THROMBOCYTOPENIA 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., 1960Thrombocytopenia: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-84094-6 1. Thrombocytopenia-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 thrombocytopenia. 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 THROMBOCYTOPENIA............................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Thrombocytopenia......................................................................... 4 E-Journals: PubMed Central ....................................................................................................... 59 The National Library of Medicine: PubMed ................................................................................ 61 CHAPTER 2. NUTRITION AND THROMBOCYTOPENIA ................................................................... 103 Overview.................................................................................................................................... 103 Finding Nutrition Studies on Thrombocytopenia...................................................................... 103 Federal Resources on Nutrition ................................................................................................. 106 Additional Web Resources ......................................................................................................... 106 CHAPTER 3. ALTERNATIVE MEDICINE AND THROMBOCYTOPENIA ............................................ 109 Overview.................................................................................................................................... 109 National Center for Complementary and Alternative Medicine................................................ 109 Additional Web Resources ......................................................................................................... 112 General References ..................................................................................................................... 113 CHAPTER 4. DISSERTATIONS ON THROMBOCYTOPENIA .............................................................. 115 Overview.................................................................................................................................... 115 Dissertations on Thrombocytopenia .......................................................................................... 115 Keeping Current ........................................................................................................................ 116 CHAPTER 5. CLINICAL TRIALS AND THROMBOCYTOPENIA ......................................................... 117 Overview.................................................................................................................................... 117 Recent Trials on Thrombocytopenia........................................................................................... 117 Keeping Current on Clinical Trials ........................................................................................... 122 CHAPTER 6. PATENTS ON THROMBOCYTOPENIA ......................................................................... 125 Overview.................................................................................................................................... 125 Patents on Thrombocytopenia.................................................................................................... 125 Patent Applications on Thrombocytopenia ................................................................................ 143 Keeping Current ........................................................................................................................ 161 CHAPTER 7. BOOKS ON THROMBOCYTOPENIA ............................................................................. 163 Overview.................................................................................................................................... 163 Book Summaries: Federal Agencies............................................................................................ 163 Book Summaries: Online Booksellers......................................................................................... 165 The National Library of Medicine Book Index ........................................................................... 165 Chapters on Thrombocytopenia.................................................................................................. 166 CHAPTER 8. MULTIMEDIA ON THROMBOCYTOPENIA .................................................................. 171 Overview.................................................................................................................................... 171 Bibliography: Multimedia on Thrombocytopenia ...................................................................... 171 CHAPTER 9. PERIODICALS AND NEWS ON THROMBOCYTOPENIA ............................................... 173 Overview.................................................................................................................................... 173 News Services and Press Releases.............................................................................................. 173 Newsletter Articles .................................................................................................................... 175 Academic Periodicals covering Thrombocytopenia .................................................................... 175 CHAPTER 10. RESEARCHING MEDICATIONS................................................................................. 177 Overview.................................................................................................................................... 177 U.S. Pharmacopeia..................................................................................................................... 177 Commercial Databases ............................................................................................................... 178 Researching Orphan Drugs ....................................................................................................... 178 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 183 Overview.................................................................................................................................... 183
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NIH Guidelines.......................................................................................................................... 183 NIH Databases........................................................................................................................... 185 Other Commercial Databases..................................................................................................... 187 The Genome Project and Thrombocytopenia.............................................................................. 187 APPENDIX B. PATIENT RESOURCES ............................................................................................... 193 Overview.................................................................................................................................... 193 Patient Guideline Sources.......................................................................................................... 193 Finding Associations.................................................................................................................. 199 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 201 Overview.................................................................................................................................... 201 Preparation................................................................................................................................. 201 Finding a Local Medical Library................................................................................................ 201 Medical Libraries in the U.S. and Canada ................................................................................. 201 ONLINE GLOSSARIES................................................................................................................ 207 Online Dictionary Directories ................................................................................................... 209 THROMBOCYTOPENIA DICTIONARY ................................................................................. 211 INDEX .............................................................................................................................................. 299
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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 thrombocytopenia 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 thrombocytopenia, 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 thrombocytopenia, 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 thrombocytopenia. 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 thrombocytopenia, 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 thrombocytopenia. 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 THROMBOCYTOPENIA Overview In this chapter, we will show you how to locate peer-reviewed references and studies on thrombocytopenia.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and thrombocytopenia, 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 “thrombocytopenia” (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: •
Management of the Oral and Maxillofacial Surgery Patient with Thrombocytopenia Source: Journal of Oral and Maxillofacial Surgery. 59(4): 421-427. April 2001. Contact: Available from W.B. Saunders Company. Periodicals Department, P.O. Box 629239, Orlando, FL 32862-8239. (800) 654-2452. Summary: Patients with disorders of coagulation and bleeding can be among the most challenging surgical patients to manage. Intraoperative or postoperative bleeding can contribute to life threatening complications in even the most benign surgical procedures. This article reviews the management of the oral and maxillofacial surgery patient with thrombocytopenia. Thrombocytopenia is usually caused by an increased destruction of platelets brought on by nonimmunologic and immunology disorders. Adequate
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numbers and function of platelets play a critical role in the coagulation pathway. A thorough understanding of platelet physiology and platelet disorders is therefore essential in the management of the patient with thrombocytopenia who are undergoing oral and maxillofacial surgery. The authors suggest that a careful preoperative evaluation will help the surgeon treat these patients and help prevent potentially catastrophic intraoperative or postoperative bleeding. The article includes three illustrative case reports. 2 figures. 1 table. 19 references.
Federally Funded Research on Thrombocytopenia The U.S. Government supports a variety of research studies relating to thrombocytopenia. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to thrombocytopenia. 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 thrombocytopenia. The following is typical of the type of information found when searching the CRISP database for thrombocytopenia: •
Project Title: A MURINE MODEL OF HEMATOPOIETIC ENGRAFTING CELLS Principal Investigator & Institution: Mcniece, Ian K.; Professor; Medical Oncology; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2003 Summary: (provided by applicant): High dose chemotherapy followed by stem cell transplantation (SCT) is routinely used for treatment of patients with hematological malignancies and solid tumors. Patients receiving SCT have significant periods of neutropenia and thrombocytopenia and prolonged periods of depressed immune cells, particularly recipients of cord blood (CB) grafts. Ex vivo expansion of hematopoietic grafts could provide more rapid engraftment and decrease graft failure of CB recipients. Despite extensive studies to determine the hematopoietic cells that are responsible for rapid hematopoietic recovery, there is debate to which cells provide recovery of neutrophils, platelets and immune cells. Therefore there is debate as to which cells should be expanded ex vivo. We hypothesize that i) distinct mature precursor cells are responsible for neutrophil, platelet and lymphoid engraftment, ii) intermediate engraftment is provided by committed and/or multipotential precursors, and iii) long term engraftment is provided by totipotent hematopoietic stem cells (HSC). Using a mouse transplant model we will determine the cells providing short term engraftment, intermediate cell engraftment and long term durable engraftment These studies will
2 Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).
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evaluate the contribution of candidate stem cell populations to both short term and long term engraftment The goal of this project is to identify and characterize the murine cells responsible for recovery of each lineage of hematopoietic cells. In addition, mouse ex vivo expansion studies will be conducted to characterize the growth factor cocktails that stimulate optimal generation of each of these populations. We also hypothesize that ex vivo expanded cells require additional growth factors when infused in vivo and we will determine the growth factors that provide optimal engraftment of expanded cells in vivo. These studies will be combined to identify the optimal numbers of each population and optimal timing of transplantation and growth factor treatment We propose that these studies will lead to better defined mouse grafts that provide optimal engraftment and will then provide the basis for evaluating human hematopoietic grafts for equivalent populations and further ex vivo expansion studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ABNORMAL MEGAKARYOCYTE DEVELOPMENT Principal Investigator & Institution: Drachman, Jonathan G.; Puget Sound Blood Center 921 Terry Ave Seattle, Wa 98104 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2007 Summary: (provided by applicant): The overall goal of this grant is to identify critical genes and biochemical pathways involved in normal megakaryocyte (MK) differentiation. We propose to do this by studying rare clinical conditions in which MK maturation and platelet production are abnormal, resulting in inherited thrombocytopenia or thrombocytosis. Concurrently, a "systems biology" approach will be applied to study and interpret the molecular fingerprint of abnormal MKs and platelets from these pedigrees in comparison to normal individuals. Specific Aims for this proposal are: Aim 1: Evaluate and study novel forms of inherited/congenital thrombocytopenia and thrombocytosis. Aim 1A: Confirm and characterize a gone for autosomal dominant thrombocytopenia on chromosome 10. Having previously limited the linkage interval to approximately 5 x 10 6 bases of genomic DNA, we will identify the mutation within this interval and study the normal function of the encoded gone product. Aim 1B: Study rare families with previously uncharacterized forms of inherited thrombocytopenia or thrombocytosis and use genetic techniques to localize the genetic mutation. Aim 2: Examine differences in the transcriptome and proteome of primary cells isolated from normal adults and individuals with inherited thrombocytopenia and thrombocythemia in order to recognize and understand the downstream effects of specific mutations. Successful completion of these Aims will provide benefits to scientists, hematologists, and patients. First, it may identify novel signaling pathways, transcription factors, or cell cycle regulators that control megakaryocytopoiesis. These cellular mechanisms will help explain the specialized processes that result in polyploidy and programmed cytoplasmic fragmentation (i.e. thrombopoiesis). Clinically, these studies will result in greater awareness of inherited thrombocytopenia, potentially leading to earlier identification, better therapies, and avoiding unnecessary procedures when an incorrect diagnosis is made. Finally, these studies may help in the targeted development of better platelet lowering drugs using rational design to improve on currently available options such as anagrelide, hydroxyurea, and interferon. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ACTIVATION OF HEMOSTASIS Principal Investigator & Institution: Bennett, Joel S.; Professor; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104
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Timing: Fiscal Year 2001; 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 •
Project Title: ADOPTIVE TRANSFER OF CD8+ CTLS TO CONTROL EIAV Principal Investigator & Institution: Mealey, Robert H.; Vet Microbiology and Pathology; Washington State University 423 Neill Hall Pullman, Wa 99164 Timing: Fiscal Year 2001; Project Start 15-JUL-1998; Project End 30-JUN-2003 Summary: Research Proposal: The long-term goal of this research is to define the role of CTLs in the control of EIAV, a lentivirus of horses which cause a persistent infection characterized by recurrent episodes of viremia with concurrent fever, thrombocytopenia, and anemia. Horses infected with EIAV eventually control the viremia and associated clinical disease, and remain lifelong inapparent carriers. Work using foals affected with severe combined immunodeficiency (SCID) has shown that lymphocyte responses are required to terminate the viremia following acute infection. In addition, continued immunologic control mechanisms are likely responsible for maintenance of the inapparent carrier state, as evidenced by recrudescence of clinical disease following immunosuppression. The fact that EIAV- specific CD8+ CTLs are detected con-incident with the termination of the initial viremia following acute infection, prior to the appearance of neutralizing antibody, suggests that CTLs are involved in control of viremia. In addition, inapparent carriers have EIAV-specific CTLm in PBMC. The proposed research will test the hypothesis that EIAV-specific
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CD8+ CTLs will prevent or reduce viremia following EIAV challenge. In the specific aims, Env and Gag/Pr-specific CD8+ CTLs from PBMC from inapparent carriers will be selected, stimulated and expanded using retroviral vector-transduced autologous equine kidney stimulator cells, and adoptively transferred to ELA-A matched SCID foals. These foals will then be infected with EIAV and the protective effects determined. If the foals are protected, the protective effects of CD8+ CTLs specific for the conserved Gag proteins p15, p26a, and p26b will be evaluated. The results of this research should provide insight into the mechanisms of immune control of other lentiviral infections, including HIV-1. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AIDS AND THROMBOCYTOPENIA--DRUG ABUSERS AND HOMOSEXUALS Principal Investigator & Institution: Karpatkin, Simon; Professor; Medicine; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2001; Project Start 30-SEP-1986; Project End 31-AUG-2005 Summary: HIV-1-infected intravenous drug abusers and homosexuals develop thrombocytopenia (HIV-1-ITP) which is particularly severe in drug abusers. Although originally thought to be a disorder of immune peripheral destruction, there is now abundant evidence for impaired megakaryocytopoiesis (Mkp) and platelet production playing a major role, particularly in patients with more severe disease. We have discovered that high affinity anti-platelet GPIIIa 49-66 is sequestered within circulating immune complexes and that this anti- platelet Ab is capable of inhibiting Mkp in vitro with induction of apoptosis; and inducing platelet fragmentation in vitro in the absence of complement. We and most investigators have also noted that although MK and CD34+ progenitor cells are not infected with HIV-1, stromal cells can be infected. Activated stromal/endothelial cells secrete cytokines and support bone marrow angiogenesis. We therefore propose to study two mechanisms of impaired Mkp in HIV1-ITP patients: 1) Autoimmunity: Role of anti-GPIIIa Ab in inhibiting Mkp and inducing non-complement dependent platelet fragmentation; 2) Infection of stromal cells: Role of HIV-1-infected stromal1endothelial cells in secretion of inhibitory Mkp cytokines and down-regulation of angiogenesis ligands VEGF, Ang-1 and their respective receptors VEGFr and Tie-2. These studies will provide useful information regarding the mechanism of impaired Mkp in HIV-1 infection which may contribute to the treatment and eradication of the thrombocyopenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: AIDS CLINICAL TRIALS UNIT Principal Investigator & Institution: Lertora, Juan J L.; Professor and Head of Medical Pharmacolo; Medicine; Tulane University of Louisiana New Orleans, La New Orleans, La 70112 Timing: Fiscal Year 2001; Project Start 01-JAN-1996; Project End 31-DEC-2002 Summary: (Adapted from application abstract): This proposal is to establish an ACTU with a main unit based at Tulane University Medical Center and a subunit at Louisiana state University Medical Center, both in New Orleans, with the following goals. 1) To recruit 80 or more new patients per year into ACTG sponsored Phase I, II, III protocols for the treatment of HIV infection, opportunistic infections, and neurologic complications of AIDS. 2) To use GCRC for Phase I and II clinical trials and pathogenesis-related exploratory trials of new treatments for HIV. 3) To establish
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support laboratories to perform protocol mandated studies in virology, pharmacology, and immunology. 4) To systematically address women's health-related issues. 5) To recruit an ethnically diverse population of patients, representative of the regional population, in order to give minority populations and women access to ACTG clinical trials. 6) To address the subjects of compliance and patient retention, including outreach programs. 7) To work with the local CAB to include local patients and their advocates in the implementation of the ACTU research agenda. Scientifically the following areas will be emphasized: 1) Phase I pharmacokinetic, drug interactions, and toxicity studies, and pilot studies of HIV pathogenesis; 2) Correlations of plasma and intracellular drug levels with changes in viral load; 3) Pathogenesis of HIV and HTLV-I/II co-infection; 4) Therapy of HIV-induced thrombocytopenia; 5) HIV neuropathy; 6) Immune resistance of HIV; 7) Mechanisms and prevention of HIV-induced apoptosis; 8) Therapy of opportunistic diseases (mainly microporidiosis and mycobacterial infections); 9) Pathogenesis and therapy of cervical dysplasia in HIV infected women Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ANTIBODIES IN PATHOGENESIS OF HIV-1 TROMBOCYTOPENIA Principal Investigator & Institution: Ditzel, Henrik J.; Professor; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2001; Project Start 01-JUN-1999; Project End 31-MAY-2004 Summary: The major objective of this grant is to define the relative contributions of polyreactive nd monoreactive antibodies against platelets in HIV-1 associated thrombocytopenia (HIV-ITP). The central hypothesis is that HIV-ITP is a result of both polyreactive and monoreactive platelet antibodies. The applicant has used an antibodyIgG phage combinatorial library to isolate monoclonal Fab fragments from the bone marrow of 2 HIV-ITP patients which react with human platelets. He plans to: 1) Test these Ab's in 2 mouse models: a Balb/c mouse known to react with human anti-GPIIIa Ab by developing thrombocytopenia, and a SCID mouse engrafted with human platelets where the human Ag's share no homology; 2) Generate human IgG1 Ab's by attaching the constant region to the Fab Ab's-and determine their in vivo effect; 3) Isolate a panel of platelet-associated Ab's by panning vs platelets and their products obtained from normal and HIV-ITP patients; 4) Define the platelet-associated Ag's recognized by these filamentous Fab Ab's by classical means as well as by employing a phage directed platelet cDNA library to produce the Ag-and determine the relative contributions of these Ab's against patient serum Ab's with in vitro competition assays as well as with in vivo effect of these Ab's. He will also look for molecular mimicry with foreign Ag's. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ANTICARDIOLIPIN PHOSPHOLIPIDS
ANTIBODIES
AND
OXIDIZED
Principal Investigator & Institution: Witztum, Joseph L.; Professor; Medicine; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 92093 Timing: Fiscal Year 2001; Project Start 01-JAN-1997; Project End 31-JUL-2005 Summary: Patients with the antiphospholipid antibody syndrome (APS) have autoantibodies to certain phospholipids (aPL) such as cardiolipin and/or the lupus anticoagulant and clinically experience recurrent venous or arterial thrombosis, history of fetal death and autoimmune thrombocytopenia. Increased aPL also appear to predict increased risk of stroke and myocardial infarction in otherwise healthy men as well.
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However, controversy exists about the target antigens of aPL, and even university laboratories cannot agree who has elevated aPL titers. In turn, clinical management is hampered by lack of an underlying hypothesis to explain why antibodies should form to such ubiquitous compounds as PL. We have developed the novel hypothesis that many aPL are directed against epitopes of oxidized PL (OxPL) and/or against covalent adducts of OxPL and associated PL binding proteins, such as beta2GPI. Our hypothesis suggests that states of enhanced lipid peroxidation, as occurs in inflammation or atherosclerosis, leads to oxidation of PL (such as in LDL or in membranes of apoptotic or dying cells) which creates neo self-determinants and immunogenic epitopes. The resultant autoantibodies can then target such neoepitopes in many tissues, and may have a variety of biological consequences. Cardiolipin (CL) is the most common PL used to test for aPL. We have shown that APS plasma bind exclusively to OxCL, or to OxCL adducts with beta2GPI, and not to native CL. We propose to further test our hypothesis by determining if antibodies to other OxPL are also present in sera from patients and mice with lupus- like syndromes. We will generate a panel of such aOxPL murine monoclonals from (NZWxBXSB) F1 males. Similar Fab and scFv antibodies will be generated from a human phage-display library. We will determine the epitopes to which they bind and their impact on in vitro and in vivo coagulation, with an emphasis on the Protein C pathway. We will treat lupus-prone mice with potent antioxidants to see if changes in aPL titers and/or other clinical parameters occur. Understanding the etiology of even some of the aPL should lead not only to development of more standardized assays, which should improve our ability to detect high risk individuals, but also to consideration of new therapeutic modalities for patients with aPL and APS (e.g. aggressive anti-inflammatory and/or antioxidant interventions). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ASSESSMENT OF HD-AD VECTORS AND FACTOR IX AND APOA-1 Principal Investigator & Institution: Beaudet, Arthur L.; Professor and Chair; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: The overall goals of this project are to further define the safety and toxicity of helper-dependent adenoviral (HD-Ad) vectors, to delineate the pathogenesis of the thrombocytopenia observed with the HD-Ad vectors, to attempt to identify mechanisms to circumvent the thrombocytopenia, to develop experience with these vectors in primates, and to move incrementally towards clinical trials with these very promising HD-Ad vectors. The pathogenesis of the thrombocytopenia will be studied in mice, focusing on direct interactions between platelets and vector and between endothelial cells and vector. One very important aim will be to evaluate safety, toxicity, and short-term expression using high doses of HD-Ad vectors in juvenile baboons. Because of the desire to initiate clinical trials with maximum safety, we are comparing the expression of factor IX and apolipoprotein A-I (apo A-I) with IM administration utilizing a muscle-specific promoter and IV administration aimed at expression in hepatocytes. Another aim will be to put in place all of the necessary reagents and commitments to prepare GMP quality HD-Ad vector suitable for use in pre-clinical and clinical studies. Toxicity studies with GMP quality vector will be conducted in mice and baboons. In longer-term experiments in baboons, we will test whether over-expression of apo A-I will protect against atherosclerosis in baboons. Finally, we propose to develop a clinical trial to introduce the HD-Ad vectors into the clinic using either IM or IV administration. No IRB-approved protocol is available at present, but the major possibilities under consideration include expression of factor IX in patients with
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hemophilia B or expression of apo A-I in patients with coronary artery disease and low production of apo A-I. The long-term significance of this project is to attempt to develop HD-Ad vectors designed to increase expression of the LDL receptor and/or apo A-I in humans. If successful, this approach could have a major impact on prevention or reduction of atherosclerosis in the human population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AUTOIMMUNE THROMBOCYTOPENIA Principal Investigator & Institution: Mcmillan, Robert; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2001; Project Start 30-SEP-1998; Project End 31-AUG-2003 Summary: (Adapted from applicant's abstract) Autoimmune thrombocytopenia is often due to antibodies reactive with platelet glycoprotein (GP) complexes, particularly GPIIb/IIIa. Autoepitopes are often divalent cation-dependent. The investigators will focus on two research areas: autoantibody characterization and antigenic localization. Autoantibody characterization. They will: 1) Demonstrate the presence of plateletassociated and plasma antibodies and focus on antibodies against GPIIb/IIIa, since these are most common; 2) Evaluate antibody clonality by examining light chain and IgG subtype characteristics and 3) Study autoantibody binding to megakaryocytes in vitro and determine if bound antibody effects megakaryocyte maturation, activates complement or induces phagocytosis. Antigen localization. They will: 1) Determine if rabbit antibody to the GPIIb/IIIa calcium-bindings sites will inhibit autoantibody binding; 2) Test autoantibody binding to a series of large recombinant peptides, spanning glycoproteins Iib and IIIa. They will insert specific PCR-generated cDNA fragments into a vector which results in their expression by E. Coli as fusion proteins with a 6X-histidine tag which can then be affinity-purified using a nickel nitrilotricacetic acid resin column. Antibodies which bind to one of the large peptides will be studied further by determining binding patterns to smaller peptides within this region; 3) Evaluate epitopes, not identified by this technique, with random peptide libraries and GPIIb/IIIa chimeras. Antibodies are incubated with fUSE5 filamentous phage expressing several million random peptide sequences. Phage expressing sequences which bind to antibodies are separated from non-specific phage by serial 'planning' with staphylococcal-A protein agarose followed by acid elution. The sequence of the specific peptide(s) is determined. In addition, they will develop human/xenopus and human/avian GPIIb/IIIa chimeras which they will use to examine the binding patterns of human antiplatelet autoantibodies. Results of these studies will be correlated with the patients' clinical course and thrombopoietin levels. In addition, the effect of immune thrombocytopenia on the patients' quality of life will be studied. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BCI2 ANTISENSE AGAINST CHEMORESISTANCE IN ELDERLY AML Principal Investigator & Institution: Marcucci, Guido; Assistant Professor; Internal Medicine; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (Provided by applicant): Elderly patients with acute myeloid leukemia (AML) treated with conventional dose chemotherapy achieve a clinical response significantly lower than younger patients, likely because of the overrepresentation of poor prognostic factors in this group. Since AML is relatively common in the geriatric
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population, it is imperative to design innovative therapeutic strategies to improve the dismal outcome of elderly AML patients. To overcome chemoresistance in leukemic blasts, we and others have hypothesized that chemotherapy-induced cytotoxicity may be enhanced by using G3139, a bcl-2 antisense with the ability to down-regulate the antiapoptotic protein bcl-2 in vitro and in vivo. We have conducted a pilot study of G3139, fludarabine, and cytarabine in relapsed/refractory acute leukemia (OSU 9977), demonstrating significant clinical response and no dose limiting toxicity of G3139. In the first 12 patients enrolled, 4 achieved CR and 2 had no evidence of disease with persistent neutropenia/thrombocytopenia. Of the 6 responders, 3 were >60 years old, suggesting that G3139 can safely and effectively be administrated in elderly AML. Specific Aim #1 will conduct a phase I/II of G3139 in combination with cytarabine and daunorubicin in elderly patients with primary AML (CALGB 100005), which has been approved in concept by the NCI and Cancer and Leukemia Group B. An initial phase I portion will evaluate the dose of daunorubicin to be used in the subsequent phase II. Specific Aim #2 will evaluate the pharmacokinetics of G3139. We will validate an electrospray liquid chromatographic/mass spectrometry-based method to assess plasma levels of G3139. In our hands this assay has already shown a limit of detection of 50 nanograms/ml. Specific Aim #3 will examine the correlation of the PK data with changes in mRNA and protein levels of bcl-2, caspase cascade activation, and clinical response. It is expected that the analysis of the clinical and correlative laboratory results will support testing of this combination in a phase III setting. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BECTON DICKINSON FACS CALIBUR 4 COLOR WITH SORT UNIT Principal Investigator & Institution: Pollard, K. Michael.; Associate Professor; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2002 Summary: A group of fourteen qualifying Users have detailed a broad range of experimental plans that require flow cytometry analysis as summarized herein: 1) Analysis of lymphoid cell populations for the presence or absence of constitutive and/or inducible cell surface marker expression in response to xenobiotic-induced and/or accelerated systemic autoimmunity; 2) Use of autoantibodies to study gene specific cell cycle regulation, tissue expression of transgenic autoantigen, and autoantigen fate during apoptosis; 3) Analysis of the role of mitochondria and intracellular acidification during cell death; 4) Expression and fate of transcription factors in hematopoiesis and leukemia, using selection and sorting of retroviral infected cells with specific cDNAs and GFP; 5) Analysis of autoepitopes in autoimmune thrombocytopenia and effect of autoantibodies on megakaryocytopoiesis; 6) Studies on lymphohematopoietic cells and their activation status in response to hepatitis B, and C virus infection in humans, chimpanzee and mice; 7) Studies on structure and expression of platelet membrane receptors and their role in platelet function; 8) Analysis of repair of mitochondrial dysfunction through gene transfection, and analysis of repair via measurement of membrane potential, reactive oxygen species and cell growth; 9) Characterization of signaling pathways in airway inflammation, using selection and sorting of transfected airway epithelial cells; 10) Development of new detection: - methods to identify mutations associated with chronic granulomatosus disease; 11) Analysis of adhesive and metastatic properties of tumor cell variants using selection and sorting to isolate stable transfectants expressing mutant forms of integrins; 12) Analysis of the assembly, transport and expression of the high affinity IgE receptor, complex using cells transfected with various components of the complex; 13) and 14) Studies in
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transplantation which examine the delivery of potential therapeutic genes to target cell populations via infection with retroviral vectors. Flow cytometry will be used to select and sort cell populations prior to and after transplantation studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CAPILLARY DNA SEQUENCER/GENETIC ANALYZER Principal Investigator & Institution: Cashdollar, Lester W.; Blood Center of Southeastern Wisconsin Milwaukee, Wi 532012178 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2004 Summary: (provided by applicant): The Blood Research Institute (BRI) of The Blood Center of Southeastern Wisconsin has an established, long-term commitment to bloodrelated research. More than 15 Principle Investigators lead research programs in the fields of cardiovascular biology, immunology, immunohematology, immunoregulation, control of bleeding and thrombosis and transfusion medicine. Six Core Laboratories (Molecular Biology, Protein Chemistry, Hybridoma, Flow Cytometry, Biophysics, and Histology) provide research services for the laboratories at the BRI. Experienced technologists are responsible for the day-to-day operation of the Core Labs and provide the services requested by investigators. Each Core Lab has a Scientific Advisor who is a BRI Investigator with experience in the technology and services provided. The Manager of Core Labs oversees the operation of these support labs. DNA Sequencing is a service provided by the Molecular Biology Core Lab. To meet the needs of BRI researchers we are requesting funds to purchase an ABI Prism 3100 Genetic Analyzer. Projects initiated by nine NIH-funded investigators and those initiated by three new investigators require this facility to accomplish their research goals. These project titles are: Identification of Rare Platelet-Specific AIIoantigens that Trigger Neonatal AIIoimmune Thrombocytopenia; Characterization of Recombinant Fab Fragments that Mimic the Behavior of Drug-Dependent Antibodies; Molecular Basis of A and B Blood Group Antigen Expression of Platelets; Structure and Function of vWAgll; Molecular and Cellular Consequences of vWf Alteration; Role of GPIb in Thrombotic Mechanisms; Integrative Approach to Coronary Thrombosis; Protein Sorting to Endothelial Cells Secretory Granules; Analysis of T cell Responses to Platelet AIIoantigens; Function of HLA-DR Polymorphisms Studied by Mutagenesis; Modulating GVH/GVL Post BMT Using TK Expressing T Cells; Characterization of the Molecular Requirements for Regulation of Cellular Adhesion by PECAM-1; Establishment of Mouse Models to Study the In Vivo Consequences of Constitutive Integrin Activation and Functions of the PECAM-1 ITIM; Thrombomodulin Function in Cellular Physiology; Mouse Model of Juvenile Onset Thrombosis; Use of Genomic Technologies to Facilitate the Identification of the Lymphopenia/IDDM Gene Physiological Role of Fibrin Anti-Thrombin I Activities; Mechanisms of Vase-Occlusion in Sickle Cell Disease; Identification and Characterization of Human Homologs of Murine Histocompatibility Antigens, H60, H4, and H71; New Function of KU70 in Apoptosis Regulation; Role of PLCy1 in B Cell Development and Function. The acquisition of a capillary DNA sequencer will not only support the research projects described above but will also broaden the capabilities of younger investigators, post-doctoral fellows supported by our NIH Training Grant and graduate students who train at the BRI. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CELLULAR THROMBOCYTOPEN
