, 300 Vial, 62, 300 Vinblastine, 297, 300 Vinca Alkaloids, 300 Vincristine, 297, 300 Vinorelbine, 123, 300 Viral, 6, 16, 35, 51, 53, 60, 62, 174, 186, 231, 272, 296, 297, 300 Viral Proteins, 53, 300 Viral vector, 16, 300 Virion, 60, 186, 300 Virulence, 52, 227, 229, 295, 300 Virus, 6, 16, 49, 51, 54, 60, 62, 63, 65, 67, 94, 99, 173, 186, 227, 231, 239, 246, 251, 253, 277, 286, 289, 296, 299, 300 Viscera, 290, 300 Viscosity, 230, 256, 300 Visual Acuity, 263, 300 Vitreous, 286, 300 Vitreous Body, 286, 300 Vitro, 6, 8, 9, 11, 12, 14, 15, 17, 20, 21, 25, 27, 28, 30, 32, 49, 51, 52, 56, 57, 58, 59, 65, 68, 69, 81, 96, 100, 101, 102, 116, 150, 157, 169, 178, 184, 185, 221, 229, 230, 244, 251, 259, 279, 300 Vivo, 5, 6, 7, 8, 9, 11, 12, 14, 15, 17, 21, 22, 25, 27, 28, 29, 32, 33, 34, 40, 41, 51, 52, 53, 57, 58, 59, 65, 100, 101, 116, 141, 146, 155, 163, 171, 184, 185, 221, 229, 251, 259, 273, 300 Void, 39, 164, 300 W White blood cell, 224, 263, 265, 268, 269, 270, 277, 301 Whooping Cough, 276, 301 Womb, 298, 301 Wound Healing, 5, 38, 41, 49, 144, 158, 233, 249, 260, 266, 301 X Xanthine, 25, 301 Xanthine Dehydrogenase, 25, 301 Xenograft, 11, 143, 224, 301 X-ray, 35, 54, 233, 250, 261, 266, 271, 284, 301 Y Yeasts, 250, 276, 301 Z Zygote, 238, 301
320
Heparin
Zymogen, 235, 280, 281, 301