AND
MOLECULAR
BASIS
OF
HIV
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BASED
Principal Investigator & Institution: Ratajczak, Mariusz Z.; Research Assistant Professor; Medicine; University of Louisville University of Louisville Louisville, Ky 40292 Timing: Fiscal Year 2001; Project Start 30-SEP-1998; Project End 31-AUG-2003 Summary: (Adapted from applicant's abstract) Autoimmune mechanisms are known to play a role in the thrombocytopenia observed in individuals infected with the human immunodeficiency virus (HIV) who suffer from the Acquired Immune Deficiency Syndrome (AIDS). However, immunologic mechanisms alone are unlikely to account for all aspects of the pathogenesis of thrombocytopenia seen in AIDS. Among these other mechanisms are possible direct effects of the HIV, or its associated proteins, on the development of megakaryopoietic progenitors in the bone marrow, or the ability of these cells to carry out thrombopoiesis, the process of platelet production. It is also possible that these effects may be brought about indirectly by effects of the virus, or viral proteins, on marrow stromal and accessory cells supportive of megakaryocytopoiesis. To investigate these issues, The applicants propose the following four specific aims: I. Determine the effect of HIV infection on megakaryopoiesis and platelet formation. They will infect human megakaryocytic cells at various stages of development with HIV-1 and HIV-2 viruses and examine the ability of these cells to differentiate into mature megakaryocytes and form platelets. If these processes are impaired, they will determine the mechanism(s) involved. II. Characterize the chemokine receptors on megakaryocytes and the influence of their corresponding ligands on megakaryopoiesis. They will characterize the chemokine receptors displayed on uninfected and infected megakaryocytes, and study the influence of these receptorligand pairs on the developmental biology of these cells. These studies will shed light on the function of these chemokines during megakaryocytopoiesis and thrombopoiesis. III. Investigate the role of HIV proteins and HIV-induced cytokines on thrombocytopenia. They will evaluate the influence of viral proteins and inflammatory cytokines elaborated during infection by accessory cells on the developmental biology of megakaryopoietic precursors and mature cells. IV. Develop strategies for preventing HIV-induced thrombocytopenia. Inhibitory mutants of chemokines have already been developed and shown to prevent HIV infection. Based on findings in the first 3 specific aims, they plan to test blocking chemokines and monoclonal antibodies, and blocking of various cytokines on megakaryopoiesis both ex vivo and in NOD/SCID (non obese diabetic/severe combined immunodeficiency) mice/human hematopoietic chimeras. In toto, the studies proposed in this grant will increase the knowledge about pathogenesis of AIDS associated thrombocytopenia and may lead to development of new strategies for its treatment of prevention. (End of Abstract) Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CELLULAR DEFECTS IN THE WISKOTT/ALDRICH SYNDROME Principal Investigator & Institution: Remold-O'donnell, Eileen; Cbr Institute for Biomedical Research 800 Huntington Ave Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 01-JUN-1997; Project End 31-MAY-2004 Summary: The Wiskott-Aldrich (WAS) is a severe X-linked blood cell disease caused by mutations of the WASP (Wiskott-Aldrich syndrome protein) gene. The most common manifestations of this disease are thrombocytopenia and T lymphocyte based immune defects (eczema etc.). To define the molecular event(s) in Wiskott-Aldrich cells with respect to the role of WASP we intend to undertake biochemical and cell-biological
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approaches to characterize the pathology of WAS. We will identify blood cell populations from healthy individuals and from WASP- and WASP-defective patients that express WASP. We will determine whether WASP interacts with blood cell components such as CD43, GPIb, actin filaments, ezrin, moesin, Ca++ ions and the protease calpain. We will characterize interacting molecules by immune precipitation and by binding studies with GST fusion proteins of WASP and domains of WASP. We will investigate the effect of WASP depletion in T cells on cytoarchitecture, structure of microvilli, and density and distribution of CD43, ezrin, radixin, moesin and calpain. The relevance of WASP-depletion in Jurkatt cells will be evaluated by comparison with Tcells from WASP patients. We will define defective biochemical event(s) by studying pairs of WASP+ and WASP- T-cells to identify biochemical and morphological events responsible for the nonresponsiveness to immobilized anti-CD3. We will identify neoepitopes of WAS-patient platelets and lymphocytes responsible for premature loss of the cells from circulation. These studies will allow us to define the molecular events leading to platelet and T.lymphocyte defects and loss in the WAS. We hope to contribute to a better understanding of his disease and to establishing a basis for the development of new rational therapeutic modalities. We anticipate that these studies will also contribute to the understanding of mechanisms that regulate the function and lifespan of T lymphocytes and platelets in normal individuals and their respective disregulation in immunodeficiency diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHEMOKINE RECEPTORS AND ITP AND HIV THROMBOCYTOPE Principal Investigator & Institution: Rafii, Shahin; Associate Professor of Medicine; Medicine; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2001; Project Start 30-SEP-1998; Project End 31-AUG-2003 Summary: (Adapted from applicant's abstract) Thrombocytopenia is one of the life threatening hematologic disorders that may occur as a result of autoimmune process or during the asymptomatic and clinical stage of HIV-1 infection. It is hypothesized that disruption of chemokine network, and adhesive interactions between megakaryocytes (MKs) and bone marrow endothelium (BMEC) as it may occur during HIV infection, plays a seminal role in the failure of MK transmigration and platelet release. The exact mechanism and site of platelet formation is not well defined. Studies have shown that transmigration of MK through BMEC, may be critical for platelet formation. The investigators have discovered that mature polypoid MKs express the chemokine receptor (HIV co-receptor): CXCR4. Stromal Derived Factor 1 (SDF1) which is the ligand for the CXCR4, promotes transmigration of MKs through BMEC monolayers. They have also identified a novel endothelial cell derived factor (ECDF1) that selectively induce migration of MKs through BMEC. Transendothelial migration of MKs in response to SDF1 or ECDF1 enhances formation of functional platelets. Interaction of migration MK with adhesion molecules expressed on MBEC such as E-selectin and PECAM is critical for MK migration and optimal platelet formation. They have also discovered that HIV can inject MKs through CXCR receptor, interfering with transendothelial migration of Mks, and platelet release. In this proposal they plan to 1) Define the mechanism whereby SDF1 and ECDF1 modulate adhesion molecule adhesion molecule expression of MK and BMEC cells. 2) Characterize cellular signaling pathways such as apoptotic pathways that may be induced by transmigration of Mks. 3) Take advantage of the availability of MK and BMEC derived from E-selectin knockout mice to study the role of these factors in regulation of CXCR expression. Both MKs and BMEC express CD4 and CXCR4, and are therefore susceptible to HIV infection. Therefore, it is planned to define
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the mechanism whereby HIV infection of either Mks and BMEC may influence chemokine receptor, and adhesion molecule expression resulting in dysfunction or platelet formation. Whether HIV-1 gp120 or other factors including megakaryopoietins that interact with CXCR4 may also influence platelet formation will also be explored. They plan to over-express CXCR4 and SDF1 within the milieu of marrow microenvironment by adenoviral vectors to explore the possibility of augmenting platelet production. This project should lead to the definition of the role of chemokines and adhesion molecules expressed by BMEC that regulate platelet production. Identification of chemokine receptors that may regulate platelet production may elucidate pathogenesis of thrombocytopenia in HIV or other thrombocytopenic states and suggest potential pharmacological interventions. Modulation of chemokine receptors expression by adenoviral vectors overexpressing SDF1, ECDF1 or their receptors may allow for developing therapies to ameliorate thrombocytopenia in vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CLINICAL HEMOSTASIS
TRIALS
IN
TRANSFUSION
MEDICINE
AND
Principal Investigator & Institution: Mccullough, Jeffrey; Professor; Lab Medicine and Pathology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): The continuing evolution in medical care, adoption of high technology therapies, and advances in blood banking technology have led to innovations in transfusion therapy. Wise decisions about the use of novel blood products and the management of hemostatic disorders has created a need for a national clinical trials network to evaluate new therapies. The University of Minnesota has a long history of successful transfusion medicine and hemostasis clinical trials. There is an excellent productive relationship between key clinical services and hemostasis and transfusion medicine. The resources to successfully produce novel blood products or to provide new therapies for hemostatic conditions are available through our Molecular and Cellular Facility and Cell Therapy Laboratory and through excellent relationships with traditional blood suppliers. Therefore we propose a transfusion medicine and a hemostasis protocol each of which addresses important clinical issues that need scientific study in a muiticenter network. Preliminary studies have suggested that doses of platelets substantially higher or lower than present practice might lead to an overall reduction in the need for platelets while maintaining adequate hemostasis in thrombocytopenic patients. Therefore, our first proposed trial will compare doses of platelets two times larger and half as large with the present standard dose of platelets for their ability to maintain hemostasis in thrombocytopenic patients. The second clinical trial will compare plasma exchange with high dose steroids for the treatment of thrombotic microangiopathy (TM) secondary to solid organ or stem cell transplantation. Plasma exchange is clearly beneficial in patients with thrombotic thrombocytopenic purpura but TM secondary to transplantation has a different pathophysiologic mechanism and the optimum treatment for this form of TM is not known. This trial will add to the understanding of the management of this difficult clinical situation and will determine which of these therapies is most efficacious. We believe these clinical trials address two extremely important issues; their design illustrates our ability to develop clinical trials and the supportive resource description establishes our ability to provide novel blood components and carry out successful clinical trials. The investigators in this project and other leaders of major clinical programs at the University of Minnesota are
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interested and willing to participate in these and other clinical trials that may be developed through this network. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CYTOKINE CONJUGATES FOR TREATING THROMBOCYTOPENIA Principal Investigator & Institution: Cox, George N.; Bolder Biotechnology, Inc. 4056 Youngfield St Wheat Ridge, Co 800333862 Timing: Fiscal Year 2002; Project Start 01-MAR-2000; Project End 30-JUN-2004 Summary: (provided by applicant): Most human protein therapeutics require frequent dosing due to rapid clearance of the proteins from the body. Development of second generation protein pharmaceuticals that can be injected less frequently is of considerable interest to patients and healthcare providers. We propose to create long-acting forms of IL-11 and TPO by creating larger versions of these proteins with longer circulating halflives. These modified IL-11 and TPO proteins will possess biological activities equal or superior to natural IL-I 1 and TPO in vivo, but will require less frequent dosing, on the order of once every one to three weeks, rather than daily. During Phase I we constructed IL-11 and TPO fusion proteins and demonstrated that certain of them possess near wild type in vitro bioactivities. We also demonstrated that one of the IL-11 fusion proteins has a significantly longer half-life than IL-11 in a rat. During Phase II, we will manufacture sufficient quantities of the modified proteins for more extensive pharmacokinetic and animal efficacy studies. The improved characteristics of the novel IL-11 and TPO proteins will reduce the amount of protein required per patient, improve patient compliance and quality of life and result in considerable cost savings to patients and healthcare providers. These proteins will find utility in treating thrombocytopenia resulting from cancer chemotherapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CYTOSKELETAL MECHANISMS OF PLATELET FORMATION Principal Investigator & Institution: Italiano, Joseph E.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2006 Summary: (provided by applicant): Blood platelets play an essential role in hemostasis. The purpose of this proposal is to investigate the cytoskeletal mechanics of platelet formation using a mouse megakaryocyte (MK) culture system. Platelet formation follows a defined set of morphogenetic shape changes driven by microtubules (MTs) and actin filaments within the MK cytoskeleton. It begins with the extension of large pseudopodia from the MK that appear to use cortical bundles of MTs to elongate into proplatelets which ultimately form prominent coils of MTs at their bulbous ends. Linear arrays of MTs that line the proplatelet shaft serve as tracks for the translocation of platelet components into developing platelets. Repeated bending and branching of proplatelets plays a crucial role in platelet formation. This actin-dependent process, which amplifies proplatelet ends, is essential for generating the beaded appearance of proplatelets. This MK culture system will be used to investigate the role of MTs and actin filaments in the mechanics of platelet formation. Aim I will define how MT forces elongate proplatelet processes and determine how the marginal MT coil forms during platelet morphogenesis. Dynamic changes in the MT cytoskeleton will be observed as it functions in living MKs to establish the contribution of MT assembly and/or sliding in proplatelet elongation and MT coil formation. In Aim 2, structural and biochemical methods will be used to characterize and define the mechanism of organelle and granule
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transport along MTs into developing platelets. Aim 3 will examine the mechanism of actin-dependent proplatelet bending/branching. In the last aim, we will examine platelet morphogenesis at the molecular level and define when the membrane skeleton of the discoid platelet assembles and is locked into place by the vWf receptor-filaminactin linkage. Understanding the cytoskeletal mechanics of platelet formation may provide insights into how platelets are produced and yield strategies for treatment of thrombocytopenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DEVELOPMENT OF ANTI-NRNP AUTOANTIBODIES Principal Investigator & Institution: James, Judith A.; Associate Professor; Oklahoma Medical Research Foundation Oklahoma City, Ok 73104 Timing: Fiscal Year 2002; Project Start 05-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Autoantibodies are universally found in patients suffering from systemic lupus erythematosus. The presence of these antibodies has led investigators to conclude that SLE is an autoimmune disease. In some clinical settings powerful evidence supports the conclusion that specific autoantibodies induce tissue injury and are responsible for clinical manifestations. Anti-Sm and anti-nRNP autoantibodies are commonly found at extraordinary concentrations in the sera of lupus patients. When these autoantibodies are found concomitantly they are associated with renal disease and a poor disease prognosis. Anti-nRNP autoantibodies in the absence of Sin are associated with a more limited form of lupus. Anti-nRNP is also associated with other autoimmune diseases, such as mixed connective tissue disease, Raynaud's phenomenon, scleroderma and myositis. This proposal sets forth to explain the development of anti-spliceosomal autoimmunity. Through our previous work studying the fine specificity of autoantibodies binding to the spliceosome, we have identified over 150 peptide epitopes, 40 of which tend to be shared among patients. We have found that the fine specificity progresses from a small number to as many as 86 different antigenic regions for an individual patient over time. Patients with anti-Sm antibodies appear to initially bind the structure defined by PPPGMRPP. This response evolves by epitope spreading to other structures of the antigen. Immunization with this peptide has led to a novel model of lupus complete with spliceosomal autoimmunity, anti-double-stranded DNA antibodies, renal disease, thrombocytopenia, and seizures. Immunization with the closely related PPPGRRP sequence, which is found in a virus and which crossreacts with Sm, also induces anti-spliceosomal autoimmunity. We request the resources to identify the initial target epitopes of anti-nRNP autoantibodies in SLE sera. We will confirm that PPPGMRPP, as well as the first epitopes of anti-nRNP, are indeed the first epitope(s) of the anti-spliceosomal response. We will utilize a largely untapped resource allowing analysis of humoral events prior to SLE diagnosis (see Project 1). We will find peptides from the environment (especially from microorganisms) which are similar to the initial target epitopes and will determine if the initial target peptide epitopes from the spliceosome (and their structurally similar peptides from the environment) are cross-reacting antigens. We will also determine whether the peptides from the spliceosome or environment induce lupus autoimmunity after peptide immunization. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DEVELOPMENTAL AND GENETIC DEFECTS OF IMMUNITY Principal Investigator & Institution: Ochs, Hans D.; Pediatrics; University of Washington Grant & Contract Services Seattle, Wa 98105
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Thrombocytopenia
Timing: Fiscal Year 2001; Project Start 21-JUL-1995; Project End 30-JUN-2004 Summary: Since the identification of the gene responsible for the Wiskott- Aldrich syndrome (WAS), we have focused our research efforts on the WAS protein (WASP). The goal of this proposal is to define the molecular basis for classic WAS and its milder form, X-linked thrombocytopenia (XLT), and to study the many functions attributed to WASP in human and murine systems. Because of their central importance for the function of WASP, we have selected the pleckstrin homology (PH) domain and the SH3 binding domain of WASP for detailed analysis. Mutation analysis of patients with WAS/XLT has identified many missense mutations within the PH domain that result in XLT. PH domains are known to bind to membrane lipids (e.g., PIP2) and thus are responsible for localizing PH domain containing proteins to the cell membrane. Using an in vitro binding system, we will investigate whether naturally occurring mutations within the PH domain interfere with the binding of WASP to PIP2 and if site directed mutagenesis generates PH domains that no longer bind to PIP2. In contrast, mutations within the SH3 binding domain of WASP result in a severe WAS phenotype. Naturally occurring mutations and mutations obtained by site directed mutagenesis of the SH3 binding domain of WASP, expressed as GST-fusion proteins, will be used to demonstrate a loss of binding to SH3 containing adapter proteins and kinases known to interact with normal WASP. The effect of mutations within the PH and SH3 domain on tyrosine phosphorylation of WASP will also be investigated. Based on the observation that lymphocytes from patients with classic WAS, but not with XLT, show accelerated apoptosis and increased caspase-3 activity, we will investigate different death pathways to identify the mechanisms leading to this accelerated apoptosis. Finally, we have established a breeding colony of WAS deficient (KO) mice that will allows us to study in vivo the immune defect caused by mutations of WASP, using a T cell dependent antigen that is given at low or high doses by different routes to determine antibody responses, and an in vivo HSV infection model to study the generation of antigen-specific CTLs. The usefulness of WASP KO mice to study abnormal platelet function and accelerated apoptosis in vivo will be explored. Results from these investigations will clarify the function of WASP, explain the phenotypes of WAS/XLT and will undoubtedly have implications for optimal therapy of affected patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ECLS IN MULTIPLE ORGAN FAILURE Principal Investigator & Institution: Bartlett, Robert H.; Professor of Surgery; Surgery; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2001; Project Start 01-AUG-1980; Project End 30-JUN-2003 Summary: Over the last 25 years our laboratory research on extracorporeal gas exchange and perfusion (ECMO) has progressed from oxygenator design, through the physiologic response to ECMO, through the development of extracorporeal technology to safe, simple automated systems which can be used to support cardiac or pulmonary function for days. Clinical success with ECMO indicates that expansion to total mechanical extracorporeal life support (ECLS) is feasible, but expansion of the technology requires a solution to two problems: 1) anticoagulation and thrombocytopenia, and 2) multiple organ failure. Despite many innovative approaches to anticoagulation and new prosthetic surfaces, systemic heparin anticoagulation is still required for extracorporeal circulation. A new group of anticoagulants inhibit clotting at specific early stages of the cascade. We will evaluate inhibitors of Factor IXa and Xa, used systemically or on the surface. Nitric oxide, a potent inhibitor of platelet adherence and activation, can be
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incorporated into the plastic materials and ventilating gas in the ECMO system, eliminating surface thrombogenesis, platelet consumption, and systemic anticoagulation without affecting endogenous platelet function. This research will develop and characterize thrombosis prevention leading to prolonged extracorporeal circulation without anticoagulation or thrombocytopenia. This will allow extension of mechanical life support from weeks to months, and initiate new approaches to ECLS. The nonthrombogenic surface combined with high blood flow and a unique albumin-based hemodiafiltration system can extend mechanical life support to liver failure and sepsis. The significance of this research is to decrease the mortality from cardiorespiratory and multiple organ failure. By studying prolonged support in experimental animals we will improve our understanding of the mechanisms and treatment of multiple organ failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ETS-1 AND ELF-1 AND MEGAKARYOPOIESIS Principal Investigator & Institution: Barton, Kevin P.; Ob, Gyn, and Reproductive Med; Loyola University Medical Center Lewis Towers, 13Th Fl Chicago, Il 60611 Timing: Fiscal Year 2001; Project Start 01-AUG-1997; Project End 31-JUL-2002 Summary: Dr. Barton has the long term goal of pursuing independent investigation in the field of hematopoiesis. Receipt of a Mentored Clinical Scientist Development Award will facilitate the development of Dr. Barton's investigative skills and experience by enhancing his knowledge in several areas of hematopoiesis and megakaryopoiesis as outlined in the experimental plan. Dr. Barton along with his sponsor, Dr. Jeffrey M. Leiden have developed an educational environment that has provided the candidate essential training in the production and analysis of gene targeted and transgenic mice. The advisors have been chosen in order to enhance these skills, and extend them to the study of megakaryopoiesis. Dr. Barton is committed to developing a career as an academic physician-scientist investigating the transcriptional regulation of hematopoiesis. The educational environment provided by this proposal together with the sponsor and advisors will foster his progression to an independent investigator. Over the next 5 years Dr. Barton will focus on defining the role that two members of the Ets family of transcription factors, Ets-l and Elf.l, serve in megakaryopoiesis. The genes for Ets-1 and Elf-I will be disrupted by targeted homologous recombination in ES cells. Homozygous- mutant mice will be produced, and the affects on megakaryocyte development, gene expression, platelet production and function extensively analyzed in the yolk sac, fetal liver, and adult bone marrow. In addition, ES cells with homozygous deletions in the Ets- 1 and Elf-l gene will be used to produce chimeric animals. The contribution of these Ets-I and Elf-I deficient cells to the megakaryocyte and platelet pools will be assessed. Finally, Dr. Barton will optimize in vitro culture conditions for megakaryocyte differentiation from ES cells. This system will allow in vitro analysis of the affects of transgenes on megakaryocyte development. These studies have broad important basic biological implication in addressing fundamental questions of megakaryocytic lineage determination and transcriptional regulation of megakaryocyte specific genes. The potential clinical relevance of these studies is similarly.broad, and encompasses the primary hematologic disorders associated with hemorrhage such as Bernard-Soulier syndrome, Glanzmann thrombasthenia, and the thrombocytopenic states associated with a megakaryocytic thrombocytopenia and myelodysplasia, as well as the thrombocytosis of the myeloproliferative disorders. Understanding the transcriptional regulation of the adhesion proteins in platelets has further potential clinical relevance in that platelets via their adhesive proteins are important factors in the ischemia of arterial anthrosclerotic disorders. A more complete understanding of the
20
Thrombocytopenia
factors controlling development and megakaryocyte gene expression is an essential prerequisite in order to design logical interventions for these disorders as we move into the age of molecular medicine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FASL IN PREECLAMPSIA AND IMMUNOTOLERANCE TO THE FETUS Principal Investigator & Institution: Kauma, Scott W.; Professor; Obstetrics and Gynecology; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2001; Project Start 01-JUL-1998; Project End 31-MAY-2003 Summary: Preeclampsia is a health problem of pregnancy that affects approximately 710 percent women and is associated with significant maternal/neonatal morbidity and mortality. It is characterized by vascular endothelial, hepatic and renal glomerular cell dysfunction. The placenta is thought to produce factors that result in the pathogenesis of the disease since delivery of the placenta is an effective cure. Unfortunately, the identity and role of these placental factors in the pathogenesis of preeclampsia is poorly understood. Thrombotic Thrombocytopenia Purpura (TTP) and Hemolytic Uremic Syndrome (HUS), two diseases that are clinically similar to preeclampsia, are caused by Fas/Fas ligand (FasL) induced microvascular endothelial cell apoptosis. Resent studies in our laboratory have demonstrated that FasL expression in placental trophoblast is an important mediator of maternal immune tolerance to the fetus. We also have preliminary evidence that preeclampsia is associated with increased placental FasL production and secretion into the maternal circulation. Taken together, these findings suggest an important role for Fas/FasL as a mechanism in the pathogenesis of preeclampsia. Specifically, our hypothesis states that preeclampsia is associated with increased levels of circulating FasL resulting in apoptosis of microvascular endothelial, hepatic, and renal glomerular cells. Furthermore, Th1 cytokines and lipid peroxides which are increased in preeclampsia may augment Fas/FasL mediated apoptosis in these target cells. These hypotheses will be tested with regards to the following specific aims: 1. To determine the sources involved in the increased expression and systemic delivery of FasL in preeclampsia. 2. To evaluate the regulation of FasL expression by hypoxia, maternal lymphocyte and placental derived cytokines. 3. To determine the role of Fas mediated cell apoptosis in the pathophysiology of preeclampsia. These studies will significantly advance our understanding of the mechanisms involved in the pathogenesis of preeclampsia and provide new rationales for the treatment of this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GENE REGULATION OF THROMBOPOIETIN EXPRESSION Principal Investigator & Institution: Mc Carty, John M.; Div of Hematology and Oncology; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2001; Project Start 01-SEP-1998; Project End 31-AUG-2003 Summary: One of the least understood aspects of hematopoiesis is the process of megakaryocyte development. The recent cloning of thrombopoietin (TPO), an essential cytokine regulator of this process, allows investigation of the molecular basis for maintenance of physiologically appropriate platelet levels to proceed. Northern blots have revealed several disparate tissues to express TPO, but the cells which are responsible for TPO expression in vivo have not been identified. Two main models of TPO serum level regulation have been proposed. One asserts that TPO expression is
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constitutive in liver and kidney, and that serum levels are mediated via protein metabolism by an expanding or contracting platelet mass. A second suggests that in states of significant platelet variability, TPO mRNA levels may vary inversely to platelet mass. We provide experimental evidence which supports constitutive TPO expression in the liver and kidney, and mRNA-based regulation in the marrow and spleen. We plan to study the molecular basis of TPO gene regulation with an eye to understanding how the basal and inducible tissue-specific expression of the TPO gene translates into physiologically appropriate serum protein levels. To achieve these ends, we propose a research plan of three specific aims: 1. To identify the cellular and histologic sites of basal and inducible TPO production in mouse models of thrombocytopenia by in situ hybridization, RNA analysis of primary cell fractions and lines and RT-PCR; 2. To refine in vitro models of constitutive and inducible tissue-specific TPO gene expression and identify the relative contribution of transcriptional enhancement and mRNA accumulation in cells which increase TPO mRNA levels in response to thrombocytopenic sera; 3. To compare the functional organization of the TPO gene by DNAseI hypersensitive site mapping, by RNAse protection assays and 5' RACE analysis to characterize hTPO 5' mRNA isoforms during perturbations in platelet and megakarcyocyte mass, by identification of functionally relevant cis-acting elements of the TPO promoter by reporter gene analysis, refining these sequences by DNAse I footprint and mobility shift assays, and confirming the functional contribution of these sequences to constitutive and inducible tissue-specific TPO expression by site directed mutagenesis and determining their functional role by gain of function/loss of function analysis in reporter gene assays. We provide data to suggest these aims are feasible and will result in useful data as a basis for future studies. Understanding the mechanisms by which this regulator of megakaryocyte maturation is controlled will provide insight into normal and dysregulated megakaryocytopoiesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENE THERAPY FOR THE WISKOTT ALDRICH SYNDROME Principal Investigator & Institution: Strom, Ted S.; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2004; Project Start 10-DEC-2003; Project End 30-NOV-2008 Summary: (provided by applicant): The goal of this application is the development of an effective and safe methodology for treating hematopoietic diseases with gene therapy. The work is focused on a murine model of the Wiskott-Aldrich syndrome (WAS), which in humans causes the triad of eczema, immunodeficiency and thrombocytopenia due to deficiency of the WAS protein (WASP). Although curable by bone marrow transplantation, many patients with WAS lack a suitable donor, and therefore alternative therapeutic approaches are required. The murine model faithfully reproduces the human condition with respect to immunodeficiency and thrombocytopenia. The applicant's preliminary data have established sensitivity to challenge with mycobacterium bovis and influenza in the murine WAS model providing quantifiable assays for evaluating the effects of gene transfer. Four specific aims are proposed: 1) to correct the immunodeficiency of murine WAS; 2) to determine the degree of myeloablation required to achieve phenotypic correction of immune function in murine WAS; 3) to correct the thrombocytopenia of murine WAS; and 4) to evaluate the mechanisms responsible for murine WAS thrombocytopenia. The studies are focused on correlating the pattern of and levels of WASP expression in various hematopoietic lineages with phenotypic correction of the immunodeficiency and thrombocytopenia. If necessary, various vector designs will be explored in the context
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of optimizing the outcome of the gene therapy intervention. Quantitative data generated in a murine model will be useful in developing future human clinical trials. The environment at St. Jude Children's Research Hospital is particularly conducive to training in these areas. Areas of relevant expertise include the use of oncoretroviral vectors to correct immunodeficiencies (Dr. Brian Sorrentino), the development and use of oncoretroviral and lentiviral vectors to treat severe beta-thalassemia (Dr. Derek Persons) and general expertise in the development of lentiviral vectors (Dr. Arthur Nienhuis). The applicant will also draw on outstanding expertise in congenital immunodeficiencies (Dr. Mary Ellen Conley), in T-cell immunology (Dr. Peter Doherty) and in platelet function (Dr. Carl Jackson). The proposed work will therefore allow the applicant to build upon his previous clinical training in clinical pathology and hematopathology and laboratory experience in virology and to enhance his potential for success as an independent investigator. (End of Abstract) Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC MACROTHROMBOCYTOPENIAS
ANALYSIS
OF
HEREDITARY
Principal Investigator & Institution: Kelley, Michael J.; Associate Professor of Medicine; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2001; Project Start 15-FEB-2001; Project End 30-NOV-2002 Summary: (Adapted from investigator's abstract): Macrothrombocytopenias with leukocyte inclusions are a set of hereditary clinical syndromes characterized by giant platelets and thrombocytopenia that include May-Hegglin anomaly (MHA), Fechtner syndrome, and Sebastian syndrome. The cause of these disorders is not known, but a gene causing MHA has recently been localized to chromosome 22. The PI has refined the mapping of this gene causing MHA in three families to a 6 cM, 1 Mb region of chr 22. The goal of the application is to identify the gene responsible for MHA and begin genetic investigation of related syndromes. Family ascertainment and characterization will be performed, as well as examination of candidate disease genes. When the causative gene is identified, biochemical and physiological analysis will be pursued including development of a murine model of the disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETICS OF SEVERE SLE DEFINED BY THROMBOCYTOPENIA Principal Investigator & Institution: Scofield, R Hal.; Associate Professor; Oklahoma Medical Research Foundation Oklahoma City, Ok 73104 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): The candidate for this K24:Mid Career Investigator in Patient Oriented Research is an experienced and productive physician-scientist whose work has concentrated upon autoimmune rheumatic diseases, including systemic lupus erythematosus. The candidate has made important contributions to the understanding of SLE pathogenesis, including genetic. He carries out this work in the Arthritis & Immunology Program at Oklahoma Medical Research Foundation, one of the largest and most productive research units dedicated to the study of immune-mediated rheumatic illness. SLE is complicated, with a wide range of manifestations. Use of stratification of a disease population has proven very useful in other diseases (BCR1 gene, for example). We hypothesize (and the preliminary data demonstrate) that the clinical phenotypes of SLE are valuable in uncovering the genetics of SLE. Thrombocytopenia predicts severe disease and death in SLE, making the identification
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of related genetic risk factors especially important. We selected the 38 pedigrees that had an SLE patient with thrombocytopenia from 179 pedigrees multiplex for SLE. Linkage was established at 11p13 (Iod=5.72) in the 13 African-American pedigrees. Nephritis, serositis, europsychiatric involvement, autoimmune hemolytic anemia, anti-double stranded DNA and antiphospholipid antibody were associated with thrombocytopenia. SLE is more severe in the families with a thrombocytopenic SLE patient, whether or not thrombocytopenia in an individual patient is considered. This project will explore the genetics of the severe phenotype of SLE defined by thrombocytopenia. In particular, the PI will concentrate on the statistically powerful finding on chromosome 11p13, the strongest found to date in SLE. In the first specific aim, the genetic interval will be fine mapped with DNA microsatellite markers in order to confirm linkage and narrow the interval. In Specific Aim 2 the PI will search for genetic association with SLE by typing at single nucleotide polymorphisms throughout the defined interval supporting linkage. In Specific Aim 3, the genetic polymorphism(s) responsible for the linkage will be sought by sequencing genes within the now narrowly defined linkage interval. Finally, Specific Aim 4 will assemble a new cohort of families multiplex for SLE so that linkages and associations as well as particular polvmorphisms can be prospectively confirmed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENOMIC HEMATOPOIESIS
APPROACH
TO
INVESTIGATING
EX
VIVO
Principal Investigator & Institution: Papoutsakis, Eleftherios T.; Walter P. Murphy Professor; Chemical Engineering; Northwestern University 633 Clark St Evanston, Il 60208 Timing: Fiscal Year 2003; Project Start 01-APR-1993; Project End 31-MAR-2008 Summary: (provided by applicant): High-dose chemotherapy with autologous or allogeneic stem-cell rescue results in prolonged pancytopenia that is accompanied by infectious and bleeding complications requiring antibiotic and transfusion therapy and, at times, prolonged hospitalization. Infusion of large numbers of ex vivo expanded hematopoietic cells -as a supplement to the conventional auto- or allograft - has the potential to close the window of neutropenia and/or thrombocytopenia. Furthermore, the recently discovered plasticity of hematopoietic stem cells suggests that these readily available stem cells may be used for generating autologous or allogeneic cells and tissues for non-hematopoietic cell and gene therapies. Success of such therapies depends on the ability to generate large numbers of cells with the desired, therapy-dependent state of cell differentiation. This remains an elusive task despite the great progress in basic and applied biology. Culture conditions, such as cytokine combinations and presentation, oxygen tension (pC2) and pH, alter stem- and progenitor-cell differentiation and proliferation with substantial patient-to-patient variability. Little is known about the underlying molecular biology of these effects, and specifically, about the large-scale transcriptional program during differentiation. Such knowledge has large predictive and diagnostic potential for both ex vivo and in vivo outcomes. Thus, a comprehensive examination of the transcriptional program of ex vivo expanded human primary myeloid cells - initiated with CD34+ cells - will be examined using 8,300-gene DNA microarrays, and key findings further explored using standard molecular-biology tools. Studies include examination of the temporal and differential transcriptional program of G and Mk cells cultured either under high or low pC2 and/or pH, and with different cytokine combinations. Specific issues to be examined include the extent to which apoptosis is linked to Mk differentiation; if Mk apoptosis employs a machinery similar to that of general apoptosis; and why, in contrast to Mk cultures, there is such a
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Thrombocytopenia
low level of apoptosis in G cultures. Furthermore, gone-clustering and regulatorynetwork techniques applied to DNA-microarray data may lead to the discovery of unknown Mk- and G-differentiation genes. These experiments will provide the basis for future studies in which clinical specimens could be examined in the context of clinical stem cell transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GLYCOSAMINOGLYCANS: TREATMENT FOR ALZHEIMER'S DISEASE Principal Investigator & Institution: Hanin, Israel; Professor and Chairman; Neurostructural Analysis, Ltd 2109 W 5Th Ave, Ste B Columbus, Oh 43212 Timing: Fiscal Year 2001; Project Start 30-SEP-1998; Project End 30-NOV-2002 Summary: (adapted from applicant's abstract): The long-term objective of this proposal is to find novel treatment strategies in Alzheimer's disease. Phase I of this Small Business Technology Transfer application focused on C3, an ultra low molecular weight product of fractionated heparin. C3, a glycosaminoglycan (GAG), is composed mainly of 4-10 oligosaccharides, and has an appalent molecular weight of 1,940 and a USP value of 12 U/mg. In F344 rats C3 was shown to cross the blood brain barrier. It also prevented tau-2 immunoreactivity and astrocytosis (comparable to the type of neurodegeneration observed in Alzheimer's disease) that had been induced by injection of Abeta(25-35), directly into the amygdala in the brain of rats. C3 also increased the arborization of dendrites in the hippocampus; hence it may have neurotrophic activity in the brain. C3, and/or other, related GAGs, may therefore be effective as adjuncts in the treatment of Alzheimer type degeneration. Studies in this Phase II application will screen C3, as well as four related. ultra low molea about lar weight GAGs in the ~ 2000 molecular weight range. They will be subjected to a variely of tests in F344 male rats, aimed at selecting the best candidates for potential commercial application. Specific Aim 1 will establish the blood brain barrier permeability of these compounds, to exclude those that have a low penetrability into the brain. Specific Aim 2 will characterize the bleeding and thrombocytopenic potential of the remaining compounds, to exclude those that should not be used chronically in patients. Specific Aim 3 will measure the ability of the remaining GAGs to prevent tau-2 immunoreactivity and astrocytosis in brains following Abeta (25-35) injection into the amygdale of rats. Employing Golgi methodology, Specific Aim 4 will analyze the effect of the success about l GAGs on hippocampal dendritic morphometry, in young and aged rats, with and without their prior exposure to Abeta (25-35). Specific Aim 5 will evaluate attenuation and/or reversal of behavioral dysfunction in aged rats by the GAGs, using the open field, two-way conditioned avoidanee response, and Morris Water Maze tests. Brain cholinergic function will be assessed in these rats at the completion of the behavioral tests. Finally, Specific Aim 6 will establish the pharmacokinetic and pharmacodynamic profile of the selected GAGs. These studies should yield one, or possibly more, promising candidate(s) for subsequent extensive toxicological studies, followed by early clinical development. PROPOSED COMMERCIAL APPLICATION: This research introduces a new strategy to identify, screen and synthesize homogeneous glycosaminoglycans, which could ultimately be tested in clinical trials in patients with Alzheimer's Disease. the potential commercial outcome of these studies would be the development of new, effective agents for the prevention and/or treatment of Alzheimer's Disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: INTERACTIONS
GRANULOCYTIC
EHRLICHIOSIS:
25
CELL-PATHOGEN
Principal Investigator & Institution: Borjesson, Dori L.; Veterinary Diagnostic Medicine; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2006 Summary: (provided by applicant): Human granulocytic ehrlichiosis (HGE) is an emerging, potentially fatal, tick-borne zoonotic disease caused by an obligate intracellular bacterium. Although Anaplasma phagocytophila, formerly the HGE agent, lives and replicates primarily within granulocytes, multiple cytopenias, especially thrombocytopenia, are a consistent hallmark of infection. The interaction of A. phagocytophila with neutrophils and platelets in vivo and the manner in which these interactions contribute to infection efficiency, cytopenias, pathogen distribution and transmission are still unclear. The goal of this project is to understand pathogen interaction with host cells in light of hematologic abnormalities and in vivo infection kinetics utilizing a murine model of HGE and in vitro cell techniques. Study objectives are first, to determine leukocyte and platelet interaction with, and response to, A. phagocytophila and, second, to determine the role, if any, these interactions play in determining pathogen distribution and transmission. The central hypothesis for the proposed research, based on preliminary data, is that during early infection, A. phagocytophila adheres to and activates both granulocytes and platelets resulting in alterations in cell adhesion and distribution that directly affect cell-pathogen trafficking and facilitate pathogen replication and transmission. The proposed work is focused on an emerging, zoonotic disease with potentially serious hematologic alterations. Significant positive impacts of this work will include enhanced understanding of in vivo bacterial pathogenesis as well as elucidation of possible targets for interruption of the transmission cycle from animal host to tick vector. The purpose of the proposed Mentored Clinical Scientist Development (KO8) award is to provide the candidate with the mentoring and resources needed for transition into the position of an independent academic clinician-scientist. The award is ideally suited to this candidate who has completed her professional veterinary degree, clinical pathology training and PhD in Comparative Pathology but has not completed postdoctoral research training. Currently, the candidate is a junior faculty member at a strong research institution with a clear mandate and desire to pursue an independent research program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HANTAVIRUS: HEMORRHAGIC FEVER IMMUNOPATHOGENESIS Principal Investigator & Institution: Libraty, Daniel H.; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2003; Project Start 01-OCT-2003; Project End 30-SEP-2008 Summary: Hantaviruses are RNA viruses that cause hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS). HPS and HFRS are characterized by fever, myalgia, rapid onset of a vascular leak syndrome, hemoconcentration, and thrombocytopenia. In HPS, the lung is the prominent target organ; while, in HFRS, the kidney is the prominent target organ. Hantaviruses are NIAID category A priority pathogens with regards to biodefense, as they can produce severe, potentially fatal, diseases, are transmitted by aerosol, and do not have effective vaccines or specific therapeutics. The goal of this project is to understand the immunologic mechanisms that lead to HFRS. Several lines of evidence suggest that HFRS is not caused by direct cytopathic effects of hantaviruses, but rather by exuberant
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Thrombocytopenia
host immunopathological responses. This project will rely on samples provided from a prospective cohort study of Puumala (PUU) virus infections, a HFRS-associated hantavirus in Finland. The first aim will be to characterize dendritic cell functions and humoral immune responses that affect the PUU virus burden, using flow cytometry, antibody detection assays, and quantitative viral RT-PCR. The second aim will be to analyze the patterns and temporal regulation of cellular immune responses throughout acute PUU virus infection. ELISAs, multiplex immunoassays, quantitative RT-PCR, and genomic screening techniques will be used to examine immune response mediators in a comprehensive fashion, along with virus levels and disease severity. The third aim will be to characterize the antigen specificity and behavior of T lymphocyte responses during and after PUU virus infection. CD8+ and CD4+ T cell epitopes from PUU virus proteins will be identified using cell cloning techniques, ELISPOTs, cytotoxic T lymphocyte (CTL) assays, and mapping with overlapping synthetic peptides. Effector mechanisms of vascular leakage will be studied by examining interactions between endothelial cells and PUU virus-specific T cell clones. Peptide stimulation with intracellular cytokine staining and peptide-HLA Class I and II tetramers will be used to identify and quantify antigen-specific T cell responses across a spectrum of PUU virus disease. Elucidation of the immunopathogenetic mechanisms in PUU virus infection will contribute to the development of effective vaccine strategies and immune-based therapies of HFRS and HPS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HEMATOPOIETIC STEM CELLS & LYMPHO-HEMATOPOIESIS: ALCOHOL Principal Investigator & Institution: Wolcott, Robert M.; Microbiology and Immunology; Louisiana State Univ Hsc Shreveport P. O. Box 33932 Shreveport, La 71103 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Chronic ingestion of alcohol can affect many aspects of hematopoiesis and the function of hematopoietic lineage cells. The deleterious effects of chronic alcohol include thrombocytopenia, neutropenia and lymphopenia, as well as pancytopenia. Vacuolization of bone marrow cells is common and, although rare, hypocellularity of the bone marrow has been observed. Many patients show a marked immunodeficiency associated with neutropenia and lymphopenia. The hematological complications observed in alcoholic patients suggest that alcohol abuse places excessive demands on the hematopoietic system. Throughout life, the hematopoietic system is maintained by a population of self-renewing, pluripotent hematopoietic stem cells (HSC's) that generate all of the hematopoietic lineages through the production of oligopotent progenitors. HSCs are rare in the bone marrow yet, due to their selfrenewal, they are long-lived and under normal circumstances are not depleted within the lifetime of the organism. However, there are studies that suggest that HSCs can be exhausted under extraordinary circumstances. The hypothesis to be tested in this proposal is that alcohol abuse imparts excessive demands on the hematopoietic system that can lead to premature senescence of HSC's. Corollary hypotheses that will also be addressed are that alcohol has a direct toxic effect on HSC's; and alcohol adversely affects the microenvironment of the bone marrow leading to aberrant hematopoiesis. The goals of this proposal are to determine the effects of chronic alcohol ingestion on the number, longevity, and function of HSCs using a murine model. The effects of alcohol on the different stages of hematopoietic development will be determined at the phenotypic and functional levels and the effects on the microenvironment will be assessed by determining the effects of on the expression of hematopoietic cytokines and
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the ability of the marrow to sustain hematopoiesis. The effects of alcohol on the in vivo function of HSC's will be determined by competitive reconstitution assays at limiting dilution. To determine if alcohol accelerates senescence of HSC's secondary and tertiary transplantations of HSC's will be done over a three-year period. To determine whether normally quiescent HSC's are activated by alcohol feeding, the sensitivity of these cells to cytotoxic drugs will be assessed by quantitating surviving HSC's and determining the rate of recovery of bone marrow homeostasis following injection of the cytotoxic drug. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HEPARIN-INDUCED THROMBOCYTOPENIA Principal Investigator & Institution: Visentin, Gian Paolo.; Associate Professor; Blood Center of Southeastern Wisconsin Milwaukee, Wi 532012178 Timing: Fiscal Year 2001; Project Start 01-MAR-2001; Project End 30-NOV-2004 Summary: (Investigator's abstract) Heparin-induced thrombocytopenia, with or without thrombosis (HIT/T), is an important cause of morbidity and mortality in patients treated with this otherwise extremely useful anticoagulant. From studies in our lab and by others, much has been learned about HIT/T in recent years but its pathogenesis is still not understood adequately at the molecular level. HIT/T is remarkable, and probably unique among immune disorders in several respects: 1) the responsible antibodies appear to be specific for complexes made up of two normal body constituents, heparin and platelet factor 4 (PF4), 2) antibodies with this specificity are produced by a high percent of certain patient populations given heparin but are almost never found in persons not exposed to heparin and 3) only a minority of patients who make antibodies develop HIT/T. In this application, I propose studies to determine the molecular basis for immune response to PF4:heparin that appears to be central to the pathogenesis of HIT/T. In one phase of this work, I will characterize immunoglobulin V genes utilized in mounting a pathogenic response and define at a molecular level the epitopes on PF4:heparin complexes recognized by HIT/T antibodies and characterize Ig CDR3 sequences critical for this interaction. In the other phase II, I will apply methods recently developed in our laboratory to generate antigen-specific T cell lines and clones from blood of patients with HIT/T and will utilize these to characterize T cell receptor utilization and immunogeneic peptides derived from PF4. The hypothesis on which this application is based is that a more complete understanding for the molecular basis of the unusual immune response characteristic of HIT/T will suggest new approaches to diagnosis, treatment, prevention and identification of patients at risk for this disorder. More speculatively, findings made could provide clues to the mechanism(s) by which heparin triggers an antibody response to PF4 - an otherwise immunologically inert protein - and could therefore be relevant to certain autoimmune and immune complex disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TRANSFUSION
HLAMATCHMAKER
FOR
TRANSPLANTATION
AND
Principal Investigator & Institution: Duquesnoy, Rene J.; Pathology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-DEC-2007 Summary: (provided by applicant): HLAMatchmaker is a new algorithm to determine HLA compatibility at the structural level. Donorrecipient HLA matching is assessed by intralocus and interlocus comparisons of polymorphic amino acid tdplet sequences in
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Thrombocytopenia
alloantibody-accessible positions of HLA molecules. For many patients, HLAMatchmaker can identify mismatched HLA antigens that are zero-triplet mismatches and should therefore, be considered fully histocompatible at the structural level. Recent studies have shown that HLA class I triplet matching correlates with excellent kidney transplant outcome and that HLAMatchmaker provides a useful strategy to identify more compatible donors. After working with the various HLAMatchmaker programs downloaded from our website, many HLA professionals share our belief that this algorithm is superior to the conventional HLA matching system especially for sensitized patients as well as minority groups for whom it is often difficult to find compatible donors. This project deals with studies on refining and expanding the HLAMatchmaker algorithm and how this program can be used in a clinical setting. There are four objectives: (1) Study the serological identification of triplet-defined of epitopes recognized by human monoclonal alloantibodies, (2) Determine the relative immunogenicity of triplet-defined epitopes, (3) Assess clinical relevance of HLAMatchmaker in platelet transfusion support of refractory thrombocytopenic patients and stem cell transplantation from unrelated donors, (4) Apply HLAMatchmaker for determining the structural basis of HLA class II compatibility. These studies will increase our understanding of the structural basis of HLA compatibility. The ultimate goal of this project is the application of HLAMatchmaker as a new donor selection strategy in transplantation and platelet transfusions nationwide Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HOST CELL INTERACTIONS BY PATHOGENIC BORRELIAE Principal Investigator & Institution: Leong, John M.; Associate Professor; Molecular Genetics & Microbiol; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2001; Project Start 01-APR-1995; Project End 31-DEC-2005 Summary: (Adapted from the Applicant's Abstract): Borrelia burgdorferi is the causative agent of Lyme disease, and B. hermsii and B. turicatae are causative agents of tick-borne relapsing fever. Pathogen-host cell interactions are thought to be critical determinants of the site and severity of infection, and Dr. Leong's group has focused on Borreliae recognition of two classes of host cell molecules: (1) glycosaminoglycans (GAGs); and (2) integrins and their associated proteins. For B. burgdorferi, they have found that differences in GAG recognition were associated with differences in host cell typespecific binding, and identified a surface protein, Bgp, that may be the major B. burgdorferi GAG receptor. This bacterium also recognizes the activation-dependent platelet integrin alphaIIbbeta3 and thereby selectively binds to activated (vs. resting) platelets. This integrin-binding activity is predicted to target the Lyme disease spirochete to the vessel wall at sites of platelet adherence, and could explain a salient feature of Lyme disease: vascular pathology of the arterial circulation. In Dr. Leong's studies of relapsing fever spirochetes, high-level GAG-binding correlated with highlevel growth in the bloodstream, and a variable major protein, VspB, promoted attachment to GAGs. Additionally, in contrast to B. burgdorferi, B. hermsii bound and activated resting platelets. The platelet activation activity is apparently mediated by the integrin-associated platelet-signaling molecule CD9. Dr. Leong speculates that prior to the development of an antibody response, attachment of relapsing fever spirochetes to the vessel wall, either directly via GAGs or indirectly, via activated and adherent platelets, could diminish the clearance of bacteria from the bloodstream by the reticuloendothelial system. Continued replication by these adherent bacteria would
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result in high level bacterial seeding of the bloodstream. Interaction of spirochetes with platelets could also contribute to thrombocytopenia, a common manifestations of relapsing fever. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HUMAN GRANULOCYTIC EHRLICHIOSIS: NORTH CENTRAL U.S. Principal Investigator & Institution: Johnson, Russell C.; Professor; Microbiology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2001; Project Start 01-FEB-2001; Project End 31-JAN-2006 Summary: Human granulocytic ehrlichiosis (HGE) is an emerging tick-borne acute febrile illness. The agent of HGE is closely related to or identical to the horse pathogen Ehrlichia equi and is transmitted by Ixodes scapularis, the same tick that transmits the agents of Lyme disease and babesiosis. The HGE agent infects blood polymorphonuclear neutrophils resulting in neutropenia and a thrombocytopenia. HGE may be a mild to potentially fatal disease. HGE was first described in Minnesota and Wisconsin in 1994 and subsequently more than 400 cases have been described in the U.S. In contrast to Lyme disease which frequently occurs in children, the rates and severity of HGE increase with age. This age-specific incidence of HGE and our large aging population presents a potentially major public health problem with corresponding economic consequences. This emerging public health problem highlights the importance of early diagnosis and treatment in preventing complications of infection, and targeting of prevention and control studies to populations at highest risk. The research proposed in this application is designed to aid in achieving the above goals by analyzing the epizootiology of HGE in the North Central U.S. Our specific aims are: to investigate the hypothesis that white-tailed deer serve as a large mammal reservoir of the agent of HGE and to identify the small mammal reservoirs of the HGE agent. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: 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 2001; 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
30
Thrombocytopenia
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 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: IMMUNE RECONSTITUTION FOLLOWING HIV INFECTION Principal Investigator & Institution: Zack, Jerome A.; Professor; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-AUG-1994; Project End 30-NOV-2006 Summary: (provided by applicant): HIV infection causes pathological consequences that extend far beyond CD4+ cell depletion, which include anemia, granulocytopenia, thrombocytopenia and myelodysplastic/hyperplastic alterations of bone marrow. We have developed the SCID-hu mouse as a means of assessing pathogenic mechanisms of HIV and therapeutic modalities to combat these pathogenic effects. The SCID-hu mouse bears a human hematopoietic organ (Thy/Liv) that harbors long-lived human hematopoietic progenitor cells and directs their differentiation through the T-lymphoid lineage. In addition, human pluripotent hematopoietic progenitor cells can be recovered from these implants, and can be induced to differentiate along the myeloid and erythroid lineages ex vivo, thus the SCID-hu mouse possesses characteristics of both human thymus and bone marrow. Our earlier studies have shown that HIV infection causes a loss of CD4+ thymocytes, and a decrease in the ability of CD34+ progenitor cells to form myeloid and erythroid colonies in response to cytokine stimulation ex vivo. However reconstitution of these differentiative processes can be induced by HAART. Furthermore, the inhibitory effects on myeloid and erythroid differentiation appear to be indirect. More recently we have found that infection of these implants is associated with an increase in expression of two cellular genes (IP-10 and MIG) which are known to inhibit hematopoietic colony formation by precursor cells. The studies proposed herein will employ the SCID-hu mouse system to address mechanisms involved in HIVinduced perturbation of hematopoiesis and explore ways to augment reconstitution in the context of HAART. We will do this by the following Specific Aims: 1) Explore means to increase reconstitution of thymopoiesis following HIV-induced depletion of CD4 cells; 2) Explore means to increase reconstitution of hematopoietic colony-forming activity following HIV infection; 3) Define the roles of IP-10 and MIG-1 in HIV-induced loss of colony forming activity; 4) Further explore indirect mechanisms which could lead to hematopoietic abnormalities in vivo. A greater understanding the mechanisms leading to these hematopoietic abnormalities may allow development of better therapies for the consequences of HIV disease.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMPACT OF ENDOTHELIN IN INTRAUTERINE GROWTH RESTRICTION Principal Investigator & Institution: Thaete, Larry G.; Evanston Hospital Evanston, Il 60201 Timing: Fiscal Year 2001; Project Start 18-JUN-2001; Project End 31-MAY-2006 Summary: (Adapted from applicant's description): Intrauterine growth restriction (IUGR) occurs in 4 to 7% of all infants delivered in developed countries, and is a major contributor to perinatal morbidity and mortality. Inadequate uteroplacental perfusion is fundamental to most cases of IUGR in humans. Endothelin-1 (ET-1) and nitric oxide (NO) are vascular mediators which are important for the regulation of uterine and placental vascular tone. The investigators hypothesize that increased endogenous ET-1, a locally active vasoconstrictor, is critically important in the pathophysiology of IUGR. They will evaluate the molecular mechanisms regulating the activities of both ET-1 and NO in uteroplacental perfusion and IUGR. They also will evaluate the role of endogenous ET-1 in the pathophysiology of IUGR, using ET-1 receptor antagonists. The investigators will use two different animal models of IUGR which were selected because of the opportunity they provide to study the roles of these two mediators. 1) Chronic maternal hypoxia is a model of IUGR which is associated with increased endogenous ET-1 as well as decreased nitric oxide synthase (NOS) activity. This model will be used to evaluate the efficacy of ET-1 antagonists to improve uteroplacental perfusion and prevent IUGR. 2) Chronic NOS inhibition is another established model of IUGR which also is associated with increased circulating endogenous ET-1. Additionally, NOS inhibition in the rat mimics human preeclampsia, a condition commonly associated with IUGR. The investigators will use this model to evaluate whether ET-1 antagonism prevents the preeclampsia-like state, as well as IUGR, caused by chronic NOS inhibition. In each of these models, they will evaluate the molecular mechanisms which regulate ET-1 activity. Additionally, in the hypoxia model the investigators will evaluate the molecular mechanisms regulating NO activity. The goal is to better understand the regulation of uteroplacental perfusion, to delineate the molecular mechanisms regulating the synthesis and activity of ET-1 and NO, and, using ET-1 antagonists, to evaluate the specific role of ET-1 in the pathophysiology of IUGR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: IMPROVED SURGICAL ANTICOAGULATION USING A HCII AGONIST Principal Investigator & Institution: Cardin, Alan D.; Celsus Laboratories, Inc. 12150 Best Place Cincinnati, Oh 45241 Timing: Fiscal Year 2001; Project Start 01-MAR-2001; Project End 31-AUG-2002 Summary: (Investigator's abstract) Thrombin bound to fibrin, the vessel wall and/or to extracorporeal surfaces is resistant to inhibition by heparin/antithrombin Ill (HAT). Intimatan, a dermatan disulfate semi-synthetically enriched in iduronic acid-N-acetyt-Ogafactosamine 4,6-O-disulfate, mediates the sustained inhibition of surface-bound thrbmbin. Intimatan, a potent heparin cofactor II (HCII) agonist, targets HCII to the same exosite of thrombini targeted by hirudin but not by RAT. In the pig model of cardiopulmonary bypass surgery (CPB), Intimatan, relative to heparin, maintained extra-corporeal patency at a 10-fold lower anti-thrombin dose, generated a 4-fold lower activated clotting time (ACT) and reduced bleeding 2-fold without anticoagulant
32
Thrombocytopenia
neutralization. Presently unknown is whether Intimatan interacts with heparin-induced thrombocytopenia (HIT) antibody or its hemorrhagic effect relative to danaparoid and hirudin. These anticoagulants, although approved for HIT, are neither optimally safe or effective in CPB and this patient population most often develops heparin antibody. The specific aims of the Phase I STTR are to determine (relative to the anticoagulants currently approved for HIT): (1) the HIT cross-reactivity of Intimatan and its potential to ameliorate heparin/heparin antibody platelet activation; (2) its antithrombotic potency and (3) its hemorrhagic effects. It is anticipated that these studies will further the development of Intimatan for CPB based on a superior therapeutic profile and mechanism of action. PROPOSED COMMERCIAL APPLICATION: The composition of matter and use claims of intimatan as an inhibitor of thrombin generation and complement activation issued in 1999 in U.S. Patent 5,922,690. The differentiated mechanism of action of Intimatan provides a competitive advantage over existing modalities for the prevention/treatment of a wide vista of thrombo-embolic disorders in terms of lower manufacturing cost, enhanced anticoagulation efficacy against pathologic thrombosis and in device/procedure settings (CPB, dialysis, angioplasty, stents, cardiac assist devices), lower dosages, less bleeding, use in HIT patients and amelioration of hypercoagulability in HIT. Its value as a radiopharmaceutical for medical imaging of vascular diseases (including treatment of cancer) having a thrombin component is also realized. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INACTIVATION OF THE PIGA GENE IN HEMATOPOIETIC STEM CELL Principal Investigator & Institution: Bessler, Monica; Barnes-Jewish Hospital Ms 90-94212 St. Louis, Mo 63110 Timing: Fiscal Year 2001; Project Start 01-JUL-1999; Project End 31-MAY-2003 Summary: The human gene PIGA (phosphatidylinositol glycan class A) encodes a protein subunit of the a1-6-N-acetylglucosaminyltransferase complex, which catalyses an early step in the biosynthesis of the glycosyl phosphatidylinositol (GPI) anchor. In patients with Paroxysmal Nocturnal Hemoglobinuria (PNH), an acquired hemolytic anemia, a somatic mutation in the X linked PIGA gene occurs in a hematopoietic stem cell. Although PIGA -induced defects account for the deficiency of GPI-linked proteins on the cell surface of the affected blood cells, the basis for the expansion of defective hematopoietic progenitors in the bone marrow of PNH patients is unknown. Since PNH frequently evolves from Aplastic Anemia (AA) and since bone marrow failure is commonly associated with PNH, we hypothesize that the inability to link certain surface proteins to a GPI-molecule provides the clone with a growth advantage in a background of impaired hematopoiesis. The aim of the proposed research is to investigate this hypothesis and to study the growth behavior of PIGA negative cells in hematopoiesis. First we will therefore create an animal model in which the homologue murine Piga gene is inactivated in a proportion of hematopoietic progenitor cells just as in patients with PNH. To do this we will employ conditional gene inactivation using the Cre- loxP system of bacteriophage P1. A mouse that is able to inactivate its Piga gene in the presence of the Cre recombinase will be obtained by homologous recombination introducing two loxP sites into the Piga gene. Hematopoietic cells with a recombined, inactive Piga gene will occur in the progeny of matings between these mice and mice in which Cre expression is directed by a spatial and/or temporal specific promoter. As a result of Cre-dependent recombination of the loxP sites a proportion of cells will lack GPI-linked proteins. We will then compare PIGA(+) and PIGA(-) embryonic and adult
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hematopoiesis in the same mouse under a variety of circumstances, including the administration of selected cytokines along with agents known to injure bone marrow precursor cells. Competition between cells expressing wild type Piga and those expressing the recombined Piga allele will enable us to uncover even subtle differences in any stages of hematopoietic differentiation. In this way we hope to identify the factors that differentially influence the growth of PNH and normal hematopoietic progenitor cells and allow the PNH cells to become the dominate population while normal hematopoiesis is impaired. These experiments will increase our understanding of the functional role of GPI-linked proteins in hematopoiesis and provide new insights into the regulation of stem cell development in the bone marrow. The findings could provide the scientific foundation of new therapeutic modalities for PNH and other bone marrow failure syndromes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INHERITED DISEASES AFFECTING PLATELET FUNCTION Principal Investigator & Institution: Swank, Richard T.; Cancer Research Scientist Vi; Roswell Park Cancer Institute Corp Buffalo, Ny 14263 Timing: Fiscal Year 2001; Project Start 01-AUG-1995; Project End 30-JUN-2005 Summary: Knowledge of genes responsible for inherited diseases which affect platelet function and synthesisis is minimal. Consequently, there is a lack of precise molecular diagnostic tests as well as efficacious treatments. The Hermansky-Pudlak Syndromes (HPS) are a group of recessively inherited diseases of humans that cause prolonged bleeding, platelet storage pool deficiency and lung fibrosis, leading to considerable morbidity and premature death. Recent studies have demonstrated that the disease is multigenic in humans and mice. One of the mouse genes, gunmetal (gm), is of additional interest in that it reduces rates of platelet synthesis due to a mutation in the Rab geranylgeranyl transferase (RabGGTase) gene. The long term goals of this proposal are: a) to utilize the inherent advantages of inbred mice to identify additional HPS genes at the molecular level, b) to apply this knowledge to identify mutations in human HPS patients not yet molecularly defined and c) ultimately to devise effective diagnostic approaches and therapies for the disease. A secondary goal is to contribute to basic knowledge of genes which regulate the synthesis and trafficking of subcellular organelles such as platelet dense granules, lysosomes and melanosomes. The Specific Aims of the proposal are to: 1) complete the identification and partial characterization of the mouse sandy (sdy) HPS gene; 2) identify and partially characterize the mouse light ear (le) HPS gene; 3) identify and partially characterize the mouse muted (mu) HPS gene; 4) isolate the human homologues of cloned mouse HPS genes and test for alterations of these genes in human HPS kindreds: 5) clarify the mechanism(s) by which decreased RabGGTase activity causes abnormalities in platelet synthesis and organelle function. Large interspecific mouse backcrosses are used to construct high resolution genetic maps of each mouse HPS gene. Physical maps of the critical genetic regions will be constructed by selection of BACs (bacterial artificial chromosomes) which span the critical genetic intervals. Genes within BACs will be identified by exon trapping, cDNA selection and whole BAC sequencing. Candidate genes will be sequenced to detect mutations. The same genes will be analyzed in human HPS patients, not yet molecularly diagnosed, by cDNA sequencing and related techniques to determine if mutations in these genes are the cause of HPS in these patients. The consequences of a reduction in levels of RabGGTase in gunmetal mice will be analyzed by comparing levels of geranylgeranylation of multiple Rab GTPases and by comparing the subcellular distribution of Rabs in tissues of gunmetal and normal mice.
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Thrombocytopenia
Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INNATE IMMUNITY HEMORRHAGIC FEVER VIRUSES Principal Investigator & Institution: Finberg, Robert W.; Professor of Medicine & Microbiology; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: This project will examine the role of the innate immune system in the pathophysiology of the viral hemorrhagic fevers. Two viruses which are potential agents of bioterrorism, will be studied: 1) Ebola virus, a filovirus, which induces an acute illness characterized by fever, leucopenia, shock, and death, and 2) Lymphocytic Choriomeningitis Virus LCMV an arenavirus which causes an illness characterized by leucopenia and thrombocytopenia in mice and meningitis in humans. The high mortality rate associated with Ebola infection has been demonstrated to be directly associated with cytokine release which occurs after viral infection of macrophages. The mechanism by which Ebola induces this cytokine response will be defined and compounds will be screened for their ability to inhibit this activity. Preliminary data indicate a major role for Toll Like Receptor 2 (TLR-2) and CD14 in the cytokine response to LCMV. TLR-2 and CD14 are pattern recognition proteins whose role in bacterial sepsis has been recently defined. Both have also been associated with the immune responses to viruses. Using transfected cell lines and available knockout mice the mechanism by which these proteins affect both initial induction of cytokines as well as the subsequent immune responses to LCMV and Ebola virus will be defined. The specific TLRs (and other "pattern recognition proteins") involved in these responses as well as their interactions will be studied. The effect of these early recognition events on long-term Band T cell immunity will be investigated. These studies will result in a better understanding of the role that the innate immune system has in mediating the pathophysiology of hemorrhagic fever viruses and should lead to new therapeutic approaches to these diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: INVOLVEMENT DIFFERENTIATION
OF
RUNX1
IN
MEGAKARYOCYTIC
Principal Investigator & Institution: Goldfarb, Adam N.; Pathology; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2003; Project Start 23-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): Understanding the transcriptional regulation of megakaryocytic lineage commitment will provide guidance in designing treatments for many bone marrow disorders associated with thrombocytopenia. We have identified the myeloid transcription factor RUNX1 as a protein upregulated early in megakaryocytic differentiation and downregulated early in erythroid differentiation. This expression pattern is unique in that virtually all other megakaryocytic transcription factors, such as GATA-1, FOG-1, NF-E2, and SCL/tal, display shared expression in both megakaryocytic and erythroid lineages. The restricted coexpression of RUNX1 and GATA-1 in megakaryocytes led us to discover that these factors strongly cooperate in the activation of a megakaryocytic promoter. This cooperation depends on RUNX1 binding sites present in the promoter and on the RUNX1 cofactor CBFbeta. Coimmunoprecipitation assays demonstrate physical association of RUNX1/CBFbeta with GATA. This novel functional and physical association correlates with the recent clinical
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implications of both the GATA-1 and RUNX1 genes in hereditary syndromes with thrombocytopenia. A dominant-negative variant of RUNX1 consists of a fusion with the ETO transcriptional repressor that results from the t(8;21) chromosomal abnormality frequently found in acute myeloid leukemia. We have found that the RUNX1-ETO oncoprotein, in contrast to wild type RUNX1, potently inhibits GATA-1 activation of a megakaryocytic promoter. In addition, RUNX1-ETO demonstrates physical interaction with GATA-1. Thus, one of the oncogenic effects of RUNX1-ETO may consist of blocking GATA driven hematopoietic differentiation. The major aims of this project are: 1) Delineation of the developmental consequences and molecular mechanisms of RUNX1 synergy with GATA-1 in megakaryopoiesis; 2) Determination of the developmental consequences and molecular mechanisms of RUNX1-ETO inhibition of GATA factors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LONG THROMBOCYTOPENIA
ACTING
THROMBOPOIETIN
FOR
TREATING
Principal Investigator & Institution: Doherty, Daniel H.; Bolder Biotechnology, Inc. 4056 Youngfield St Wheat Ridge, Co 800333862 Timing: Fiscal Year 2002; Project Start 20-SEP-2002; Project End 31-DEC-2004 Summary: (provided by applicant): Thrombopoietin (TPO) is a cytokine that stimulates the proliferation and differentiation of megakaryocytes, the precursors to blood platelets. Recombinant human TPO is a promising treatment for stimulating platelet production in patients with thrombocytopenia resulting from myelosuppressive chemotherapy. We propose to create modified TPO proteins that are equal or superior to natural TPO at stimulating platelet formation in vivo, but which require less frequent dosing, on the order of once per week to once every third week. Optimally, the compound could be administered once per chemotherapy cycle. During Phase I we will identify sites in TPO that can be modified without affecting the protein's in vitro bioactivity. During Phase II, we will manufacture sufficient quantities of the modified TPO proteins for testing in animal models of thrombocytopenia. The improved characteristics of the novel TPO proteins will reduce the amount of TPO required per patient, improve patient compliance and quality of life and result in considerable cost savings to patients and healthcare providers. These proteins will find utility in treating thrombocytopenia resulting from myelosuppressive chemotherapy and drug complications. Information gained from these studies will aid in creating long-acting versions of structurally related cytokines and growth factors for use in treating cancer, infectious disease and hematopoietic disorders. PROPOSED COMMERCIAL APPLICATIONS: The long-acting TPO proteins under development potentially can be used to restore platelet production in patients with thrombocytopenia resulting from chemotherapy. The U.S. market for platelet-stimulating agents is estimated to be in excess of $300 million. These modified TPO proteins will require much less frequent dosing than existing products, providing significant cost savings to patients and healthcare providers. Additional expected benefits include improved drug efficacy, reduced toxicity and improved patient quality of life. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISMS OF WASP FUNCTION IN T CELL RESPONSES Principal Investigator & Institution: Geha, Raif S.; Professor; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215
36
Thrombocytopenia
Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: The Wiskott Aldrich syndrome (WAS), an X-linked primary immunodeficiency characterized by deficient T cell function, thrombocytopenia and eczema, is caused by mutations in the WASP gene. WASP is recruited to the immune synapse (IS) where it is thought to be activated by the small GTPase Cdc42 to initiate Arp2/3 mediated actin polymerization. Actin polymerization is important for formation, IL-2 secretion and proliferation by T cells in response to TCR ligation. T cells from patients and mice deficient in WASP fail to increase their cellular F-actin, secrete IL-2 and proliferate followinq TCR ligation. This suggests that WASP plays a critical role in actin dependent changes that are essential for T cell activation. Our preliminary data suggests that following TCR ligation WASP can be recruited to lipid rafts and the IS by phosphorylated ZAP-70 and that this is mediated by the adapter protein CrkL which bridges p-ZAP-70 to the WASP partner WIP. Interestingly the majority of WASP missense point mutations in WAS are located in the WIP binding WH1 domain. Furthermore, there is data to suggest that the proline rich region of WASP which interacts with SH3 domain containing protein may also be involved in localization of WASP to the IS. We hypothesize that WASP recruitment to GEMs and the IS is mediated by WIP and by the polyproline rich region of WAS, and that it plays a critical role in T cell activation and in the dynamic actin changes in T cells following TCR ligation. To test this hypothesis, we propose to: 1. Analyze the ability of WASP-/- T cells to form an immune synapse and to undergo actin based cytoskeletal changes following TCR ligation by a). examining IS formation with anti-CD3 coated beads, MHC class IIpeptide bilayers and antigen presenting cells, b). analyzing reorganization of cellular Factin, actin cytoskeleton architecture changes and cell motitity following engagement of the TCR/CD3 complex. 2. Examine the ability of WASP-/- T cells to form lipid rafts in which key signaling molecules are concentrated leading to activation of the IL-2 gene. We will analyze the composition and stability of lipid rafts and the sustained activation of Ca ++mobilization, signaling intermediates and transcription factors that regulate IL2 gene expression. 3. Assess the role of WIP binding and of the polyproline rich region of WASP in WASP recruitment to lipid rafts and IS. We will generate and test WASP mutants that fail to bind WIP or that lack the polyproline rich region, and examine the recruitment to lipid rafts and IS of WASP mutants that fail to bind WlP or lack the polyproline rich region. 4. Dissect the role of WASP recruitment to lipid rafts in TCR signaling. We will analyze TCR signaling in T cells of WASP-/- mice reconstituted with WASP mutants that perturb its recruitment to lipid rafts. We will determine if targeting signals in WASP mutants to lipid raft bypasses the physiologic pathway of WASP recruitment to lipid rafts for TCR signaling. The results of these studies should help elucidate the mechanism of WASP function in T cell activation and will have important implications for our understanding of normal immunity to infection and for immunologic diseases that include immunodeficiency diseases, cancer, and autoimmunity and allergic diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MEGAKARYOCYTE MATURATION
REAGENTS
SPECIFIC
FOR
THEIR
Principal Investigator & Institution: Brown, Ronald L.; Director, Research and Development; Quality Biological, Inc. 7581 Lindbergh Dr Gaithersburg, Md 20879 Timing: Fiscal Year 2001; Project Start 01-SEP-1999; Project End 30-JUN-2003 Summary: The overall objective of this proposal is to develop a clinical-grade Megakaryocyte Development Medium (MDM) that supports the ex vivo development
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37
of human megakaryocytes. Use of this unique medium will provide information on several critical gap-areas concerning these elusive yet critically important cells; lipid metabolism, regulation of maturation, and clinical utility. The innovative aspects are the studies on enhancing lipid metabolism, the use of cytokine/matrix molecule combinations, and an in vivo megakaryocyte-transplantation model. MDM will have clinical use in developing therapies for thrombocytopenia and other platelet disorders, in that it allows generation of large numbers of megakaryocytes (> 10/9) that are not possible via routine bone marrow aspiration. MDM also allows for the standardization of megakaryocyte culture conditions between laboratories. Building on the successful results of our Phase I studies, we have designed relevant and highly critical experiments in our Phase II proposal to investigate the following goals. Specific Aim 1 addresses the further optimization of MDM, with a particular focus on enhancing megakaryocyte lipid metabolism. Specific Aim 2 examines the effects of specific cytokines and matrix molecules as complex regulatory signals. Specific Aim 3 is to test and/or long-term engraftment. This aim also provides a pre-clinical animal model for cellular-based therapies of platelet disorders. Specific Aim 4 is to scale these cultures up to levels producing 1-5 x 10/9 megakaryocytes per culture. Successful completion of this Phase II proposal will result in a widely used commercial product, a clinically relevant animal model, and much needed information to further our studies on the development of these biologically important cells. PROPOSED COMMERCIAL APPLICATION: The development of clinical grade reagents that will support megakaryocyte proliferation and differentiation will be valuable in developing novel approaches for the treatment of hematopoietic disorders such as thrombocytopenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: METABOLIC CONSEQUENCES OF SECURIN DISRUPTION Principal Investigator & Institution: Melmed, Shlomo R.; Professor and Director; CedarsSinai Medical Center Box 48750, 8700 Beverly Blvd Los Angeles, Ca 90048 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Cell cycle-dependent securin proteins regulate sister chromatid separation by inhibiting separin function. We isolated and have characterized pituitary tumor transforming gene (PTTG) from rat pituitary tumor cells, and PTTG is functionally homologous to yeast securin. PTTG is overexpressed in several tumor types, and also in some normal replicating tissues (including testis, lympocytes). When the PTTG gene was deleted, resultant knockout mice were viable, fertile and exhibited splenic and testicular hypoplasia and thrombocytopenia. Surprisingly, after 6 months, male PTTG -/- mice do not gain weight, develop profound hyperglycemia, hypoinsulinemia, and hypo-leptinemia with intact insulin sensitivity. In preliminary experiments, pancreatic beta cells appear hypoplastic with diminished islet insulin immunoreactivity, and no evidence for autoimmune islet involvement. This proposal aims to study the role of mammalian securin in pancreatic beta cell function by assessing insulin transcription, secretion and action, regulation of adipocyte hormones and assessment of pancreatic beta cell development and replication, and pancreatic regeneration. As securin-deficient diabetes is restricted to male mice, intact or gonadectomized PTTG -/- animals will be treated with sex steroids, and their impact on glycemia and pancreatic function assessed. These studies highlight the role of a cell cycle-regulating protein in pancreatic beta cell development and function. In the context of this unique genetic background, these experiments identify securin as a critical factor for pancreatic cell function and provide insights into a novel monogenic cause of diabetes.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MODELING OF PLATELET ALLOANTIGENS Principal Investigator & Institution: Barron-Casella, Emily A.; Pediatrics; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 01-JUL-1998; Project End 30-JUN-2003 Summary: The long-term goal of this new R29 proposal is to understand the antigenic determinants and immunologic requirements involved in alloimmunization. This proposal focuses on human platelet alloantigen 1 (HPA-1). HPA-1 is a biallelic system; a single nucleotide difference between alleles creates a polymorphism at position 33 of GP IIIa, a component of the fibrinogen receptor. Homozygotes for HPA-1a encode a leucine at position 33; homozygotes for HPA-1b encode proline. HPA-1 is the most common cause of two bleeding disorders, neonatal alloimmune thrombocytopenia and posttransfusion purpura. In both disorders, anti-HPA-1a antibodies are made against HPA-1a GPIIIa, leading to thrombocytopenia. In this proposal, experiments are designed to further explore the HPA-1a and test the feasibility of making a murine model. In pursuing this goal, important questions about the HPA-1 system will be addressed. The specific aims are 1) to further define the structural requirements for HPA-1a antigenicity, 2) to determine if the structural requirements for HPA-1a antigenicity can be recreated in murine GPIIIa, and 3) to test the feasibility of making an animal model of HPA-1a alloimmunization by first creating a murine cell line expressing an HPA-1a fibrinogen receptor. By manipulating recombinant proteins containing human GPIIIa domains, the role of the polymorphism, the three N-terminal disulfide bonds, and the long range Cys5 Cys435 disulfide bond in HPA-1a antigenicity will be evaluated. This information will be used to recreate an HPA-1a-like antigen in murine GPIIIa and the criteria for eliciting an anti-HPA-1a response in mice will be determined. The ability of HPA-1a murine GPIIIa to assemble into a fibrinogen receptor and bind ligand in transfected megakaryoblastic cells will also be tested. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MODELS OF THROMBOCYTOPENIA PATHOLOGY & TREATMENT Principal Investigator & Institution: Mckenzie, Steven E.; Professor and Director of Cardeza Founda; Pediatrics; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2001; Project Start 30-SEP-1998; Project End 31-AUG-2003 Summary: Immune thrombocytopenias cause considerable morbidity and mortality throughout life. Major treatment options include splenectomy and intravenous immunoglobulin (IVIG). The diversity in response to these treatments implies a diversity in pathologic mechanisms. Yet to be explored is a role for thrombopoietin (TPO) therapy. The goal of this research is to produce mouse models of immune thrombocytopenia which recapitulate the pathologic features in man and provide a valid system within which to study therapy. Specific Aim 1 is to place our human FcgammaRIIA transgene on a spontaneously autoimmune background, W/BF1, which generates immune thrombocytopenia. W/BF1 mice lack the equivalent of the human FcgammaRIIA gene. Our FcgammaRIIA transgenic mice sustain more severe immune thrombocytopenia following injection of anti-platelet antibodies than wild type mice, therefore establishing the importance of FcgammaRIIA. We will breed the IIA transgene onto the NZW and BXSB backgrounds and produce W/BF1 male mice in whom thrombocytopenia will be assessed as a function of FcgammaRIIA transgene status.
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Aim 2 is to examine the response to splenectomy and IVIG therapy in W/BF1 mice. The hypothesis is that the presence of FcgammaRIIA on platelets and macrophages will diminish the effectiveness of the response. The mice will undergo splenectomy or receive IVIG, and we will measure the rate, magnitude and duration of response. Aim 3 is to determine the effects of TPO therapy on immune thrombocytopenia in W/BF1 mice. The hypothesis is that exogenous pharmacologic doses of TPO will ameliorate immune thrombocytopenia despite continued antibody-mediated destruction. We will use daily subcutaneous injections of a TPO peptide mimetic alone or in combination with IVIG or splenectomy. We will determine the dose response and schedule needed to achieve the maximal increase in platelet count. Our mouse model of thrombocytopenia recapitulates the features of human disease and will lead to improved outcome for patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR PERMEABILITY
&
FUNCTIONAL
ASPECTS
OF
VASCULAR
Principal Investigator & Institution: Stan, Radu-Virgil; Cellular & Molecular Medicine; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 92093 Timing: Fiscal Year 2001; Project Start 20-AUG-2001; Project End 31-JUL-2005 Summary: The main function of vascular endothelium is the mediation and control of transendothelial exchanges of water and solutes (both small and large molecules) between blood plasma and the interstitial fluid. This function IS OBVIOUSLY "vital", judged on the dependency on it of all the cells from all tissues and organs. While the morphological structures involved in transendothelial exchanges have been identified (i.e. caveolae, transendothelial channels, fenestrae and intercellular junctions), there is very little to no biochemical evidence on the molecular composition of the structures involved, their biogenesis and regulation. The major goals of this research proposal are to elucidate the specific chemical composition and function of the endothelial differentiations such as fenestrae and caveolae and their stomatal diaphragms. The finding will also document a novel aspect of the transendothelial transport namely the possibility and ways of its modulation (in rate and components transported). Besides their impact on the understanding of the normal physiological process of the transendothelial transport, the data could be used further in the study of the pathophysiology of several human diseases (e.g. tumor angiogenesis, diabetes, retinopathy, psoriasis, pulmonary, fibrosis, thrombocytopenia, allergic encephalomyelitis, arterial hypertension) where such transport modulations have been shown to occur. These studies could also provide novel transport related endothelial specific molecular markers that could be used in designing strategies for drugs and gene targeting to selected microvascular beds. The techniques employed are cell fractionation, cell free-assays, in-vivo screening methods, two- dimensional electrophoresis, cell culture, transfections, light and electron microscopy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR AND GENETIC ANALYSIS OF A BLOOD CELL DISEASE Principal Investigator & Institution: Snapper, Scott B.; Assistant Professor of Medicine; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 01-SEP-1997; Project End 31-AUG-2002
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Thrombocytopenia
Summary: (Adapted from applicant's abstract) The goal of this project is to use genetic approaches to determine the function of the protein recently found to be mutated in patients with the Wiskott-Aldrich Syndrome (WAS), a severe X-linked disease that is characterized by a B-and T-cell immunodeficiency, eczema, bloody diarrhea, and thrombocytopenia. Two strategies will be used to develop a mouse model of the WAS. First they have targeted and disrupted the murine homologue of the human WAS gene in murine embryonic stem (ES) cells to generate WAS-deficient stem cells. For a rapid analysis of the effects of the WAS-deficiency on lymphoid development, they have generated somatic chimeras in the recombinase activating gene-2-deficient (RAG2-/-) complementation system. RAG2-deficient mice are unable to rearrange immunoglobulin and T-cell receptor genes and therefore lack mature B and T cells. WAS-deficient ES cells have been introduced into RAG2-/- blastocyts; all of the B- and T-cells from resulting chimeric mice are of ES cell origin; thus one can analyze the role of WASp selectively in lymphocyte development and function. Preliminary studies suggest that murine WASlymphocytes have defects that closely resemble the human disease. WAS-deficient ES cells will also be used to generate germline WAS- mice for the analysis of more widespread effects and for long term studies. Experiments will be carried out to determine whether the germline WAS-deficient mice and the WAS-deficient RAG2deficient chimeras are valid models to study the human disease. In vivo complementation analyses will be performed with various regions of the WAS gene to define and characterize functional domains of the protein. This application is for a Mentored Clinical Scientist Development Award to an Applicant who has received graduate training in microbiology and immunology, and has completed post graduate training in internal medicine and clinical gastroenterology. The applicant's long term goals are to establish and direct his own independent basic research program in studies related to diseases that affect the human immune system with clinical interests in diseases that affect the mucosal immune system. Accordingly, these studies are cosponsored by Dr. Frederick Alt from the Department of Genetics at the Howard Hughes Medical Institute and the Center for Blood Research and by Dr. Daniel Podolsky from the Gastrointestinal Unit at the Massachusetts General Hospital, both at Harvard Medical School. (End of Abstract) Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MPL: SIGNAL TRAFFICKING AND MEGAKARYOCYTOPOIESIS Principal Investigator & Institution: Dahlen, Debra D.; Puget Sound Blood Center 921 Terry Ave Seattle, Wa 98104 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): The overall objectives of this project are to gain insight into the signal transduction mechanisms of the growth factor thrombopoietin (TPO) and its receptor, Mpl, and to provide in-depth training in molecular biology for Dr. Debra Dahlen. This career development award will enable Dr. Dahlen to achieve her immediate goal of exploring the role of Mpl in stem cell proliferation and differentiation and her long-term career goal of becoming an independent clinician-scientist involved in laboratory- based research affiliated with a major academic medical center. To achieve these goals, Dr. Dahlen will follow a research career development plan consisting of a program of didactic sessions and a laboratory- based research project under the sponsorship of Dr. Jonathan G. Drachman and under the consulting guidance of Drs. Jan Abkowitz, Tony Blau, Ken Kaushansky, Thalia Papayannopoulou, and Dennis Willerford. The specific aims of this research project are to: 1) determine tile receptor motifs that facilitate internalization of Mpl, and to identify the mechanism by
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which this occurs". 2) identify the signaling sequences necessary for normal intracellular trafficking and determine the intracellular fate of Mpl and 3) investigate the function of TPO/Mpl internalization and intracellular trafficking in cellular proliferation and megakaryocyte development/differentiation. The research plan includes site-directed mutagenesis, FACS analysis, Western blotting, subcellular fractionation, confocal microscopy, proliferation assays, signal transduction studies in cell lines and primary cells, and development of novel chimeric proteins. Although an ambitious set of experiments, the wide variety of techniques and methodology will help develop the breadth of Dr. Dahlen's scientific experience. The clinical significance of this project is threefold: 1) TP0/MpI signaling is non-redundant in normal stem cell and megakaryocyte biology; 2) Mpl expression is associated with a poor prognosis in hematologic malignancies; and 3) abnormalities in MpI signaling have been associated with several rare forms of inherited thrombocytopenia. Understanding the mechanisms of intracellular trafficking of MpI and its interaction with other signaling molecules may lead to novel approaches in the treatment of a number of hematologic and other diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MULTICENTER NETWORK OF MATERNAL-FETAL MEDICINE UNITS Principal Investigator & Institution: Egerman, Robert S.; Associate Professor; Obstetrics and Gynecology; University of Tennessee Health Sci Ctr Memphis, Tn 38163 Timing: Fiscal Year 2000; Project Start 05-MAY-1996; Project End 31-DEC-2003 Summary: The Department of Obstetrics and Gynecology at the University of Tennessee, Memphis has been part of the Maternal-Fetal Medicine Network since April 1986. With this application, we hope to participate in a large multicenter network designed to develop and conduct clinical trials in the field of Maternal-Fetal Medicine, which could not be undertaken in a single center. In comparison to our previous application, we have recently expanded our resources and facilities to include patients at all major hospitals in the city. The obstetric population will now total approximately 13,000 women of various ethnic and economic groups. We are particularly interested in pursuing trials which require large sample size in order to adequately address specific questions and those regarding rare events of obstetric interest. The Principal Investigator, Dr. Baha Sibai, and the Alternate Principal Investigator, Dr. Brian Mercer, as well as the faculty in the Division of Maternal-Fetal Medicine continue to be active in Network administrative activities, and the design and conduct of protocols. The Principal Investigator currently participates on the Concurrent Research Committee, the Ad Hoc Committee on Preterm Studies, and the "High-Risk" Aspirin Protocol, the Interim Progesterone, and the Preliminary Terbutaline subcommittees. The Alternate Principal Investigator chairs the "Premature Rupture of Membranes" protocol and the Chart Review Subcommittee. He serves on the Capitation Subcommittee, Preterm PROM Pathology Subcommittee, Preterm Prediction Protocol Subcommittee, Obstetrical Determinants of Neonatal Survival Protocol Subcommittee, Neural Tube Defect Protocol Subcommittee and the Preliminary MgSO4 Subcommittee. He has recently submitted for consideration a clinical trial regarding tocolytic, corticosteroid and antimicrobial therapy after PROM. We are applying to continue as a clinical research center within the Network and agree to join protocols in existence and participate in the design of protocols in cooperation with other centers selected by the NICHD. The University of Tennessee, Memphis, and the Department of Obstetrics and Gynecology are committed to collaborative Maternal-Fetal research as documented by listed publications and the
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Thrombocytopenia
enclosed letters of commitment. The Division of Maternal-Fetal Medicine agrees to cooperate with the policy of capitation of research costs for each individual protocol, in addition to a base budget. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NFE2 AND BETA 1 TUBULIN IN PLATELET DIFFERENTIATION Principal Investigator & Institution: Shivdasani, Ramesh A.; Assistant Professor of Medicine; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 01-JUL-1999; Project End 30-JUN-2004 Summary: Blood platelets mediate hemostasis as well as diverse pathologic processes, including thrombosis and inflammation, and thrombocytopenia is a frequent, doselimiting complication of cancer chemotherapy. The importance of platelets in diseases that are common in the United States is thus well recognized. This makes it necessary to understand how terminally differentiated megakaryocytes (MKs) fragment and release blood platelets. Despite the discovery of thrombopoietin (Tpo) and its signal transduction pathways in MKs, the cellular and molecular basis of terminal MK maturation and platelet release remain unknown. Mice lacking the erythromegakaryocytic transcription factor NF-E2 have severe, usually lethal, thrombocytopenia resulting from a late arrest in MK cytoplasmic differentiation. Hence, they constitute a powerful and unique model to study thrombocytopoiesis, and are an important tool in the P.I.'s long-term goal of defining molecular aspects of platelet production. MKs deficient in NF-E2 have a cell-autonomous defect and fail to produce proplatelets, the precursors of blood platelets, in culture. However, the transcriptional targets of NF-E2 and the relevant biochemical pathways of terminal MK differentiation are not known. Initial efforts to identify genes that fail to be expressed in the absence of NF-E2 have led to a MK-and platelet-specific beta tubulin isoform (beta1) that normally appears late in MK differentiation, localizes to proplatelets and platelet marginal bands, and possibly mediates the cytoplasmic reorganization that accompanies platelet release. Beta1 tubulin expression is completely lost in the absence of NF-E2 function. Preliminary data thus strongly suggest that loss of beta1 tubulin expression in MKs might explain in part why blood platelets are not produced in the absence of NF-E2. The Specific Aims of this proposal include determining whether the absence of beta1 tubulin in NF-E2-deficient cells reflects direct regulation by this transcription factor, and whether restoring beta1 tubulin expression in the defective MKs is sufficient to rescue some or all aspects of thrombocytopoiesis. Further, we propose to use gene targeting in mice to test the essential roles of beta1 tubulin in vivo, independent of its putative relation to NF-E2. Finally, we propose to use a previously successful mRNA subtraction strategy to identify and characterize additional molecular targets of NF-E2 that may participate in platelet biogenesis. The results of these studies should substantially improve the current understanding of how MKs produce blood platelets. 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
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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 •
Project Title: NOVEL THERAPIES IN HEMOSTASIS AND TRANSFUSION MEDICINE Principal Investigator & Institution: Bussel, James B.; Associate Professor of Pediatrics; Pediatrics; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): This application is in response to RFA HL-02-001 entitled Transfusion Medicine/Hemostasis Clinical Network and is a consortium of the New York Presbyterian Hospital - Weill Cornell College of Medicine-Columbia College of Physicians and Surgeons. It provides health care to > 20% of the New York City metropolitan area and has access to > 20 million people within 2 hours. It is an amalgam of physicians and scientists involved in clinical research in Hemostasis and Transfusion Medicine with expertise in Pediatrics, Internal Medicine, Pathology, and Surgery. The group has both the patient population and the clinical expertise required to participate in clinical trials proposed by other centers in the Network. Specific Aim 1 is a clinical trial of refractory ITP, defined as children and adults with ITP who have failed to respond to splenectomy. It intends to focus on the pathophysiology of refractory ITP by comparing two novel treatments. One, rituximab, is an anti-CD20 which depletes the recipient of B cells and should be an effective immunosuppressant in a "pure" autoantibody disease like ITP. There is preliminary data describing its effectiveness which should optimize its use. The other arm intends to use thrombopoietin or mimetic (TPO) to increase the platelet count by stimulating platelet production. This arm hypothesizes that a critical element in refractory ITP is a decreased production of platelets which can be rectified by stimulation with TPO. A registry of splenectomy will be included to facilitate enrollment of eligible patients. Specific Aim 2 intends to optimize granulocytes for transfusion. This would be of great potential benefit to patients with prolonged, severe neutropenia who suffer considerable morbidity and occasional mortality from infection. There is also the high cost of prolonged hospitalizations. In the past, studies of granulocyte transfusion showed little benefit and significant toxicity. The current study will explore different methods of preparation of granulocytes and also novel techniques for evaluation of their efficacy. Specific Aim 3 demonstrates that the consortium is able to participate in protocols for a wide variety of disorders of hemostasis and transfusion medicine. The consortium includes Dr. Grima of the NY Blood Center who annually phereses approximately 20 TTP patients; a leading center, Cornell, for management of patients with alloimmune thrombocytopenia;and a large hemophilia center. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Thrombocytopenia
•
Project Title: PATHOBIOLOGY AND GENE TRANSFER IN CARDIOVASCULAR DISEASE Principal Investigator & Institution: Chan, Lawrence; Professor of Medicine; Medicine; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 30-SEP-1997; Project End 31-DEC-2007 Summary: (provided by applicant): The overall goal of this Program Project is to develop improved vectors for gene delivery in vivo and to test their efficacy in disease models in animals. The Program Project centers on the helper-dependent adenovirus system (HD-Ad) first developed at Baylor. HD-Ads are Ads that lack all viral protein genes. During the last funding cycle we showed that HD-Ads are highly efficient in transferring gene in vivo. There is minimal toxicity and transgenes delivered by such vectors are expressed for >2 year in baboons and for the lifetime of the recipient mice (2.5 years). In this competing renewal application, Dr. Stefan Kochanek (University of Cologne), a leader in HD-Ads, has formally joined the Program. As Dr. Frank Graham, director of one of the projects directed in the ongoing Program, will be retiring at the termination of the current cycle, his project will be directed by Dr. Philip Ng, a Grahamtrained expert in HD-Ad who joined Baylor in November 2001. The Program will continue to improve HD-Ads and treatment protocols and to further test these vectors for toxicity and efficacy in disease models in mice and nonhuman primates. In Project 1 (Chan/Beaudet) we will generate an improved version of chimeric cDNA/genomic LDL receptor (LDLR) HD-Ad, and a dual LDLR+apoAI transgene vector, that will be tested in LDLR-deficient mice and rhesus monkeys, and to test the efficacy and toxicity of a glucose 6 phosphatase (G6Pase) HD-Ad for the treatment of glycogen storage disease 1a (GSD-1a) in mice and dogs (using a GSD-1a dog colony at Duke University). In Project 2 (Beaudet/Chan) we will elucidate the pathogenesis of HD-Ad-induced thrombocytopenia, a significant side effect of these vectors, evaluate the safety and toxicity of HD-Ads in nonhuman primates, and examine the efficacy of skeletal muscle gene transfer of Factor IX and apoAI as an alternative tissue target for HD-Ads in Factor IX-deficient and wild-type mice and in hyperlipidemic baboons. Data from these experiments will support possible clinical trials of muscle-directed therapy of Factor IX deficiency. In Project 3 (Kochanek) we will develop improved procedures for high-yield production of RCA (recombinant Ad)-free HD-Ads and vectors with enhanced hepatic transcription, and new pretreatment protocols and vector modifications that improve liver targeting and reduce toxicity; lastly, we will also determine chromosomal integration frequencies of HD-Ads. In Project 4 (Ng) we will optimize procedures and scaling up methods for HD-Ad production with reduced helper contamination and develop reagents suitable for clinical applications. The projects are supported by an Administrative Core (Chan), a Vector Production Core (Oka, PI) and a Nonhuman Primate Core (K. D. Carey, at the Southwest Foundation for Biomedical Research at San Antonio). HD-Ads are highly promising gene transfer vectors. The improvements in HD-Ads and the preclinical experiments proposed in this application will pave the way towards the application of this technology to their possible use in the treatment of human disease in clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PATHOGENESIS OF AUTOIMMUNE THROMBOCYTOPENIA Principal Investigator & Institution: Nugent, Diane J.; Children's Hospital of Orange County 455 S Main St Orange, Ca 92868 Timing: Fiscal Year 2001; Project Start 30-SEP-1998; Project End 31-AUG-2003
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Summary: (Adapted from applicant's abstract) Idiopathic Thrombocytopenia (ITP) is an autoimmune disorder characterized by production of antiplatelet antibodies and consequent immune-mediated platelet destruction. The initial stimulus for the autoantibody response in ITP is not known, even though it is one of the most common autoimmune diseases affecting both adults and children. ITP may occur as an isolated phenomenon or in association with many conditions, for example: acquired or congenital immune dysregulation, pregnancy, viral infection like HIV or EBV, or systemic lupus erythematosus (SLE). The dominance of antiplatelet autoantibodies in such a wide variety of immune diseases suggests that there may be an alternative mechanisms to antiplatelet production as compared to other autoimmune diseases. In this grant, the applicants present a model for ITP and hypothesize that the platelet itself may act to short circuit the process of antigen specific immunoglobulin production allowing the emergence of autoantibodies which are normally restricted by a network of anti-idiotypic T and B cell clones. Ordinarily, somatic mutation and antigen selection in the B lymphocyte proceed under the strict supervision and symmetrical evolution of idiotype specific T cell clones. In their model, the platelet, mimicking a T cell, could promote polyclonal expansion of previously restricted clones without the concomitant involvement of regulatory T cells or macrophages. To test this hypothesis, the applicants will focus their efforts in following areas: SPECIFIC AIM #1: To determine the effect of ligation of CD40, membrane lg (mig) receptor, and FcRyIII on IL-1alpha and IL-1beta gene expression and production in B cells and dendritic cell/macrophages. SPECIFIC AIM #2: To determine the effect of polyclonal expansion and epitope shifts, they will use limited oligonucleotide substitutions (within the immunoglobin framework or CDR3 region) to measure changes in antigen binding using a uniquely engineered baculovirus protein expression system. Their long term goal is to identify the dysregulation which drives the production of platelet autoantibody. They believe that interruption of this process will return the immune system to a more restricted process of B cell immunoglobulin production allowing T cell regulation to further limit the emergence of autoreactive clones. (End of Abstract) Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PHARMACOLOGY TREATMENTS OF ITP
AND
BIOENGINEERING
OF
NEW
Principal Investigator & Institution: Balthasar, Joseph P.; Associate Professor; Pharmaceutical Sciences; State University of New York at Buffalo Suite 211 Ub Commons Amherst, Ny 14228 Timing: Fiscal Year 2001; Project Start 11-APR-2001; Project End 31-MAR-2005 Summary: Immune thrombocytopenia (ITP), a common autoimmune disease, affects a large population of individuals worldwide; in the U.S. alone, as many as 33,000 new cases occur each year. Approximately 25-30 percent of chronic ITP patients are refractory to standard therapy (corticosteroid immunosuppression and splenectomy), and are at high risk for fatal hemorrhage. No feasible alternative therapies are presently available. Progress toward the development of new treatments has been impeded by difficulties associated with conducting investigations in ITP patients and by the unavailability of suitable animal models of the disease. A primary significance of this proposal lies in its potential to develop mechanistically relevant, quantitative animal models of immune thrombocytopenia. Extremely promising results have been obtained in our laboratory in the development of passive and active animal models of ITP. Further validation and complete development of these experimental models, as proposed in Aim number 1, will permit, for the first time, quantitative evaluation of the
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Thrombocytopenia
efficacy of existing and new therapies. The project plans to take the advantage of the animal models to examine hypotheses regarding the mechanisms of action of an effective, yet unfeasible therapy of chronic ITP, pooled immunoglobulin (IVIG, Aim number 2). Delineation of the pathways by which IVIG achieves effects may lead to the development of new therapies with improved pharmaceutical and therapeutic characteristics. Furthermore, the proposal plans to develop and test two new therapies for ITP: (1) a novel bioreactor for the antigen-specific removal of pathogenic antibodies (Aim number 3), which is expected to carry significant advantages over clinically approved methods for ITP treatment (e.g., Protein A immuno- adsorption); and (2) a new liposomal immunotherapy (Aim number 4), designed to improve upon anti-Rho(D) immunotherapy, which is approved for use in non-splenectomized ITP patients as an inhibitor of auto-antibody mediated elimination of platelets. Findings gathered from the body of proposed studies may offer insight in the design of effective combination therapy for treating ITP and other autoimmune diseases, which, as a group, affect over 50 million Americans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PLACENTAL HEMATOPOIESIS
HORMONES
AND
THE
CONTROL
OF
Principal Investigator & Institution: Linzer, Daniel I.; Professor; Biochem/Molecular & Cell Biol; Northwestern University 633 Clark St Evanston, Il 60208 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2007 Summary: (provided by applicant): Mammalian pregnancy provides a unique window on the regulation of hematopoiesis, with massive changes in the maternal blood system at the same time that de novo hematopoietic development occurs in the fetus. A central hypothesis of this work is that these hematopoietic changes are induced in part by pregnancy-specific factors produced by the placenta. The unusual patterns of hematopoiesis may reflect novel activities, in which case analysis of placental hematopoietic hormones will reveal new regulatory pathways. Placental hormones in the cytokine superfamily in the mouse include prolactin-like proteins E (PLP-E) and F (PLP-F) which stimulate mouse megakaryocyte differentiation and synergize with other cytokines to stimulate the growth of various mouse and human myeloid precursors. PLP-E and PLP-F bind to the same receptor, which does not appear to be shared with other cytokines. PLP-E, but not PLP-F, is also expressed in the mouse bone marrow in response to low platelet levels (thrombocytopenia), and administration of this hormone leads to recovery from thrombocytopenia. The goals of this proposal are to expand our understanding of how these two hormones are expressed and how they act, and through these studies to reveal new aspects of the control of hematopoiesis and the adaptation to pregnancy. The Specific Aims of this proposal are: (1) to identify the PLPE and PLP-F receptor; (2) to determine how hormone binding to receptor leads to signaling events and to changes in gene expression that are distinct from the responses to other cytokines; (3) to define the effects these hormones have on hematopoiesis in vivo; and (4) to characterize how the PLP-E gene is controlled in the placenta and the bone marrow. In addition to revealing basic aspects of the control of hematopoiesis in pregnancy and in disease, these studies are expected to point to new therapeutic approaches in the treatment of thrombocytopenia and other hematopoietic disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PROLIFERATIVE SWITCH FOR GENETICALLY MODIFIED CELLS Principal Investigator & Institution: Blau, C Anthony.; Associate Professor; Medicine; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2001; Project Start 10-AUG-1997; Project End 31-JUL-2005 Summary: (provided by applicant): This application is a request for renewal of our R01 entitled: "A proliferative switch for genetically modified cells," which was funded beginning in August 1997. The stated goal of that application was "to apply newly developed technology to the expansion of genetically modified hemopoietic cells in vitro or in vivo." We have achieved that goal. Our approach uses a derivative of the thrombopoietin receptor (mpl) that delivers a conditional growth signal in response to a drug called a chemical inducer of dimerization (CID). In specific aim 1 we will humanize the mpl vector. In specific aim 2 we will test our humanized vector in normal mice and in a mouse model of mpl deficiency. In specific aim 3 we will test the humanized vector in a canine model. in specific aim 4 we will test the humanized vector in hemopoietic cells taken from patients with mpl deficiency. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PROLONGED AND SEVERE THROMBOCYTOPENIA IN NEONATES Principal Investigator & Institution: Sola, Martha C.; Pediatrics; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant): Thrormbocytopenia is one of the most common hematologic problems among patients in Neonatal Intensive Case Units (NICU), affecting 20-35 percent of NICU patients. In 20-25 percent of these patients the thrombocytopenia is severe and requires treatment with platelet transfusions. In adults, the administration of recombinant thrombopoietin (rTpo) is being investigated as an alternative to platelet transfusions. Our previous in vitro and in vivo studies have shown that megakaryocyte progenitors of neonates are more sensitive to rTpo than are megakaryocyte progenitors of adults, suggesting that rTpo administration could be an effective therapy for thrombocytopenic neonates. Since rTpo does not increase the platelet count until 4 to 6 days after starting therapy, the only appropriate candidates would be neonates whose thrombocytopenia is severe and prolonged. However, the application of new therapies to thrombocytopenic neonates has been significantly hampered by our lack of understanding of even the basic kinetic mechanisms responsible for their thrombocytopenias (platelet destruction versus decreased platelet production). With the development of rTpo, there is now a pressing need to clarify these mechanisms in neonates with severe and prolonged thrombocytopenia. With this in mind, we propose to; (1) identify the kinetic mechanisms responsible for severe and prolonged thrombocytopenia in NICU patients, (2) establish the correlation between peripheral blood and bone marrow indicators of thrombopoiesis in thrombocytopenic neonates, and (3) conduct a multicenter, open-label, phase I/Il, dose-escalation trial of rTpo administration to neonates with severe and prolonged thrombocytopenia. The first two studies will use techniques specifically developed for the study of megakaryocyte number, size, and ploidy in the bone marrow of neonates, and will correlate these with newly developed indirect measures of thrombopoiesis (i.e. reticulated platelet counts, serum Tpo concentrations, and circulating megakaryocyte progenitors). The last study will test the biological effects, pharmacokinetics, and safety of rTpo administration to neonates with prolonged and severe thrombocytopenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: RADIOIMMUNOTHERAPY FOR LYMPHOMA Principal Investigator & Institution: Witzig, Thomas E.; Professor of Medicine; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2003 Summary: (Provided by applicant): The majority of non-Hodgkin's lymphomas (NHL) are malignancies of CD2O+ B-lymphocytes. There are approximately 55,000 new cases of NHL each year; and for unexplained reasons, the incidence is rising. A new form of treatment for B-cell NHL involves the use of rituximab, a monoclonal antibody that is targeted to the CD2O antigen. Yttrium-90 is a radioisotope that can be linked to the antiCD2O antibody to target radiation to the malignant B-cells. Preliminary studies have established a safe single dose of Yttrium-90 anti-CD2O antibody (Y2B8) which will produce a tumor response in 82 percent of patients (pts) with low-grade or follicular NHL. The primary toxicity of Y2B8 is reversible myelosuppression, which results in neutropenia and thrombocytopenia and the concomitant increased risk for infection or bleeding. Indium-111 conjugated to the anti-CD2O antibody (In2B8) has been developed to predict tumor and normal organ dosimetry. It is hypothesized that retreatment with Y2B8 delivered 3-4 months after the first dose will improve the complete remission (CR) rate as well as the duration of response. The overall objective of this proposal is to develop a safe treatment strategy that utilizes two sequential doses of Y2B8 separated by 12-16 weeks. After the maximum tolerated two doses (MTD) of Y2B8 is established, a phase II trial will be done to learn if the CR rate can be doubled to 50 percent. It is important to learn the normal organ (including bone marrow) and tumor dosimetry using In2B8 scanning prior to each dose of Y2B8. Statistical models using the In2B8 dosimetry results and marrow mass calculations from Tc radiocolloid scans will be investigated to learn whether marrow toxicity can be predicted. The results of the In2B8 scans will be correlated with computerized tomography (CT) and positron emission tomography (PET) scans. CT and PET will be important to evaluate at the time of the second dose of Y2B8 because many pts have residual masses detected by CT. It is hypothesized that if the residual masses are positive by In2B8 or PET scanning that this will represent residual lymphoma rather than benign scar tissue. Since myelosuppression is the major toxicity of Y2B8, it is hypothesized that this can be decreased by utilizing prophylactic colony stimulating factors. After the MTD is established, additional pts will be treated with prophylactic granulocyte macrophage colony stimulating factor (GM-CSF) and thrombopoietic growth factor (Interleukin-II, oprelvekin) to learn whether the myelosuppression can be ameliorated and whether the dose of Y2B8 can be increased. Bone marrow exams will be performed before and after Y2B8 to evaluate marrow toxicity and effect on marrow cytogenetics. Although it is unusual for humans to develop an antibody to this antibody (human anti-murine antimouse antibody - HAMA), it is unknown whether pts will have a higher HAMA rate after two doses of Y2B8 and this will be examined in this protocol. We anticipate that this novel radioimmunotherapy approach will result in more effective treatment for pts with NHL. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ROLES OF THE WASP N-TERMINUS IN HEMATOPOIETIC CELLS Principal Investigator & Institution: Tsuboi, Shigeru; Professor; Burnham Institute 10901 N Torrey Pines Rd San Diego, Ca 92037 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007
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Summary: (provided by applicant): Wiskott-Aldrich syndrome (WAS) is an X chromosome-linked recessive disorder characterized by a crinical triad of eczema, thrombocytopenia and immunodeficiency. The gene responsible for this disorder was identified and shown to encode a multi-domain protein, Wiskott-Aldrich syndrome protein (WASP). WASP stimulates actin assembly through its C-terminus, but the physiological roles of the WASP N-terminus remain unknown.The principle investigator, I have identified calcium integrin binding protein (CIB) as a WASP Nterminus binding partner. The preliminary results suggest that WASP and CIB may participate in platelet aggregation and leukocyte migration by modulating integrins' affinities for their ligands. And also, I have isolated a cDNA encoding a novel WASP Nterminus-interacting protein (WIP-2). WJP-2 sequence suggests that WIP-2 is involved in chemotaxis. Based on these critical findings, to understand the roles of the WASP Nterminus in hematopoietic cells, the following specific aims are proposed.I. To elucidate the molecular mechanisms underlying the affinity modulation of integrin allb(33 for its ligand by WASP, CIB and PIP2 in platelets. II. To determine the molecular basis underlying bleeding in XLT patients. III. To determine the roles of WASP and CLB in chemotactic migration of leukocytes. IV. To determine the roles of a novel WASP Nterminus interacting protein (WIP-2) in Ieukocyte migration.Elucidating the roles of the WASP N-terminus in hematopoietic cells will provide important information about critical biological processes such as cell migration, and it should facilitate the development of potential therapeutic agent to treat XLT and WAS Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SHIGA LIKE TOXIN AND RENAL CELL DYSFUNCTION Principal Investigator & Institution: Kohan, Donald E.; Chief, Division of Nephrology; Internal Medicine; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2001; Project Start 01-FEB-1997; Project End 31-JAN-2003 Summary: Post-diarrheal hemolytic uremic syndrome (HUS) is the leading cause of acute renal failure in children. The HUS is characterized by acute renal injury, microangiopathic hemolytic anemia, and thrombocytopenia. Renal damage predominantly involves glomerular endothelial cell swelling and detachment, fibrin accumulation, and thrombosis. Marked decreases in glomerular filtration rate (GFR) can occur without obvious histologic changes, suggesting augmented vasoconstrictor influence. The HUS is typically associated with enteric infection by shiga-like toxin (SLT) producing Escherichia coli. The toxin binds to a cell surface glycosphingolipid, GB3, is internalized, and inhibits protein synthesis. The above observations, taken together with the finding that SLT is toxic for endothelial cells, have let to the belief that SLT damage to human glomerular endothelial cells (HGEN) is central to the pathogenesis of HUS renal disease. However, little is known about how SLT interacts with glomerular endothelial cells, particularly in humans. Further, little is known about why HGEN appears to be a major target of SLT, or other factors, in HUS. We have developed a new method for studying HGEN. The current application will take advantage of this technique in order to address the above issues. Finally, very little is know about the molecular biologic events that control cell sensitivity to SLT. The current project includes studies that provide crucial information about this process. Accordingly, the specific aims are: 1) development of a human glomerular endothelial cell model to study the biologic actions of SLT; 2) determination of HGEN susceptibility to SLT toxicity including measurement of baseline GB3 expression by HGEN, identification of inflammatory factors regulating HGEN SLT sensitivity, and elucidation of paracrine and autocrine regulation of HGEN SLT sensitivity; 3) determination of the
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biologic effects of SLT and inflammatory factors on HGEN including evaluation of factors mediating SLT-induced HGEN detachment, examination of SLT modulation of HGEN-regulated fibrin accumulation, and analysis of inflammatory factor and SLT effects on HGEN vasoactive mediator production; and 4) cloning of the gene encoding human UDP-galactose: lactosylceramide alpha 1-4-galactosyl-transferase, the ratelimiting enzyme in GB3 formation. These studies provide essential information on how and why HGEN are damaged in HUS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SHORT-TERM TRAINING STUDENTS IN HEALTH PROFESSIONAL SCH. Principal Investigator & Institution: Benovic, Jeffrey L.; Professor and Vice Chairman; Microbiology and Immunology; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2003; Project Start 01-APR-1996; Project End 31-JUL-2008 Summary: (provided by applicant)The proposed program is designed to attract highly qualified medical students to careers in biomedical research, specifically to careers involving heart, lung and blood-related fields. The specific goals of the program are to: a) permit student participants to gain an understanding of the research process in heart, lung and blood related projects b) give student participants first-hand experience in the design andexecution of controlled experiments, the use of different research techniques and equipment, and the interpretation of data in heart, lung and blood related projects c) foster constructive views of the role of biomedical reseach and the effects of its accomplishments in academic and clinical medicined) expose student participants to faculty role models who are enthusiastic about research in heart, lung and blood related projects e) emphasize the importance of the role of the physician-scientist as an intermediary between the basic science research laboratory and the clinic, by formulating clinically relevant hypotheses and by translating research findings into patient care. The approach we will take to achieve these goals is to sponsor 8-10 week summer research opportunities for 8 selected medical students in modern biomedical research laboratories with faculty mentors who are engaged in active basic and clinical research into heart, lung and blood related problems. The faculty who have agreed to provide the core of mentors for this program represent a broad base of clinical and research interests, including angiogenesis, asthma, atherogenesis, hypertension, bone marrow transplantation, hypoxia, leukemia, sickle cell disease and thrombocytopenia as well as related basic science interests in apoptosis and cell signaling. This program will also provide opportunities for each traineee to attend research seminars, to present his/her work to a scientific audience, and to write up data in the form of a manuscript. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SITOSTEROLEMIA Principal Investigator & Institution: Salen, Gerald; Professor of Medicine; Medicine; Univ of Med/Dent Nj Newark Newark, Nj 07103 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2004 Summary: The major aims of this grant are to define the molecular, biochemical, and clinical defects in sitosterolemia. In this recessively inherited disease, homozygotes show accelerated atherosclerosis with aortic stenosis, fatal myocardial infarctions, tendon and tuberous xanthomas, hemolytic episodes with deformed erythrocytes and thrombocytopenia, and attacks of disabling arthritis. Chemically, plant sterols
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(sitosterol, stigmasterol, campesterol, and avenosterol) and their respective 5alphadihydro derivatives (sitostanol and campestanol) and cholestanol accumulate in all tissues except brain because of enhanced intestinal absorption and reduced hepatic removal. In addition, cholesterol biosynthesis is discordantly down-regulated in monocytes with upregulated LDL receptors to produce increased cholesterol and plant sterol deposits such that the cells resemble atherogenic foam cells. Key research objectives are (1) locate and clone the sitosterolemia gene responsible for hyperabsorption that has been mapped to 2p21, sequence mutations, and elucidate the mechanism by with the mutated product permits unrestricted uptake and transport of plant sterols through the enterocyte. Strategies include fine mapping with a dense set of microsatilliate markers to narrow the abnormal gene region to approximately 1cM, construction of YAC contig and BAC contig with critical cDNAs from the suspected and adjoining regions. Sequence candidate genes from the region for possible mutations. DNA from 40 affected homozygotes from 30 sitosterolemic families have been assembled. (2) Investigate cholesterol and plant sterol metabolism in 3 rat models where campesterol and sitosterol constitute approximately 15 percent of the plasma sterols similar to human sitosterolemia. In these models, we propose to measure sitosterol and cholesterol absorption, assess cholesterol biosynthesis (inhibited in human sitosterolemia) and evaluate the effect of long term cholesterol feeding on development of atherosclerosis, plant sterol and cholesterol accumulation and metabolism. (3) Examine the conversion of sitosterol (24-ethyl cholesterol) to cholic acid and chenodeoxycholic acid and ascertain the pathway. Sitosterolemia is a rare disease but understanding the mechanism of enhanced sterol absorption and accumulation will provide key information to formulate better treatment of atherosclerosis in the general population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FUNCTIONS
STROMAL
CYTOKINE
SIGNALING
AND
BIOLOGICAL
Principal Investigator & Institution: Yang, Yu-Chung; Professor; Pharmacology; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2001; Project Start 01-AUG-1992; Project End 31-MAR-2003 Summary: Interleukin (IL)-11 is a multifunctional cytokine which has been shown to be important in hematopoiesis and other biological processes. The cDNA encoding IL-11 was originally isolated by the P.I. from a primate bone marrow derived stromal fibroblast cell line based on the ability of the cytokine to stimulate the proliferation of an IL-6-dependent plasmacytoma cell line. Phase I and II clinical trials demonstrated that IL-11 is an important thrombopoietic agent that can be used safely in patients with severe chemotherapy-induced thrombocytopenia. The use of IL-11 in cancer patients with thrombocytopenia has recently been approved by FDA Advisory Committee. Because of its immunomodulatory activity and ability to maintain the integrity and promote healing of the gastrointestinal mucosa, IL-11 may also reduce the severity of chemotherapy-induced mucositis and associated inflammatory complications. These biological activities have led to clinical trials for treatment of chemotherapy-induced mucositis and Crohn s disease. Based on its ability to enhance thrombopoiesis, protect gastrointestinal epithelial injury and reduce inflammatory complications, IL-11 therefore represents a multifunctional cytokine that may potentially offer several benefits in cancer therapy. One of my long term research interests has been to understand the process of how cytokine signaling correlates with biological functions and understand the mechanisms of actions of cytokines in treating human diseases. We have analyzed
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the signaling events mediated by IL-11 in several different cell lines. Signaling studies have resulted in the identification of several important molecules involved in IL-11 signaling and the speculation that some of these molecules may determine IL-11 biological specificity, redundancy and pleiotropy. The observations have led to the following hypotheses which will be tested in this proposal: 1) Overexpression, antisense expression and mutations of SHP-2, JAKs/Stats, IRS and gp130 proteins will affect biological functions of IL-11; (2) Structural domain requirements for different signaling molecules may vary among members within the same cytokine superfamily and in different cell types and these differences may determine their cytokine specificity, redundancy and pleiotropy; (3) The specificity of gp130 cytokines can be determined by specific signaling molecules and genes yet to be identified. To test these hypotheses, we will (1) determine the role of SHP-2, JAKs/Stats, IRS and gp130 proteins in IL-11 signaling, (2) analyze gp130 associated molecules and (3) examine the primary response genes activated by IL-11. It is anticipated that understanding of the molecular basis of cytokine signal transduction and cellular responses may lead to new modalities of treatment for both cancer and leukemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STUDY OF TTP: INCIDENCE RATES AND RISK FACTORS Principal Investigator & Institution: Bennett, Charles L.; Professor of Medicine and Associate Dire; Medicine; Northwestern University 633 Clark St Evanston, Il 60208 Timing: Fiscal Year 2002; Project Start 09-SEP-2002; Project End 31-AUG-2006 Summary: (provided by applicant): Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterized by a pentad of symptoms including microangiopathic hemolytic anemia (MAHA), thrombocytopenia, neurologic symptoms, fever, and renal dysfunction. The diagnosis of TIP must be made in a timely manner because this condition carries with it a high mortality rate if untreated. Prompt therapy reduces substantially the mortality rate and therefore timely recognition is essential. TTP is a rare disease with an estimated annual incidence of 3.7 cases per million, and is more frequent among women. Recently, concerns have been raised that the annual incidence of TTP has increased 5 to 8 fold as a complication of therapy with commonly used antiplatelet drugs or following commonplace interventional procedures such as arterial stents. As with other rare diseases, there are significant gaps in the understanding of the pathogenesis of TTP, its distribution in the US population, risk factors, and determinants of outcome. We propose to evaluate gaps in our current knowledge of TTP among adults in the United States using a multi-center case-control study that addresses risk factors for TTP. In addition, we propose an interrelated set of translational basic science studies that may help improve our understanding of why some persons with TTP die from the illness. The primary objective of this study is to evaluate risk of incident TTP in relation to the use of antiplatelet drugs (the thienopyridines, ticlopidine and clopidogrel, the two most common non-transplant TTPassociated drugs identified in the FDA's passive surveillance program, MedWatch). Concern exists that there is a cause and effect relationship between clopidogrel, an agent that is used by two percent of the United States population, and TTP. A four year case control study is designed to investigate this specific question. The secondary objective of the study is to examine possible biologic markers as prognostic factors related to 30-day mortality following an incident TIP, including presence and activity of vWF cleaving metalloprotease, and degree of endothelial cell apoptosis. These issues are of particular relevance, as TTP is a serious and potentially fatal syndrome and has eluded scientific advances for the past seven decades. Our study is unique and will advance scientific
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knowledge in this area. The findings of this study would facilitate health care professional for future clinical actions and public policy decisions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRAINING GRANT IN HEMOSTASIS AND THROMBOSIS Principal Investigator & Institution: Cines, Douglas B.; Professor; Pathology and Lab Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2006 Summary: (Applicant's Abstract) There have been exciting advances in the areas of hemostasis and thrombosis in the past several years. Rapid advances have occurred in the understanding of the molecular basis of diseases, establishment of animal models for these disorders and in their treatment. Investigators at the University of Pennsylvania have made important contributions to these areas. We have a large and growing body of interactive investigators in these fields, but no training grant to support the training of pre- and post-doctoral fellows in hemostasis and thrombosis. At the moment, there are three large Program Projects and one SCOR in the areas of hemostasis and thrombosis on our campus. Yet, there is no organized program for training pre- and post-doctoral fellows in these areas. We believe that the further growth of research in hemostasis and thrombosis on our campus requires such a training structure. Specific areas of interest that trainees might pursue include structure/function of various coagulation factors; gene therapy for the hemophiliacs; platelet biology both in vitro and in murine models; the development and pathobiology of the vascular system; and the molecular basis of such clinical disorders such as thrombophilia and Heparin-Induced Thrombocytopenia This proposed training grant will have several key features that will make it a productive mechanism for training future investigators in hemostasis and thrombosis. The first component is a well-organized Oversight Committee that will ensure that outstanding trainee candidates are not only successful in their research, but in the obtainment of overall training in the fields of hemostasis and thrombosis. The secondcomponent is the design of a required didactic lecture series to provide the Ph.D. trainee with a well-rounded understanding of the clinical aspects of hemostasis and thrombosis and to provide the M.D. trainee with a well-rounded exposure to the various basic science issues and approaches in these fields. Another required course is the Cardiovascular Seminar Series given by national and internationally recognized investigators. The trainees will be provided with a unique opportunity to not only hear their research seminars, but to discuss the research effort by these investigators in a special session of trainees with investigator. The third component is a semi- annual evaluation form that will allow the Oversight Committee to intervene early when a trainee is having problems in either their research effort or course work. (End of Abstract) Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TRANSFUSION MEDICINE/HEMOSTASIS CLINICAL RESEARCH Principal Investigator & Institution: Neufeld, Ellis J.; Associate Professor of Pediatrics; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): The focus of this grant is randomized clinical trials for hematologic disorders, which require a multi-center approach in the NHLBI Transfusion Medicine/Hemostasis Clinical Research Network. Three Harvard teaching hospitals form a consortium for this Core Clinical Center application. Key linkages
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among the institutions are in place, including the Joint Program in Transfusion Medicine, and the Boston Hemophilia Center. Adult and pediatric hematology and transfusion medicine services are represented, as well as collaboration with the high-risk obstetrics services at our institutions. The first proposed study has a pediatric focus and two-year time frame. The aim of this randomized phase II trial is to assess the efficacy of rituximab (anti-CD20 monoclonal antibody) vs. azathioprine, in children and adolescents with severe or refractor chronic idiopathic thrombocytopenic purpura. The primary efficacy outcome will be platelet counts at study day 90. Secondary outcomes include bleeding score trend, platelet counts at one year, side effects of medication, and requirement for 'salvage' regimens during either course of therapy. Our proposed longterm study will focus on randomized treatment strategies in thrombotic thrombocytopenic purpura (TTP). The aim is to determine whether rituximab therapy in addition to prednisone and plasmapheresis will facilitate remission induction, compared to standard therapy of plasmapheresis/ prednisone alone. Primary efficacy outcomes include the fraction of patients alive with no more than 9 plasma exchange procedures at 30 days from diagnosis (early responders) and the fraction of patients alive and relapse-free at 24 months. Secondary endpoints will include the death rate, the fraction of patients in remission at 30 days, the time to first remission in each treatment group, the number of plasma exchange procedures per patients, the number of relapses per group, and the time to remission and relapse rate, in each group, stratified for the presence of absence of VWV metalloprotease inhibitors and quantification of VW protease activity. Third, we propose a multicenter consortium for a phase III randomized study comparing two different dosage regimens of intravenous gamma globulin during pregnancies at risk for neonatal alloimmune thrombocytopenia. A repository for sera, plasma, and DNA from patients in each of the transfusion network studies is proposed, to facilitate further biological studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSFUSION MEDICINE/HEMOSTASIS CLINICAL RESEARCH NETWO* 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 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Hematologic and hemostatic disorders are common causes of hospital admissions, morbidity and mortality. However, these disorders, considered individually, are uncommon, a fact that has made them difficult to study in the context of a health care system in which therapy of rare disorders is not standardized and single institution studies cannot accrue sufficient numbers of patients to reach meaningful conclusions. For this reason, a network of centers to collaboratively study such disorders is needed. In this application, we will pursue two primary goals. First, we will provide an overview of clinical research activity in hemostasis and transfusion medicine at Case Western Reserve University School of Medicine (CWRU)/University Hospitals of Cleveland (UHC), and demonstrate the benefits of including CWRU/UHC in the hemostasis/transfusion medicine clinical research consortium. The strengths of our institution in this regard include 1) the large volume of adult and pediatric patients with congenital and acquired hematologic disorders who receive care here, 2) the CWRU/UHC Cancer Center, an NCI-designated comprehensive cancer center through which a well established clinical research infrastructure is available for administering and monitoring our research activities, and 3) the experience and track record of our faculty in accruing patients to NIH-sponsored clinical trials. Our
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second goal will be to provide a comprehensive rationale and experimental approach for studying two common thrombocytopenic disorders, heparin-associated thrombocytopenia (HIT) and immune thrombocytopenic purpura (ITP). With regard to HIT, we will assess the incidence of subclinical thrombosis in newly diagnosed patients with HIT and "asymptomatic thrombocytopenia", and evaluate the need for alternative anticoagulation in these patients. We hypothesize that such therapy may not be necessary in all cases. We will also directly compare the efficacy of refludan and argotraban in preventing the development of thrombi in this patient group. In our second project, we will assess the incidence of H. pylori infection in a large cohort of patients with ITP, and determine whether eradication of H. pylori induces a remission of ITP. We hypothesize that many patients with ITP will respond to this intervention. Successful completion of these studies will provide important insights into the management of each of these disorders that will have an important and immediate impact on their management. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSFUSION MEDICINE/HEMOSTASIS CLINICAL RESEARCH NETWO* Principal Investigator & Institution: Triulzi, Darrell J.; Pathology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Core Center Program Objectives: The Pittsburgh Transfusion Medicine/Hemostasis Research Network (PTN) seeks to contribute to important multicenter clinical trials in transfusion medicine and hemostasis by capitalizing on our three strengths: 1) The integrated delivery of transfusion medicine and coagulation services to all the major University of Pittsburgh Medical Center Health System (UPMCHS) hospitals by the University of Pittsburgh faculty at the Institute For Transfusion Medicine (ITxM);2) The extraordinary patient base afforded by the UPMCHS hospitals including a Pittsburgh Cancer Institute (PCI), adult and pediatric level I trauma centers, a largest organ transplant program, a children's hospital, a women's hospital and outpatient facilities including the Hemophilia Center of Western PA and PCI; and3) The extensive experience and extertice of all three core center investigators in running and/or participating in multicenter clinical trials in transfusion medicine and hemostasis. Specific Aims: We propose two protocols to accomplish these objectives:1) Prospective Randomized Trial of Activase in the Prevention of Central Venous Access Device Infection in Hemophilia" (Project 1); and2) Multi-center, Randomized, Controlled Clinical Trial of Plasma Exchange Therapy vs Standard of Care in Children with Thrombocytopenia Associated Multi-Organ Failure (Project 2)The Core Center will provide the infrastructure and oversight necessary for the successful implementation and execution of these trials including: management of the budget for each protocol, timely establishment of program network office, coordinate resources for the operation of each protocol (e.g., research nurse, data clerk), assure timely implementation and operation of new protocols (e.g., accrural, timely data reporting, patient follow up) through biweekly research meetings with protocol investigators, establish a local DSMB for each protocol, assist protocol investigators with data analysis, interpretation, and publication, establish a Community Advisory Group to educate the community and to discuss and disseminate study results, and work with other network sites to select and revise study protocols. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CENTER
TRANSFUSION
MEDICINE/HEMOSTASIS
CORE
CLINICAL
Principal Investigator & Institution: Ortel, Thomas L.; Associate Professor; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Significant advances have been made during the last decade in our ability to diagnose and characterize blood diseases, including inherited disorders, antibody-mediated syndromes, and various acquired thrombo-tic and hemorrhagic risk factors. In addition, an expanding array of therapeutic options is now available for even the rarest of hemostatic disorders. However, because many hemostatic disorders are uncommon, few prospective, randomized clinical trials exist to assess optimal approaches to evaluate and treat these patients. In addition, although millions of patients receive transfusion support annually, few prospective studies are available to guide therapeutic decisions. This is an application from the Division of Hematology at Duke University Medical Center to participate as a Core Clinical Center in the NIH-sponsored Transfusion Medicine/Hemostasis Clinical Research Network. To achieve this, we propose the following aims: (1) Develop and propose multi-center clinical research trials that will accelerate studies in the appropriate use of blood products and novel growth factors, and in the treatment of hemostatic disorders. Clinical trials will be developed by the P.I. and his co-investigators, with protocol review and advice from collaborators and statisticians, for submission to the Network's Steering Committee. We have prepared two clinical research trials for this proposal, one designed to investigate the optimal intensity of anticoagulant therapy in patients with antiphospholipid antibody syndromes, and the second to determine the role of antithrombotic therapy in patients with heparin-induced thrombocytopenia but without evidence for thrombosis. (2) Participate in the Steering Committee and Subcommittees of the Network to ensure appropriate review of proposed studies from individual centers and development of common protocols for implementation. Activities will include organization of the Network, reviewing and finalizing common research protocols, facilitating the conduct and monitoring of all studies, and reporting study results. (3) Work with the Data Coordinating Center and the other Clinical Centers in the Network to efficiently start and complete common clinical research trials at Duke. Implementation of research protocols will include IRB review and approval, regular on-site review of study progress, review of patient recruitment with alternative plans to increase study enrollment as needed, quality control assessments, and reporting of study results. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSFUSION MEDICINE/HEMOSTASIS TRIAL SITE AT PSBC Principal Investigator & Institution: Slichter, Sherrill J.; Executive Vice President of Research; Puget Sound Blood Center 921 Terry Ave Seattle, Wa 98104 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): A Transfusion Medicine/Hemostasis Clinical Trial Site to be located at the Puget Sound Blood Center (PSBC) is proposed. PSBC is a regional blood program that distributes all blood and blood products to patients in Seattle and surrounding counties. It is anticipated that network clinical trials will be conducted at any of 6 Seattle hospitals that have a total of 2,193 beds, and, during 2001, 20,996 patients in these hospitals received over 150,000 blood products. Four University of Washington medical school faculty, based at PSBC, with extensive experience in
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clinical trials will participate with other trial sites in the network clinical trials. These physician scientists are all recognized experts in their areas of research interest; i.e., platelet and granulocyte transfusion therapy, apheresis procedures and their indications, disorders of hemostasis and thrombosis, and patients with ITP. These physicians supervise a hemostasis clinic at PSBC that specializes in hemophilia care, a coagulation laboratory, a platelet antibody laboratory, and an apheresis facility. Through these clinical activities, they are aware of patients with a variety of disorders besides those in area hospitals - who might be candidates for participation in network clinical trials. Two network clinical trials are proposed: 1) "Evaluate The Hemostatic Efficacy And Platelet Utilization Rates Of Low Versus Standard Dose Platelet Therapy;" and 2) A Multicenter Randomized Controlled Trial On The Efficacy Of Transfusion Of G-CSF Mobilized Granulocytes To Neutropenic Patients With Infection." The first trial seeks to determine whether low dose compared to standard dose platelet transfusions are able to maintain adequate hemostasis while decreasing the total number of platelets required to support thrombocytopenic patients. The primary endpoint will be hemostasis; i.e., to demonstrate non-inferiority of patients randomized to the low dose arm compared to those in the standard close arm in the percentage of patients that develop WHO Grade 2 bleeding. The second trial will evaluate the effectiveness of granulocyte transfusion therapy to determine the clinical efficacy of G-CSF mobilized granulocyte transfusions for neutropenic patients with bacteria or fungal infections. Patients will be randomized to receive daily granulocyte transfusions along with standard care or standard care alone. The primary endpoint will be the proportion of patients in each arm who demonstrate both a microbial response to their infection and who also survive at least 28 days from study entry. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSFUSION/HEMOSTASIS CLINICAL RESEARCH NETWORK Principal Investigator & Institution: Konkle, Barbara A.; Associate Professor of Medicine; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): This is an application from University of Pennsylvania School of Medicine faculty to participate in the planned Transfusion Medicine/Hemostasis Clinical Trial Network. This group includes the resources of the University of Pennsylvania Health System (UPHS), the Children's Hospital of Philadelphia (CHOP) and the Penn-Jersey Division of the American Red Cross (PJARC). UPHS and CHOP have ongoing large collaborative programs led by Barbara A. Konkle, M. D., the P.I. of this application, and Catherine Manno, M.D., a co-investigator, respectively, for the care of patients with inherited and acquired disorders of hemostasis. These programs have a long-standing record of participation in clinical trials. In addition, the institutions provide transfusion services, including the provision of cellular components and plasma, to large pediatric and adult bone marrow and stem cell transplantation programs, liver transplantation programs and trauma programs, among other specialized programs. The transfusion services provide plasmapheresis for disorders such as thrombotic thrombocytopenic purpura. Scott Murphy, M.D., a coinvestigator in this proposal, lends his experience in clinical trial networks in hematology, having been a long standing member of the Polycythemia Vera study group and an internationally recognized expert in platelet transfusion. Dr. Murphy, a faculty member of the University of Pennsylvania is the Medical Director of the PJ-ARC. Two randomized clinical trials are proposed: 1) Comparision of Platelet Concentrates
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Derived from Platelet Rich Plasma and Buffy Coats and, 2) Anticoagulation with Unfractionated Heparin Versus the Direct Thrombin Inhbitor Argatroban and the Risk of Thrombosis, Thrombocytopenia and Adverse Clinical Outcomes Following Cardiopulmonary Bypass Surgery. The University of Pennsylvania can provide extensive resources for this Network including patients for enrollment and experience in clinical trial design and enrollment. The investigators look forward to the opportunity to actively participate in such a network which will significantly advance the care of children and adults requiring transfusion or suffering from inherited or acquired disorders of hemostasis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSGENIC ANALYSIS OF PLATELET RECEPTOR EXPRESSION Principal Investigator & Institution: Ware, Jerry L.; Assistant Member; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2003; Project Start 01-MAY-1994; Project End 30-NOV-2007 Summary: (provided by applicant): The objectives of this proposal are to examine the molecular events controlling maturation of the megakaryocyte, platelet biogenesis and normal platelet function. The experimental plan utilizes transgenic animals and the expression of variant membrane receptor. Our goals are to characterize the unique biological events occurring during megakaryocytopoiesis and the consequences of these events on normal platelet function. A murine model of the human Bernard-Soulier syndrome (BSS) has been established via a targeted deletion of the a-subunit of GP Ib (GP Ibalpha), a subunit of the platelet receptor, GP Ib-IX. The mouse model displays a severe bleeding phenotype with macrothrombocytopenia mirroring the human BernardSoulier syndrome. The murine phenotype is rescued by expression of a human GP Ibalpha subunit. New data is presented establishing the cytoplasmic tail of GP Ibalpha controls platelet morphology and platelet release from the megakaryocyte. Moreover, a signal transduction pathway via the tail of GP Ibalpha is described with functional consequences for platelet release and platelet function. Experiments are proposed to test the hypotheses: i) The GP Ib-IX receptor controls aspects of megakaryocyte maturation and platelet release via structural elements within the GP Ibalpha subunit and ii) the GP Ib-IX complex contributes to megakaryocyte development via controlled signaling pathways that also become relevant for normal platelet function. Aim 1 determines the GP Ibalpha structural requirements necessary for facilitating normal platelet release and defines the molecular defect responsible for the macrothrombocytopenia in BSS. Aim 2 characterizes the megakaryocytopoiesis defect in the GP Ibalpha null mouse. Aim 3 characterizes signaling through GP Ibalpha and its role in thrombopoiesis. Aim 4 determines the hemostastic relevance of GP Ibalpha cytoplasmic interactions in genetically engineered platelets. Although clearly important, the role of the GP Ib-IX complex in thrombopoiesis is poorly understood reflecting the lack of appropriate in vitro models. However, models, such as the murine BSS, present an opportunity to study these unique events and will provide new information on the mechanisms controlling megakaryocytopoiesis, the release of blood platelets and the role of platelets in thrombus formation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: VWF PROTEINASE DEFICIENCY IN TTP WITH OR WITHOUT HIV Principal Investigator & Institution: Tsai, Han-Mou M.; Associate Professor of Medicine; Montefiore Medical Center (Bronx, Ny) Bronx, Ny 104672490
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Timing: Fiscal Year 2001; Project Start 01-JAN-1999; Project End 31-DEC-2003 Summary: Thrombotic thrombocytopenic purpura, a fatal disease characterized with disseminated platelet thrombosis in arterioles and capillaries, has been associated with HIV infection. Although plasma exchange or infusion is highly effective and has been the standard treatment since late 1970's, the incidence and case mortality rate of TTP increased by 16 and 3 folds respectively from 1971 to 1991. Concern has been raised that if the trend continues, TTP may become a serious public health problem. The etiologies and pathogenesis of TTP remain uncertain. Abundance of vWF in TTP lesions, as well as frequent occurrence of vWF multimer abnormalities, suggests that TTP is associated with a defect in the regulation of the size of vWF. In normal circulation, vWF, upon release from endothelial cells, is cleaved by a novel plasma metalloproteinase to become smaller forms. Our studies have demonstrated that vWF, when exposed to shear stress in the absence of the proteinase, exhibits an increase in its adhesive activity. Thus, vWFcleaving proteinase may play a critical role in the prevention of platelet thrombosis. The aim of this project is to determine whether a deficiency in vWF proteinase is involved in the pathogenesis of platelet thrombosis in HIV-related as well as in idiopathic TTP. In a preliminary study of 39 samples from 37 patients with acute episodes of TTP, two of whom were seropositive for HIV, a severe deficiency in the vWF-cleaving proteinase activity was detected in 100 percent of the cases. Inhibitory IgG antibodies to the proteinase were found in at least two third of the TTP plasmas. The deficiency was highly specific since it was not detected in 16 plasmas obtained at remission of TTP or 74 plasmas obtained from normal subjects as well as patients with thrombocytopenia, hemolysis, or thrombosis due to other causes. This project will expand the study on the prevalence and causes of the vWF proteinase deficiency in HIV-related and idiopathic TTP and other disorders with thrombocytopenia and microangiopathic hemolysis, will isolate and clone the vWF proteinase, and will explore, in in vitro and in vivo models, how a deficiency in vWF-cleaving metalloproteinase may lead to platelet thrombosis as encountered in TTP. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “thrombocytopenia” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for thrombocytopenia in the PubMed Central database:
3 4
Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.
With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.
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A primary production deficit in the thrombocytopenia of equine infectious anemia. by Crawford TB, Wardrop KJ, Tornquist SJ, Reilich E, Meyers KM, McGuire TC.; 1996 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190855
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Assessment of Equine Autoimmune Thrombocytopenia (EAT) by flow cytometry. by Nunez R, Gomes-Keller MA, Schwarzwald C, Feige K.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=32162
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Delayed Mortality and Attenuated Thrombocytopenia Associated with Severe Malaria in Urokinase- and Urokinase Receptor-Deficient Mice. by Piguet PF, Da Laperrousaz C, Vesin C, Tacchini-Cottier F, Senaldi G, Grau GE.; 2000 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101654
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Distinct Human Immunodeficiency Virus Strains in the Bone Marrow Are Associated with the Development of Thrombocytopenia. by Voulgaropoulou F, Tan B, Soares M, Hahn B, Ratner L.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104119
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GPIIIa-(49 --66) is a major pathophysiologically relevant antigenic determinant for anti-platelet GPIIIa of HIV-1-related immunologic thrombocytopenia. by Nardi MA, Liu LX, Karpatkin S.; 1997 Jul 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23866
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Heparin-Induced Thrombocytopenia with Associated Thrombosis in Children after the Fontan Operation Report of Two Cases. by Porcelli R, Moskowitz BC, Cetta F, Graham LC, Godwin JE, Eidem BW, Prechel MM, Walenga JM.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=152838
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Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia. by Ihara K, Ishii E, Eguchi M, Takada H, Suminoe A, Good RA, Hara T.; 1999 Mar 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15907
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Immune-mediated thrombocytopenia in horses infected with equine infectious anemia virus. by Clabough DL, Gebhard D, Flaherty MT, Whetter LE, Perry ST, Coggins L, Fuller FJ.; 1991 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=250322
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Internal-Image Anti-Idiotype HIV-1gp120 Antibody in Human Immunodeficiency Virus 1 (HIV-1)-Seropositive Individuals with Thrombocytopenia. by Karpatkin S, Nardi MA, Kouri YH.; 1992 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48476
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Severe thrombocytopenia in young calves experimentally infected with noncytopathic bovine viral diarrhea virus. by Corapi WV, French TW, Dubovi EJ.; 1989 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=250990
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Thrombocytopenia in critically ill surgical patients: a case-control study evaluating attributable mortality and transfusion requirements. by Stephan F, Montblanc JD, Cheffi A, Bonnet F.; 1999; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=29031
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Treatment with Megestrol Acetate Improves Human Immunodeficiency VirusAssociated Immune Thrombocytopenia. by Gomez F, Ruiz P, Lopez R, Rivera C.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=119971
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 thrombocytopenia, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “thrombocytopenia” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for thrombocytopenia (hyperlinks lead to article summaries): •
“A new association of mental retardation, short stature, unusual face, radio-ulnar synostosis and retinal pigment abnormalities”: Cohen syndrome with thrombocytopenia. Author(s): De Ravel TJ, Dillen K, Fryns JP. Source: Genet Couns. 2002; 13(4): 475-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12558120&dopt=Abstract
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A case of autoimmune pancreatitis complicated with immune thrombocytopenia during maintenance therapy with prednisolone. Author(s): Nakamura A, Funatomi H, Katagiri A, Katayose K, Kitamura K, Seki T, Yamamura F, Aoyagi Y, Nishida H, Mitamura K. Source: Digestive Diseases and Sciences. 2003 October; 48(10): 1968-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14627342&dopt=Abstract
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A case of thrombotic thrombocytopenic purpura and neonatal alloimmune thrombocytopenia in the same pregnancy. Author(s): Richmond JR, Koufogianis V, Benjamin A, Warner MN. Source: Bjog : an International Journal of Obstetrics and Gynaecology. 2003 May; 110(5): 533-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12742343&dopt=Abstract
6 PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.
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A genetic marker within the CD44 gene confirms linkage at 11p13 in AfricanAmerican families with lupus stratified by thrombocytopenia, but genetic association with CD44 is not present. Author(s): Kaufman KM, Rankin J, Harley IT, Kelly JA, Harley JB, Scofield RH. Source: Genes and Immunity. 2002 October; 3 Suppl 1: S86-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12215908&dopt=Abstract
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A role of autoantibody-mediated platelet destruction in thrombocytopenia in patients with cirrhosis. Author(s): Kajihara M, Kato S, Okazaki Y, Kawakami Y, Ishii H, Ikeda Y, Kuwana M. Source: Hepatology (Baltimore, Md.). 2003 June; 37(6): 1267-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12774004&dopt=Abstract
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A site involving the “hybrid” and PSI homology domains of GPIIIa (beta 3-integrin subunit) is a common target for antibodies associated with quinine-induced immune thrombocytopenia. Author(s): Peterson JA, Nyree CE, Newman PJ, Aster RH. Source: Blood. 2003 February 1; 101(3): 937-42. Epub 2002 September 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12393510&dopt=Abstract
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Abciximab-associated pseudothrombocytopenia. Author(s): Wool RL, Coleman TA, Hamill RL. Source: The American Journal of Medicine. 2002 December 1; 113(8): 697-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12505125&dopt=Abstract
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Abciximab-induced thrombocytopenia. Author(s): Griffiths C, Fisher M. Source: Qjm : Monthly Journal of the Association of Physicians. 2002 September; 95(9): 635-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12205341&dopt=Abstract
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Acute hepatitis B and isolated thrombocytopenia. Author(s): Ozaras R, Celik AD, Kisacik B, Mert A, Aki H, Ozturk R, Tabak F. Source: Journal of Clinical Gastroenterology. 2003 July; 37(1): 87-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12811220&dopt=Abstract
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Acute myelogenous leukemia in an adult with thrombocytopenia with absent radii syndrome. Author(s): Go RS, Johnston KL. Source: European Journal of Haematology. 2003 April; 70(4): 246-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12656750&dopt=Abstract
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Acute profound thrombocytopenia after use of eptifibatide for coronary stenting. Author(s): Salengro E, Mulvihill NT, Farah B. Source: Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions. 2003 January; 58(1): 73-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12508201&dopt=Abstract
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Acute profound thrombocytopenia associated with eptifibatide therapy. Author(s): Nagge J, Jackevicius C, Dzavik V, Ross JR, Seidelin P. Source: Pharmacotherapy. 2003 March; 23(3): 374-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12627937&dopt=Abstract
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Acute pulmonary thromboembolism induced by prophylactic heparin use and a heparin-coated catheter: a case of heparin-induced thrombocytopenia and thrombosis syndrome. Author(s): Nasuno A, Matsubara T, Hori T, Higuchi K, Tsuchida K, Mezaki T, Tanaka T, Hanzawa K, Moro H, Hayashi J, Tanaka K, Fuse I, Aizawa Y. Source: Circulation Journal : Official Journal of the Japanese Circulation Society. 2003 January; 67(1): 96-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12520161&dopt=Abstract
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Acute respiratory failure with thrombocytopenia in a 47-year-old woman after hiking in the Sierras. Author(s): Sankaranarayanan V, Sharp V, Ruoss S. Source: Chest. 2003 August; 124(2): 754-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12907570&dopt=Abstract
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Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa. Author(s): Bougie DW, Wilker PR, Wuitschick ED, Curtis BR, Malik M, Levine S, Lind RN, Pereira J, Aster RH. Source: Blood. 2002 September 15; 100(6): 2071-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12200368&dopt=Abstract
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Acute thrombocytopenia associated with eptifibatide therapy. Author(s): Khaykin Y, Paradiso-Hardy FL, Madan M. Source: The Canadian Journal of Cardiology. 2003 June; 19(7): 797-801. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12813613&dopt=Abstract
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Acute thrombocytopenia in patients treated with the oral glycoprotein IIb/IIIa inhibitors xemilofiban and orbofiban: evidence for an immune etiology. Author(s): Brassard JA, Curtis BR, Cooper RA, Ferguson J, Komocsar W, Ehardt M, Kupfer S, Maurath C, Swabb E, Cannon CP, Aster RH. Source: Thrombosis and Haemostasis. 2002 December; 88(6): 892-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12529735&dopt=Abstract
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Alloimmune thrombocytopenia in the fetus: current management theories. Author(s): Sosa ME. Source: The Journal of Perinatal & Neonatal Nursing. 2003 July-September; 17(3): 181-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12959479&dopt=Abstract
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Alternative methods of anticoagulation for dialysis-dependent patients with heparininduced thrombocytopenia. Author(s): O'Shea SI, Ortel TL, Kovalik EC. Source: Seminars in Dialysis. 2003 January-February; 16(1): 61-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12535303&dopt=Abstract
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Amelioration of the macrothrombocytopenia associated with the murine BernardSoulier syndrome. Author(s): Kanaji T, Russell S, Ware J. Source: Blood. 2002 September 15; 100(6): 2102-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12200373&dopt=Abstract
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An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients. Author(s): Warkentin TE, Roberts RS, Hirsh J, Kelton JG. Source: Archives of Internal Medicine. 2003 November 10; 163(20): 2518-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14609790&dopt=Abstract
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Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Author(s): Greinacher A, Lubenow N, Eichler P. Source: Circulation. 2003 October 28; 108(17): 2062-5. Epub 2003 Oct 20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14568897&dopt=Abstract
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Antenatal screening for fetomaternal alloimmune thrombocytopenia: should we be doing it? Author(s): Murphy MF, Williamson LM, Urbaniak SJ. Source: Vox Sanguinis. 2002 August; 83 Suppl 1: 409-16. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617177&dopt=Abstract
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Antibodies to anionic phospholipids and anti-beta2-GPI: association with thrombosis and thrombocytopenia in systemic lupus erythematosus. Author(s): Amoroso A, Mitterhofer AP, Del Porto F, Garzia P, Ferri GM, Galluzzo S, Vadacca M, Caccavo D, Afeltra A. Source: Human Immunology. 2003 February; 64(2): 265-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12559629&dopt=Abstract
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Anti-CD2O chimeric monoclonal antibody (rituximab) treatment of immunemediated thrombocytopenia associated with Crohn's disease. Author(s): Papadakis KA, Rosenbloom B, Targan SR. Source: Gastroenterology. 2003 February; 124(2): 583. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12557172&dopt=Abstract
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Anti-c-Mpl (thrombopoietin receptor) autoantibody-induced amegakaryocytic thrombocytopenia in a patient with systemic sclerosis. Author(s): Katsumata Y, Suzuki T, Kuwana M, Hattori Y, Akizuki S, Sugiura H, Matsuoka Y. Source: Arthritis and Rheumatism. 2003 June; 48(6): 1647-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12794833&dopt=Abstract
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Anticoagulation for patients with heparin-induced thrombocytopenia using recombinant hirudin during cardiopulmonary bypass. Author(s): Liu H, Fleming NW, Moore PG. Source: Journal of Clinical Anesthesia. 2002 September; 14(6): 452-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12393116&dopt=Abstract
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Antithrombotic drugs for the treatment of heparin-induced thrombocytopenia. Author(s): Jeske WP, Walenga JM. Source: Curr Opin Investig Drugs. 2002 August; 3(8): 1171-80. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12211410&dopt=Abstract
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Are patients with paroxysmal nocturnal hemoglobinuria at risk for heparin-induced thrombocytopenia? Author(s): Huehn C, Righini M, Starobinski M, Angelillo-Scherrer A, de Moerloose P. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 February; 1(2): 389-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12871520&dopt=Abstract
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Argatroban anticoagulation during percutaneous coronary intervention in patients with heparin-induced thrombocytopenia. Author(s): Lewis BE, Matthai WH Jr, Cohen M, Moses JW, Hursting MJ, Leya F; ARG216/310/311 Study Investigators. Source: Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions. 2002 October; 57(2): 177-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12357516&dopt=Abstract
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Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Author(s): Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG; Argatroban-915 Investigators. Source: Archives of Internal Medicine. 2003 August 11-25; 163(15): 1849-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12912723&dopt=Abstract
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Argatroban dosing in patients with heparin-induced thrombocytopenia. Author(s): Verme-Gibboney CN, Hursting MJ. Source: The Annals of Pharmacotherapy. 2003 July-August; 37(7-8): 970-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12841802&dopt=Abstract
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Argatroban for heparin-induced thrombocytopenia in hepato-renal failure and CVVHD. Author(s): Dager WE, White RH. Source: The Annals of Pharmacotherapy. 2003 September; 37(9): 1232-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12921505&dopt=Abstract
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Attempt to improve the diagnosis of immune thrombocytopenia by combined use of two different platelet autoantibodies assays (PAIgG and MACE). Author(s): Fabris F, Scandellari R, Randi ML, Carraro G, Luzzatto G, Girolami A. Source: Haematologica. 2002 October; 87(10): 1046-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12368159&dopt=Abstract
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Atypical bleeding due to idiopathic thrombocytopenia in association with low factor VIII levels. Author(s): Riordan MF, Hill FG. Source: Archives of Disease in Childhood. 2002 September; 87(3): 227-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12193435&dopt=Abstract
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Autoantibody to c-Mpl (thrombopoietin receptor) in systemic lupus erythematosus: relationship to thrombocytopenia with megakaryocytic hypoplasia. Author(s): Kuwana M, Okazaki Y, Kajihara M, Kaburaki J, Miyazaki H, Kawakami Y, Ikeda Y. Source: Arthritis and Rheumatism. 2002 August; 46(8): 2148-59. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12209520&dopt=Abstract
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Autoimmune thrombocytopenia due to chronic lymphocytic leukemia treated with fludarabine. Author(s): Wells T, Kovacs MJ. Source: The Annals of Pharmacotherapy. 2003 May; 37(5): 671-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708944&dopt=Abstract
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Avoiding misdiagnosis of imported malaria: screening of emergency department samples with thrombocytopenia detects clinically unsuspected cases. Author(s): Hanscheid T, Melo-Cristino J, Grobusch MP, Pinto BG. Source: Journal of Travel Medicine : Official Publication of the International Society of Travel Medicine and the Asia Pacific Travel Health Association. 2003 May-June; 10(3): 155-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757689&dopt=Abstract
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B-cell compartment as the selective target for the treatment of immune thrombocytopenias. Author(s): Zaja F, Vianelli N, Sperotto A, De Vita S, Iacona I, Zaccaria A, Masolini P, Tomadini V, Tani M, Molinari AL, Baccarani M, Fanin R. Source: Haematologica. 2003 May; 88(5): 538-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12745273&dopt=Abstract
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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814331&dopt=Abstract
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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12780795&dopt=Abstract
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Biphasic rattlesnake venom-induced thrombocytopenia. Author(s): Offerman SR, Barry JD, Schneir A, Clark RF. Source: The Journal of Emergency Medicine. 2003 April; 24(3): 289-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12676300&dopt=Abstract
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Bivalrudin use in off-pump myocardial revascularization in patients with heparininduced thrombocytopenia. Author(s): Bott JN, Reddy K, Krick S. Source: The Annals of Thoracic Surgery. 2003 July; 76(1): 273-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12842558&dopt=Abstract
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Can eradication therapy for Helicobacter pylori really improve the thrombocytopenia in idiopathic thrombocytopenic purpura? Our experience and a literature review. Author(s): Ando K, Shimamoto T, Tauchi T, Ito Y, Kuriyama Y, Gotoh A, Miyazawa K, Kimura Y, Kawai T, Ohyashiki K. Source: International Journal of Hematology. 2003 April; 77(3): 239-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12731666&dopt=Abstract
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Carbamazepine-induced immune thrombocytopenia. Author(s): Goraya JS, Virdi VS. Source: Neurology India. 2003 March; 51(1): 132-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865555&dopt=Abstract
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Cardiac surgery in patients with heparin-induced thrombocytopenia using preoperatively determined dosages of iloprost. Author(s): Antoniou T, Kapetanakis EI, Theodoraki K, Rellia P, Thanopoulos A, Kotiou M, Zarkalis D, Alivizatos P. Source: Heart Surg Forum. 2002; 5(4): 354-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12538117&dopt=Abstract
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Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 25-2003. A newborn boy with petechiae and thrombocytopenia. Author(s): Modlin JF, Grant PE, Makar RS, Roberts DJ, Krishnamoorthy KS. Source: The New England Journal of Medicine. 2003 August 14; 349(7): 691-700. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917307&dopt=Abstract
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Causes of thrombocytopenia in triplet gestations. Author(s): Al-Kouatly HB, Chasen ST, Kalish RB, Chervenak FA. Source: American Journal of Obstetrics and Gynecology. 2003 July; 189(1): 177-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12861159&dopt=Abstract
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CD32-mediated platelet aggregation in vitro by anti-thymocyte globulin: implication of therapy-induced in vivo thrombocytopenia. Author(s): Ankersmit HJ, Roth GA, Moser B, Zuckermann A, Brunner M, Rosin C, Buchta C, Bielek E, Schmid W, Jensen-Jarolim E, Wolner E, Boltz-Nitulescu G, Volf I. Source: American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2003 June; 3(6): 754-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12780568&dopt=Abstract
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Central venous catheters and upper-extremity deep-vein thrombosis complicating immune heparin-induced thrombocytopenia. Author(s): Hong AP, Cook DJ, Sigouin CS, Warkentin TE. Source: Blood. 2003 April 15; 101(8): 3049-51. Epub 2002 December 27. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12506031&dopt=Abstract
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Cervical spinal cord hemorrhage secondary to neonatal alloimmune thrombocytopenia. Author(s): Abel M, Bona M, Zawodniak L, Sultan R, Masterson M. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2003 April; 25(4): 340-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12679654&dopt=Abstract
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Childhood thrombocytopenia associated with Graves disease is distinct from idiopathic thrombocytopenic purpura. Author(s): Lee AC, Li CH, Wong LM. Source: Pediatric Hematology and Oncology. 2003 January-February; 20(1): 39-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12687752&dopt=Abstract
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Clinical characteristics of chronic idiopathic thrombocytopenia in Chinese children. Author(s): Wong MS, Chan GC, Ha SY, Lau YL. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2002 November; 24(8): 648-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12439037&dopt=Abstract
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Clinical course of thrombocytopenia in patients treated with imatinib mesylate for accelerated phase chronic myelogenous leukemia. Author(s): van Deventer HW, Hall MD, Orlowski RZ, Mitchell BS, Berkowitz LR, Hogan C, Dunphy CH, Koehler J, Shea TC. Source: American Journal of Hematology. 2002 November; 71(3): 184-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12410573&dopt=Abstract
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Clinical significance of a borderline titer in a negative ELISA test for heparin-induced thrombocytopenia. Author(s): Refaai MA, Laposata M, Van Cott EM. Source: American Journal of Clinical Pathology. 2003 January; 119(1): 61-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12520698&dopt=Abstract
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Clinico-hematologic features of myelodysplastic syndrome presenting as isolated thrombocytopenia: an entity with a relatively favorable prognosis. Author(s): Sashida G, Takaku TI, Shoji N, Nishimaki J, Ito Y, Miyazawa K, Kimura Y, Ohyashiki JH, Ohyashiki K. Source: Leukemia & Lymphoma. 2003 April; 44(4): 653-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12769343&dopt=Abstract
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Clonal T cell-mediated cyclic thrombocytopenia. Author(s): Fureder W, Mitterbauer G, Thalhammer R, Geissler K, Panzer S, Krebs M, Simonitsch-Klupp I, Sperr WR, Lechner K, Kyrle PA. Source: British Journal of Haematology. 2002 December; 119(4): 1059-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12472588&dopt=Abstract
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CMV-induced immune thrombocytopenia and excessive hematogones mimicking an acute B-precursor lymphoblastic leukemia. Author(s): Fisgin T, Yarali N, Duru F, Kara A. Source: Leukemia Research. 2003 February; 27(2): 193-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12526925&dopt=Abstract
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Combination platelet glycoprotein IIb/IIIa receptor and lepirudin administration during percutaneous coronary intervention in patients with heparin-induced thrombocytopenia. Author(s): Pinto DS, Sperling RT, Tu TM, Cohen DJ, Carrozza JP Jr. Source: Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions. 2003 January; 58(1): 65-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12508198&dopt=Abstract
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Combined treatment with nafamostat mesilate and aspirin prevents heparin-induced thrombocytopenia in a hemodialysis patient. Author(s): Takahashi H, Muto S, Nakazawa E, Yanagiba S, Masunaga Y, Miyata Y, Tamba K, Kusano E, Matsuo M, Matsuo T, Asano Y. Source: Clinical Nephrology. 2003 June; 59(6): 458-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12834179&dopt=Abstract
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Comment: treatment of heparin-induced thrombocytopenia. Author(s): Smythe MA, Warkentin TE. Source: The Annals of Pharmacotherapy. 2002 September; 36(9): 1483-4; Author Reply 1484. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12196076&dopt=Abstract
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Comparison of two platelet glycoprotein IIb/IIIa inhibitors, eptifibatide and abciximab: outcomes, complications and thrombocytopenia during percutaneous coronary intervention. Author(s): Suleiman M, Gruberg L, Hammerman H, Aronson D, Halabi M, Goldberg A, Grenadier E, Boulus M, Markiewicz W, Beyar R. Source: J Invasive Cardiol. 2003 June; 15(6): 319-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12777670&dopt=Abstract
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Correlation between increased platelet-associated IgG and thrombocytopenia in secondary dengue virus infections. Author(s): Oishi K, Inoue S, Cinco MT, Dimaano EM, Alera MT, Alfon JA, Abanes F, Cruz DJ, Matias RR, Matsuura H, Hasebe F, Tanimura S, Kumatori A, Morita K, Natividad FF, Nagatake T. Source: Journal of Medical Virology. 2003 October; 71(2): 259-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12938201&dopt=Abstract
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Cost of chemotherapy-induced thrombocytopenia among patients with lymphoma or solid tumors. Author(s): Elting LS, Cantor SB, Martin CG, Hamblin L, Kurtin D, Rivera E, Vadhan-Raj S, Benjamin RS. Source: Cancer. 2003 March 15; 97(6): 1541-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12627519&dopt=Abstract
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Cutaneous dalteparin reactions associated with antibodies of heparin-induced thrombocytopenia. Author(s): Payne SM, Kovacs MJ. Source: The Annals of Pharmacotherapy. 2003 May; 37(5): 655-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708940&dopt=Abstract
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Cyclic thrombocytopenia and polycythemia vera. Author(s): Kojima K, Fujii N, Omoto E, Nose S, Yoneyama M, Sugii Y, Hiramatsu H, Chikatsune M, Sato M, Takata S, Itoshima T, Tanimoto M. Source: Annals of Hematology. 2003 January; 82(1): 61-3. Epub 2002 December 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12574969&dopt=Abstract
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Cyclosporine A in the treatment of a patient with immune thrombocytopenia accompanied by myelodysplastic syndrome and nephrotic syndrome. Author(s): Park SJ, Han CW, Lee JH, Eom HS, Lee SH, Jeong DC, Lim JH. Source: Acta Haematologica. 2003; 110(1): 36-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12975556&dopt=Abstract
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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12890149&dopt=Abstract
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Danazol for the treatment of thrombocytopenia in patients with myelodysplastic syndrome. Author(s): Chan G, DiVenuti G, Miller K. Source: American Journal of Hematology. 2002 November; 71(3): 166-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12410570&dopt=Abstract
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Delayed-onset heparin-induced thrombocytopenia and cerebral thrombosis after a single administration of unfractionated heparin. Author(s): Warkentin TE, Bernstein RA. Source: The New England Journal of Medicine. 2003 March 13; 348(11): 1067-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12637624&dopt=Abstract
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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14597468&dopt=Abstract
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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14597467&dopt=Abstract
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Detection of circulating B cells secreting platelet-specific autoantibody is useful in the diagnosis of autoimmune thrombocytopenia. Author(s): Kuwana M, Okazaki Y, Kaburaki J, Ikeda Y. Source: The American Journal of Medicine. 2003 March; 114(4): 322-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12681462&dopt=Abstract
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Diagnosis and treatment of heparin-induced thrombocytopenia. Author(s): DeBois WJ, Liu J, Lee LY, Girardi LN, Mack C, Tortolani A, Krieger KH, Isom OW. Source: Perfusion. 2003 March; 18(1): 47-53. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12705650&dopt=Abstract
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Direct antithrombin agents ameliorate disseminated intravascular coagulation in suspected heparin-induced thrombocytopenia thrombosis syndrome. Author(s): Mukundan S, Zeigler ZR. Source: Clinical and Applied Thrombosis/Hemostasis : Official Journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2002 July; 8(3): 287-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12361208&dopt=Abstract
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Drug-induced thrombocytopenia: localization of the binding site of GPIX-specific quinine-dependent antibodies. Author(s): Asvadi P, Ahmadi Z, Chong BH. Source: Blood. 2003 September 1; 102(5): 1670-7. Epub 2003 May 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12738668&dopt=Abstract
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Effect of anti-CD20 (rituximab) on resistant thrombocytopenia in autoimmune lymphoproliferative syndrome. Author(s): Heelan BT, Tormey V, Amlot P, Payne E, Mehta A, Webster AD. Source: British Journal of Haematology. 2002 September; 118(4): 1078-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12199788&dopt=Abstract
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Effect of IVIgG treatment on fetal platelet count, HPA-1a titre and clinical outcome in a case of feto-maternal alloimmune thrombocytopenia. Author(s): Lucas GF, Hamon M, Carroll S, Soothill P. Source: Bjog : an International Journal of Obstetrics and Gynaecology. 2002 October; 109(10): 1195-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12387480&dopt=Abstract
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Effect of severe thrombocytopenia on patient outcome after liver transplantation. Author(s): Ben Hamida C, Lauzet JY, Rezaiguia-Delclaux S, Duvoux C, Cherqui D, Duvaldestin P, Stephan F. Source: Intensive Care Medicine. 2003 May; 29(5): 756-62. Epub 2003 April 03. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12677370&dopt=Abstract
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Efficacy and safety of splenectomy in adult chronic immune thrombocytopenia. Author(s): Zoghlami-Rintelen C, Weltermann A, Bittermann C, Kyrle PA, Pabinger I, Lechner K, Wenzl E. Source: Annals of Hematology. 2003 May; 82(5): 290-4. Epub 2003 March 22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12739064&dopt=Abstract
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Enoxaparin safety in patients with severe thrombocytopenia. Author(s): Ibrahim RB, Stroempl LE, Abella EM, Racine E. Source: The Annals of Pharmacotherapy. 2002 September; 36(9): 1478-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12196072&dopt=Abstract
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Epithelioid hemangioendothelioma of the liver associated with thrombocytopenia and coagulopathy. Author(s): Imanishi H, Kawata M, Yanagihara M, Nakayama N, Sato T, Furukawa Y, Fukunaga N, Kozuma T. Source: Hepatogastroenterology. 2002 November-December; 49(48): 1673-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12397762&dopt=Abstract
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Eptifibatide-induced acute profound thrombocytopenia presenting as refractory hypotension. Author(s): Rezkalla SH, Hayes JJ, Curtis BR, Aster RH. Source: Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions. 2003 January; 58(1): 76-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12508202&dopt=Abstract
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Eptifibatide-induced thrombocytopenia and coronary bypass operation. Author(s): Tanaka KA, Vega JD, Kelly AB, Hanson SR, Levy JH. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 February; 1(2): 392-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12871522&dopt=Abstract
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Erythromelalgia precipitated by acral erythema in the setting of thrombocytopenia. Author(s): Coppa LM, Nehal KS, Young JW, Halpern AC. Source: Journal of the American Academy of Dermatology. 2003 June; 48(6): 973-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12789198&dopt=Abstract
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European collaborative study of the antenatal management of feto-maternal alloimmune thrombocytopenia. Author(s): Birchall JE, Murphy MF, Kaplan C, Kroll H; European Fetomaternal Alloimmune Thrombocytopenia Study Group. Source: British Journal of Haematology. 2003 July; 122(2): 275-88. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12846898&dopt=Abstract
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Evaluation and treatment of thrombocytopenia in the neonatal intensive care unit. Author(s): Murray NA. Source: Acta Paediatrica (Oslo, Norway : 1992). Supplement. 2002; 91(438): 74-81. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12477267&dopt=Abstract
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Excessive argatroban anticoagulation for heparin-induced thrombocytopenia. Author(s): Reichert MG, MacGregor DA, Kincaid EH, Dolinski SY. Source: The Annals of Pharmacotherapy. 2003 May; 37(5): 652-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708939&dopt=Abstract
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Experiences with fetomaternal alloimmune thrombocytopenia at a Swedish hospital over a 10-year period. Author(s): Tiblad E, Olsson I, Petersson K, Shanwell A, Winiarski J, Wolff K, Westgren M. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2003 September; 82(9): 803-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12911440&dopt=Abstract
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Fetal anemia as a response to prophylactic platelet transfusion in the management of alloimmune thrombocytopenia. Author(s): Yeast JD, Plapp F. Source: American Journal of Obstetrics and Gynecology. 2003 September; 189(3): 874-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14526332&dopt=Abstract
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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12820817&dopt=Abstract
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Fusidic acid-induced leukopenia and thrombocytopenia. Author(s): Liao YM, Chiu CF, Ho MW, Hsueh CT. Source: J Chin Med Assoc. 2003 July; 66(7): 429-32. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14509406&dopt=Abstract
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Generalized vasculitis, thrombocytopenia, and transient lymphoproliferative disorder caused by idiopathic mixed cryoglobulinemia. Author(s): Schwartzenberg S, Levo Y, Averbuch M. Source: The American Journal of the Medical Sciences. 2003 July; 326(1): 47-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12861125&dopt=Abstract
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Gestational thrombocytopenia and pregnancy-induced antithrombin deficiency: progenitors to the development of the HELLP syndrome and acute fatty liver of pregnancy. Author(s): Minakami H, Yamada H, Suzuki S. Source: Seminars in Thrombosis and Hemostasis. 2002 December; 28(6): 515-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12536342&dopt=Abstract
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Haemorrhagic complications of thrombocytopenia and oral anticoagulation: is there a role for recombinant activated factor VII? Author(s): Kessler C. Source: Intensive Care Medicine. 2002 October; 28 Suppl 2: S228-34. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12404091&dopt=Abstract
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Heparin-coated stent and heparin-induced thrombocytopenia: true, true, and conceivably related. Author(s): Bittl JA. Source: Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions. 2003 January; 58(1): 84-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12508204&dopt=Abstract
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Heparin-induced thrombocytopenia and cardiac surgery. Author(s): Warkentin TE, Greinacher A. Source: The Annals of Thoracic Surgery. 2003 August; 76(2): 638-48. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12902132&dopt=Abstract
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Heparin-induced thrombocytopenia and cardiopulmonary bypass: perioperative argatroban use. Author(s): Lubenow N, Selleng S, Wollert HG, Eichler P, Mullejans B, Greinacher A. Source: The Annals of Thoracic Surgery. 2003 February; 75(2): 577-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12607680&dopt=Abstract
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Heparin-induced thrombocytopenia and the anesthesiologist. Author(s): Warkentin TE. Source: Canadian Journal of Anaesthesia = Journal Canadien D'anesthesie. 2002 JuneJuly; 49(6): S36-49. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12557413&dopt=Abstract
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Heparin-induced thrombocytopenia and warfarin-induced skin necrosis in a child with severe protein C deficiency: successful treatment with dermatan sulfate and protein C concentrate. Author(s): Gatti L, Carnelli V, Rusconi R, Moia M. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 February; 1(2): 387-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12871519&dopt=Abstract
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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12755937&dopt=Abstract
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Heparin-induced thrombocytopenia occurring after discontinuation of heparin. Author(s): Shah MR, Spencer JP. Source: The Journal of the American Board of Family Practice / American Board of Family Practice. 2003 March-April; 16(2): 148-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12665180&dopt=Abstract
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Heparin-induced thrombocytopenia with associated thrombosis in children after the Fontan operation: report of two cases. Author(s): Porcelli R, Moskowitz BC, Cetta F, Graham LC, Godwin JE, Eidem BW, Prechel MM, Walenga JM. Source: Texas Heart Institute Journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital. 2003; 30(1): 58-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12638673&dopt=Abstract
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Heparin-induced thrombocytopenia with pulmonary embolism and disseminated intravascular coagulation associated with low-molecular-weight heparin. Author(s): Betrosian AP, Theodossiades G, Lambroulis G, Kostantonis D, Balla M, Papanikolaou M, Georgiades G. Source: The American Journal of the Medical Sciences. 2003 January; 325(1): 45-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12544086&dopt=Abstract
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Heparin-induced thrombocytopenia with thrombotic sequelae: a review. Author(s): Goor Y, Goor O, Eldor A. Source: Autoimmunity Reviews. 2002 August; 1(4): 183-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12848994&dopt=Abstract
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Heparin-induced thrombocytopenia, paradoxical thromboembolism, and other adverse effects of heparin-type therapy. Author(s): Walenga JM, Frenkel EP, Bick RL. Source: Hematology/Oncology Clinics of North America. 2003 February; 17(1): 259-82, Viii-Ix. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12627671&dopt=Abstract
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Heparin-induced thrombocytopenia. Author(s): Pande AK. Source: J Assoc Physicians India. 2003 January; 51: 58-61. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12693457&dopt=Abstract
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Heparin-induced thrombocytopenia. Author(s): Warkentin TE. Source: Curr Hematol Rep. 2002 September; 1(1): 63-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901126&dopt=Abstract
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Heparin-induced thrombocytopenia. Author(s): Chong BH. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 July; 1(7): 1471-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12871282&dopt=Abstract
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Heparin-induced thrombocytopenia: a common complication in cardiac transplant recipients. Author(s): Hourigan LA, Walters DL, Keck SA, Dec GW. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2002 December; 21(12): 1283-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12490273&dopt=Abstract
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Heparin-induced thrombocytopenia: a complication in extracorporeal photochemotherapy (photopheresis). Author(s): Dittberner T, Schottler E, Ranze O, Greinacher A, Knobler R. Source: Journal of the American Academy of Dermatology. 2002 September; 47(3): 452-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12196761&dopt=Abstract
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Heparin-induced thrombocytopenia: acknowledging its presence in low-molecular weight heparin therapy. Author(s): Ng HJ, Lee LH. Source: International Journal of Hematology. 2003 February; 77(2): 185-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12627856&dopt=Abstract
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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12430880&dopt=Abstract
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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12752095&dopt=Abstract
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Heparin-induced thrombocytopenia: pathogenesis and management. Author(s): Saad RA. Source: British Journal of Haematology. 2003 October; 123(2): 373-4; Author Reply 374. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14531929&dopt=Abstract
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Heparin-induced thrombocytopenia: pathophysiology and new treatment options. Author(s): Harenberg J, Jorg I, Fenyvesi T. Source: Pathophysiology of Haemostasis and Thrombosis. 2002 September-December; 32(5-6): 289-94. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13679659&dopt=Abstract
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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12420239&dopt=Abstract
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Heparin-induced thrombocytopenia--recognition and treatment. Author(s): Miller PL. Source: Aorn Journal. 2003 July; 78(1): 79-86, 89. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12885069&dopt=Abstract
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Heterozygotes in the bernard-soulier syndrome do not necessarily have giant platelets or thrombocytopenia. Author(s): Nurden AT, Combrie R, Claeyssens S, Nurden P. Source: British Journal of Haematology. 2003 February; 120(4): 716-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12588363&dopt=Abstract
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High-dose cyclophosphamide with autologous lymphocyte-depleted peripheral blood stem cell (PBSC) support for treatment of refractory chronic autoimmune thrombocytopenia. Author(s): Huhn RD, Fogarty PF, Nakamura R, Read EJ, Leitman SF, Rick ME, Kimball J, Greene A, Hansmann K, Gratwohl A, Young N, Barrett AJ, Dunbar CE. Source: Blood. 2003 January 1; 101(1): 71-7. Epub 2002 August 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12393623&dopt=Abstract
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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12420238&dopt=Abstract
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How I treat heparin-induced thrombocytopenia and thrombosis. Author(s): Alving BM. Source: Blood. 2003 January 1; 101(1): 31-7. Epub 2002 August 15. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12393689&dopt=Abstract
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Human platelet antigen genotyping by PCR-SSP in neonatal/fetal alloimmune thrombocytopenia. Author(s): Hurd C, Lucas G. Source: Methods in Molecular Medicine. 2004; 91: 71-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14573930&dopt=Abstract
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Idiopathic autoimmune thrombocytopenia and neutropenia in siblings. Author(s): Patel AP. Source: European Journal of Haematology. 2002 August; 69(2): 120-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12366718&dopt=Abstract
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Idiopathic autoimmune thrombocytopenia: evidence for redistribution of platelet antibodies into the circulation after immunoadsorption treatment. Author(s): Leitner GC, Stiegler G, Horvath M, Hoecker P, Sagaster P, Panzer S. Source: American Journal of Hematology. 2003 May; 73(1): 44-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12701120&dopt=Abstract
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Immune thrombocytopenia after losartan therapy. Author(s): Ada S, Yalamanchili M, Friedenberg W. Source: Annals of Internal Medicine. 2002 October 15; 137(8): 704. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12379089&dopt=Abstract
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Immune thrombocytopenia induced by fludarabine successfully treated with rituximab. Author(s): Fernandez MJ, Llopis I, Pastor E, Real E, Grau E. Source: Haematologica. 2003 February; 88(2): Elt02. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12604433&dopt=Abstract
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Importance of predosing of recombinant human thrombopoietin to reduce chemotherapy-induced early thrombocytopenia. Author(s): Vadhan-Raj S, Patel S, Bueso-Ramos C, Folloder J, Papadopolous N, Burgess A, Broemeling LD, Broxmeyer HE, Benjamin RS. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 August 15; 21(16): 3158-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915607&dopt=Abstract
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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12753887&dopt=Abstract
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In vitro tests for assessing heparin-induced thrombocytopenia in patients after elective hip replacement. A medico-economical evaluation. Author(s): Sobas F, Colin C, Ffrench P, Trzeciak MC, Dechavanne M, Negrier C. Source: International Journal of Technology Assessment in Health Care. 2002 Summer; 18(3): 555-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12391948&dopt=Abstract
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Incidental diagnosis and tempestive therapy in a case of neonatal alloimmune thrombocytopenia due to anti-HPA-5b. Author(s): Zuppa AA, Cota F, De Luca D, Visintini F, De Turris PL, Tortorolo G. Source: Pediatric Hematology and Oncology. 2002 December; 19(8): 587-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12487835&dopt=Abstract
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Indinavir-induced thrombocytopenia. Author(s): Camino N, Nunez M, Blanco F, Gonzalez-Requena D, Gonzalez-Lahoz J, Soriano V. Source: Aids Patient Care and Stds. 2003 March; 17(3): 103-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12724005&dopt=Abstract
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Inflammatory abdominal aortic aneurysm followed by disseminated intravascular coagulation and immune thrombocytopenia. Author(s): Machida H, Kobayashi M, Taguchi H. Source: Intern Med. 2002 November; 41(11): 1032-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12487185&dopt=Abstract
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Influenza-like symptoms and thrombocytopenia in a teenager. Author(s): Ruof HR, Rudin C, Heininger U. Source: The Pediatric Infectious Disease Journal. 2003 January; 22(1): 89, 101-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12553300&dopt=Abstract
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Inherited thrombocytopenias: a proposed diagnostic algorithm from the Italian Gruppo di Studio delle Piastrine. Author(s): Balduini CL, Cattaneo M, Fabris F, Gresele P, Iolascon A, Pulcinelli FM, Savoia A; Italian Gruppo di Studio delle Piastrine. Source: Haematologica. 2003 May; 88(5): 582-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12745278&dopt=Abstract
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Inter-NICU variation in rates and management of thrombocytopenia among very low birth-weight infants. Author(s): Kahn DJ, Richardson DK, Billett HH. Source: Journal of Perinatology : Official Journal of the California Perinatal Association. 2003 June; 23(4): 312-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12774140&dopt=Abstract
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Intra-abdominal abscess caused by Listeria monocytogenes in a patient with acquired hemolytic anemia and thrombocytopenia. Author(s): Sile H, Norwood J. Source: Southern Medical Journal. 2002 November; 95(11): 1350-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12540008&dopt=Abstract
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Intracaval and intracardiac metastatic nonseminomatous germ cell tumor: a rare cause of hemolytic anemia and thrombocytopenia. Author(s): Fishman AD, Hoffman A, Volterra F, Frymus M, Gentilluci M. Source: Cancer Investigation. 2002; 20(7-8): 996-1001. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12449733&dopt=Abstract
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Is there a role for plasmapheresis/plasma exchange therapy in septic shock, MODS, and thrombocytopenia-associated multiple organ failure? We still do not know--but perhaps we are closer. Author(s): Carcillo JA, Kellum JA. Source: Intensive Care Medicine. 2002 October; 28(10): 1373-5. Epub 2002 August 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12373459&dopt=Abstract
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Isoimmunization against CD36 (glycoprotein IV): description of four cases of neonatal isoimmune thrombocytopenia and brief review of the literature. Author(s): Curtis BR, Ali S, Glazier AM, Ebert DD, Aitman TJ, Aster RH. Source: Transfusion. 2002 September; 42(9): 1173-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12430674&dopt=Abstract
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Isolated thrombocytopenia associated with oral terbinafine. Author(s): Tsai HH, Lee WR, Hu CH. Source: The British Journal of Dermatology. 2002 September; 147(3): 627-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12207625&dopt=Abstract
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Isolated thrombocytopenia: the presenting finding of typhoid fever. Author(s): Serefhanoglu K, Kaya E, Sevinc A, Aydogdu I, Kuku I, Ersoy Y. Source: Clinical and Laboratory Haematology. 2003 February; 25(1): 63-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12542445&dopt=Abstract
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Issues in the management of cancer-related thrombocytopenia. Author(s): Goodnough LT, DiPersio JF. Source: Oncology (Huntingt). 2002 November; 16(11): 1558-67; Discussion 1570, 1572-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12469931&dopt=Abstract
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Laboratory diagnosis of immune heparin-induced thrombocytopenia. Author(s): Warkentin TE, Heddle NM. Source: Curr Hematol Rep. 2003 March; 2(2): 148-57. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901146&dopt=Abstract
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Lamivudine-associated thrombocytopenia. Author(s): Lebensztejn DM, Kaczmarski M. Source: The American Journal of Gastroenterology. 2002 October; 97(10): 2687-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12385471&dopt=Abstract
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Lepirudin use in a neonate with heparin-induced thrombocytopenia. Author(s): Nguyen TN, Gal P, Ransom JL, Carlos R. Source: The Annals of Pharmacotherapy. 2003 February; 37(2): 229-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12549954&dopt=Abstract
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Life-threatening severe immune thrombocytopenia during alpha-interferon therapy for chronic hepatitis C. Author(s): Fujii H, Kitada T, Yamada T, Sakaguchi H, Seki S, Hino M. Source: Hepatogastroenterology. 2003 May-June; 50(51): 841-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12828100&dopt=Abstract
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Life-threatening thrombocytopenia associated with acute Epstein-Barr virus infection in an older adult. Author(s): Walter RB, Hong TC, Bachli EB. Source: Annals of Hematology. 2002 November; 81(11): 672-5. Epub 2002 October 29. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12454710&dopt=Abstract
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Longitudinal thrombopoietin plasma concentrations in fetuses with alloimmune thrombocytopenia treated with intrauterine PLT transfusions. Author(s): Cremer M, Dame C, Schaeffer HJ, Giers G, Bartmann P, Bald R. Source: Transfusion. 2003 September; 43(9): 1216-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12919423&dopt=Abstract
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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12424942&dopt=Abstract
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Macrothrombocytopenia and progressive deafness is due to a mutation in MYH9. Author(s): Mhatre AN, Kim Y, Brodie HA, Lalwani AK. Source: Otology & Neurotology : Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. 2003 March; 24(2): 205-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12621333&dopt=Abstract
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Magnetic resonance-guided biliary drainage in a patient with malignant obstructive jaundice and thrombocytopenia. Author(s): Faiss S, Zeitz M, Wolf KJ, Lewin JS, Wacker FK. Source: Endoscopy. 2003 January; 35(1): 89-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12510234&dopt=Abstract
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Major bleeding and severe thrombocytopenia after combined heparin and abciximabc7E3 Fab therapy. Author(s): Claeys LG, Berg W. Source: European Journal of Vascular and Endovascular Surgery : the Official Journal of the European Society for Vascular Surgery. 2003 January; 25(1): 85-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12525818&dopt=Abstract
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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12437678&dopt=Abstract
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Marked improvement of thrombocytopenia in a murine model of idiopathic thrombocytopenic purpura by pegylated recombinant human megakaryocyte growth and development factor. Author(s): Shibuya K, Kuwaki T, Tahara E, Yuki C, Akahori H, Kato T, Miyazaki H. Source: Experimental Hematology. 2002 October; 30(10): 1185-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12384150&dopt=Abstract
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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12869178&dopt=Abstract
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Mechanisms for linezolid-induced anemia and thrombocytopenia. Author(s): Bernstein WB, Trotta RF, Rector JT, Tjaden JA, Barile AJ. Source: The Annals of Pharmacotherapy. 2003 April; 37(4): 517-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12659607&dopt=Abstract
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Mechanisms underlying thrombocytopenia in the neonatal intensive care unit. Author(s): Sola MC, Rimsza LM. Source: Acta Paediatrica (Oslo, Norway : 1992). Supplement. 2002; 91(438): 66-73. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12477266&dopt=Abstract
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Methylphenidate as a possible cause of thrombocytopenia. Author(s): Kuperman AA, Yaniv I, Stahl B, Tamary H. Source: The Annals of Pharmacotherapy. 2003 July-August; 37(7-8): 1146. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12841835&dopt=Abstract
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Minocycline-induced immune thrombocytopenia presenting as Schamberg's disease. Author(s): D'Addario SF, Bryan ME, Stringer WA, Johnson SM. Source: J Drugs Dermatol. 2003 June; 2(3): 320-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12848117&dopt=Abstract
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Misdiagnosis of chronic thrombocytopenia in childhood. Author(s): Bader-Meunier B, Proulle V, Trichet C, Debray D, Gabolde M, Yvart J, Dreyfus M. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2003 July; 25(7): 548-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12847322&dopt=Abstract
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Neonatal alloimmune thrombocytopenia. Author(s): Rayment R, Birchall J, Yarranton H, Hewertson J, Allen D, Murphy MF, Roberts DJ. Source: Bmj (Clinical Research Ed.). 2003 August 9; 327(7410): 331-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12907491&dopt=Abstract
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Neonatal alloimmune thrombocytopenia: antenatal and postnatal imaging findings in the pediatric brain. Author(s): Dale ST, Coleman LT. Source: Ajnr. American Journal of Neuroradiology. 2002 October; 23(9): 1457-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12372732&dopt=Abstract
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Neonatal thrombocytopenia: causes and management. Author(s): Roberts I, Murray NA. Source: Archives of Disease in Childhood. Fetal and Neonatal Edition. 2003 September; 88(5): F359-64. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12937037&dopt=Abstract
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New types of granulocyte inclusions in hereditary macrothrombocytopenias. Author(s): Pujol-Moix N, Muniz-Diaz E, Hernandez A, Durfort M. Source: Platelets. 2002 November; 13(7): 425-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12487791&dopt=Abstract
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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12822157&dopt=Abstract
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Off-pump right atrial thrombectomy for heparin-induced thrombocytopenia with thrombosis. Author(s): Morgan JA, Kherani AR, Vigilance DW, Cheema FH, Colletti NJ, Sahar DI, Jan KM, Diuguid DL, Nowygrod R, Oz MC, Argenziano M. Source: The Annals of Thoracic Surgery. 2003 August; 76(2): 615-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12902120&dopt=Abstract
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Olanzapine-induced EDTA-dependent pseudothrombocytopenia. Author(s): Tu CH, Yang S. Source: Psychosomatics. 2002 September-October; 43(5): 421-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12297613&dopt=Abstract
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On the prophylactic and therapeutic use of danaparoid sodium (Orgaran) in patients with heparin-induced thrombocytopenia. Author(s): Schenk JF, Pindur G, Stephan B, Morsdorf S, Mertzlufft F, Kroll H, Wenzel E, Seyfert UT. Source: Clinical and Applied Thrombosis/Hemostasis : Official Journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2003 January; 9(1): 25-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12643320&dopt=Abstract
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Pathologic quiz case: a 6-year-old girl with thrombocytopenia. Author(s): Shayan K, Ye CC, Revel-Vilk S. Source: Archives of Pathology & Laboratory Medicine. 2003 July; 127(7): E305-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12823064&dopt=Abstract
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Pathology case of the month. Case of diabetes mellitus and thrombocytopenia. Author(s): Muldoon RT, Nordberg ML, Martinez RL, Heldmann M, Mansour RP, Veillon DM, Cotelingam JD. Source: J La State Med Soc. 2002 September-October; 154(5): 223-5. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12440747&dopt=Abstract
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Patients with a history of type II heparin-induced thrombocytopenia with thrombosis requiring cardiac surgery with cardiopulmonary bypass: a prospective observational case series. Author(s): Nuttall GA, Oliver WC Jr, Santrach PJ, McBane RD, Erpelding DB, Marver CL, Zehr KJ. Source: Anesthesia and Analgesia. 2003 February; 96(2): 344-50, Table of Contents. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12538175&dopt=Abstract
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Pegylated interferon-2b-associated autoimmune thrombocytopenia in a patient with chronic hepatitis C. Author(s): Sevastianos VA, Deutsch M, Dourakis SP, Manesis EK. Source: The American Journal of Gastroenterology. 2003 March; 98(3): 706-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12650821&dopt=Abstract
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Periostitis secondary to interleukin-11 (Oprelvekin, Neumega). Treatment for thrombocytopenia in pediatric patients. Author(s): Milman E, Berdon WE, Garvin JH, Cairo MS, Bessmertny O, Ruzal-Shapiro C. Source: Pediatric Radiology. 2003 July; 33(7): 450-2. Epub 2003 May 01. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12728286&dopt=Abstract
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Persistent thrombocytopenia during remission in acute leukemia does not preclude long-term disease-free survival. Author(s): Heckman KD, Weiner GJ, Burns CP. Source: American Journal of Hematology. 2002 November; 71(3): 236-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12410588&dopt=Abstract
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Pharmacoeconomic analysis of oprelvekin (recombinant human interleukin-11) for secondary prophylaxis of thrombocytopenia in solid tumor patients receiving chemotherapy. Author(s): Cantor SB, Elting LS, Hudson DV Jr, Rubenstein EB. Source: Cancer. 2003 June 15; 97(12): 3099-106. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12784347&dopt=Abstract
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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12783589&dopt=Abstract
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Plasmodium vivax malaria presenting with severe thrombocytopenia. Author(s): Makkar RP, Mukhopadhyay S, Monga A, Monga A, Gupta AK. Source: The Brazilian Journal of Infectious Diseases : an Official Publication of the Brazilian Society of Infectious Diseases. 2002 October; 6(5): 263-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12495609&dopt=Abstract
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Platelet alloimmunity: the fetal/neonatal alloimmune thrombocytopenia. Author(s): Kaplan C. Source: Vox Sanguinis. 2002 August; 83 Suppl 1: 289-91. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617155&dopt=Abstract
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Platelet autoantibodies and lupus-associated thrombocytopenia. Author(s): Michel M, Lee K, Piette JC, Fromont P, Schaeffer A, Bierling P, Godeau B. Source: British Journal of Haematology. 2002 November; 119(2): 354-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12406068&dopt=Abstract
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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12823032&dopt=Abstract
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Platelet count monitoring and laboratory testing for heparin-induced thrombocytopenia. Author(s): Warkentin TE. Source: Archives of Pathology & Laboratory Medicine. 2002 November; 126(11): 1415-23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12421151&dopt=Abstract
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Platelet glycoprotein IIb/IIIa inhibitors and thrombocytopenia: possible link between platelet activation, autoimmunity and thrombosis. Author(s): Abrams CS, Cines DB. Source: Thrombosis and Haemostasis. 2002 December; 88(6): 888-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12529733&dopt=Abstract
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Platelet substitutes in the management of thrombocytopenia. Author(s): Reid TJ, Rentas FJ, Ketchum LH. Source: Curr Hematol Rep. 2003 March; 2(2): 165-70. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901148&dopt=Abstract
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Poor response to prednisolone of idiopathic thrombocytopenia with human Tlymphotropic virus type I infection. Author(s): Matsushita K, Arima N, Ohtsubo H, Fujiwara H, Arimura K, Kukita T, Ozaki A, Hidaka S, Matsumoto T, Tei C. Source: American Journal of Hematology. 2002 September; 71(1): 20-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12221669&dopt=Abstract
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Post-splenectomy thrombocytopenia: implications for regional analgesia. Author(s): McLure HA, Trenfield S, Quereshi A, Williams J. Source: Anaesthesia. 2003 November; 58(11): 1106-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14616598&dopt=Abstract
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Prenatal management of alloimmune thrombocytopenia of the fetus. Author(s): Engelfriet CP, Reesink HW, Kroll H, Giers G, Bald R, Kanhai H, Kekomaki R, Teramo K, Panzer S, Jilma P, Ulm B, Bock J, Taaning E, Rodeck C, Goldman M, David M, Kaplan C. Source: Vox Sanguinis. 2003 February; 84(2): 142-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12609023&dopt=Abstract
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Preventing complications in heparin-induced thrombocytopenia. Alternative anticoagulants are improving patient outcomes. Author(s): Rice L, Nguyen PH, Vann AR. Source: Postgraduate Medicine. 2002 September; 112(3): 85-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12360660&dopt=Abstract
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Probable rofecoxib-induced thrombocytopenia. Author(s): Kentos A, Robin V, Lambermont M, Jurdan M, Pignarelli M, Feremans W. Source: Rheumatology (Oxford, England). 2003 May; 42(5): 699-700. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12709555&dopt=Abstract
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Prognostic value of thrombocytopenia in African children with falciparum malaria. Author(s): Gerardin P, Rogier C, Ka AS, Jouvencel P, Brousse V, Imbert P. Source: The American Journal of Tropical Medicine and Hygiene. 2002 June; 66(6): 68691. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12224575&dopt=Abstract
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Prospective testing for drug-dependent antibodies reduces the incidence of thrombocytopenia observed with the small molecule glycoprotein IIb/IIIa antagonist roxifiban: implications for the etiology of thrombocytopenia. Author(s): Seiffert D, Stern AM, Ebling W, Rossi RJ, Barrett YC, Wynn R, Hollis GF, He B, Kieras CJ, Pedicord DL, Cromley DA, Hua TA, Stein RB, Daly RN, Sferruzza A, Pieniaszek HJ, Billheimer JT. Source: Blood. 2003 January 1; 101(1): 58-63. Epub 2002 June 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12393571&dopt=Abstract
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Pseudothrombocytopenia after allogeneic non-myeloablative stem cell transplantation. Author(s): Gillis S, Eisenberg ME, Shapira MY, Or R. Source: Isr Med Assoc J. 2003 September; 5(9): 671-3. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14509163&dopt=Abstract
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Pseudothrombocytopenia as a pitfall in the treatment of essential thrombocythemia. Author(s): Braester A. Source: European Journal of Haematology. 2003 April; 70(4): 251-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12656752&dopt=Abstract
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Pseudothrombocytopenia associated with infectious mononucleosis. Author(s): Hsieh AT, Chao TY, Chen YC. Source: Archives of Pathology & Laboratory Medicine. 2003 January; 127(1): E17-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12562287&dopt=Abstract
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Pseudothrombocytopenia: a report of a new method to count platelets in a patient with EDTA- and temperature-independent antibodies of the IgM type. Author(s): van der Meer W, Allebes W, Simon A, van Berkel Y, de Keijzer MH. Source: European Journal of Haematology. 2002 October; 69(4): 243-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12431244&dopt=Abstract
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Rapid determination of anti-heparin/platelet factor 4 antibody titers in the diagnosis of heparin-induced thrombocytopenia. Author(s): Alberio L, Kimmerle S, Baumann A, Taleghani BM, Biasiutti FD, Lammle B. Source: The American Journal of Medicine. 2003 May; 114(7): 528-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12753876&dopt=Abstract
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Recombinant human interleukin-11 improves thrombocytopenia in patients with cirrhosis. Author(s): Ghalib R, Levine C, Hassan M, McClelland T, Goss J, Stribling R, Seu P, Patt YZ. Source: Hepatology (Baltimore, Md.). 2003 May; 37(5): 1165-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12717398&dopt=Abstract
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Recurring thrombocytopenia associated with structured treatment interruption in patients with human immunodeficiency virus infection. Author(s): Ananworanich J, Phanuphak N, Nuesch R, Apateerapong W, Rojnuckarin P, Ubolyam S, Phanuphak P, Ruxrungtham K. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 September 1; 37(5): 723-5. Epub 2003 August 12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12942407&dopt=Abstract
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Repeated antenatal intracranial haemorrhage: magnetic resonance imaging in a fetus with alloimmune thrombocytopenia. Author(s): Hildebrandt T, Powell T. Source: Archives of Disease in Childhood. Fetal and Neonatal Edition. 2002 November; 87(3): F222-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12390998&dopt=Abstract
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Reports of drug-induced thrombocytopenia. Author(s): Hibbard AB, Medina PJ, Vesely SK. Source: Annals of Internal Medicine. 2003 February 4; 138(3): 239. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12558372&dopt=Abstract
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Rheumatoid arthritis and immune thrombocytopenia: a report of two cases. Author(s): Ustun C, Kallab A, Loebl D, Jillela A, Majewski B, Mazzella F, Burgess R. Source: Clinical Rheumatology. 2002 November; 21(6): 543-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12447648&dopt=Abstract
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Risk factors and long-term follow-up of patients with the immune type of heparininduced thrombocytopenia. Author(s): Lindhoff-Last E, Wenning B, Stein M, Gerdsen F, Bauersachs R, Wagner R. Source: Clinical and Applied Thrombosis/Hemostasis : Official Journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2002 October; 8(4): 347-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12516684&dopt=Abstract
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Risk factors for neonatal thrombocytopenia in preterm infants. Author(s): Beiner ME, Simchen MJ, Sivan E, Chetrit A, Kuint J, Schiff E. Source: American Journal of Perinatology. 2003 January; 20(1): 49-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12638081&dopt=Abstract
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Risk factors for thrombosis in patients with immune mediated heparin-induced thrombocytopenia. Author(s): Fabris F, Luzzatto G, Soini B, Ramon R, Scandellari R, Randi ML, Girolami A. Source: Journal of Internal Medicine. 2002 August; 252(2): 149-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12190890&dopt=Abstract
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Rituximab treatment of refractory fludarabine-associated immune thrombocytopenia in chronic lymphocytic leukemia. Author(s): Hegde UP, Wilson WH, White T, Cheson BD. Source: Blood. 2002 September 15; 100(6): 2260-2. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12200396&dopt=Abstract
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Schistocytic anaemia, severe thrombocytopenia, and renal dysfunction: thrombotic microangiopathy due to severe acquired ADAMTS-13 deficiency. Case 2. Author(s): Winkler A, Kremer Hovinga JA, Bianchi V, Studt JD, Lammle B. Source: Hamostaseologie. 2003 August; 23(3): 103-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12923577&dopt=Abstract
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Sebastian platelet syndrome: a hereditary macrothrombocytopenia. Author(s): Rodriguez V, Nichols WL, Charlesworth JE, White JG. Source: Mayo Clinic Proceedings. 2003 November; 78(11): 1416-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14601703&dopt=Abstract
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Selective thrombocytopenia in children with Wilms tumor: an immune-mediated effect of dactinomycin? Author(s): Shannon A, Smith J, Nagel K, Levesque R, Warkentin T, Barr R. Source: Medical and Pediatric Oncology. 2003 November; 41(5): 483-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14515398&dopt=Abstract
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Serious thrombocytopenia due to dengue hemorrhagic fever treated with high dosages of immunoglobulin. Author(s): Ostronoff M, Ostronoff F, Florencio R, Florencio M, Domingues MC, Calixto R, Sucupira A, Souto Maior AP, Matias C, Matias K, Tagliari C, Soussain C. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 June 15; 36(12): 1623-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12802766&dopt=Abstract
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Serologic analysis of three cases of neonatal alloimmune thrombocytopenia associated with HLA antibodies. Author(s): Saito S, Ota M, Komatsu Y, Ota S, Aoki S, Koike K, Tokunaga I, Tsuno T, Tsuruta G, Kubo T, Fukushima H. Source: Transfusion. 2003 July; 43(7): 908-17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12823751&dopt=Abstract
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Serologically documented loracarbef (Lorabid)-induced immune thrombocytopenia. Author(s): Aljitawi OS, Krishnan K, Curtis BR, Bougie DW, Aster RH. Source: American Journal of Hematology. 2003 May; 73(1): 41-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12701119&dopt=Abstract
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Serum cytokine profiles in patients with Plasmodium vivax malaria: a comparison between those who presented with and without thrombocytopenia. Author(s): Park JW, Park SH, Yeom JS, Huh AJ, Cho YK, Ahn JY, Min GS, Song GY, Kim YA, Ahn SY, Woo SY, Lee BE, Ha EH, Han HS, Yoo K, Seoh JY. Source: Annals of Tropical Medicine and Parasitology. 2003 June; 97(4): 339-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12831519&dopt=Abstract
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Severe neonatal alloimmune thrombocytopenia caused by antibodies to human platelet antigen 3a (Baka) detectable only in whole platelet assays. Author(s): Harrison CR, Curtis BR, McFarland JG, Huff RW, Aster RH. Source: Transfusion. 2003 October; 43(10): 1398-402. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14507271&dopt=Abstract
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Severe neutropenia and thrombocytopenia associated with infliximab. Author(s): Vidal F, Fontova R, Richart C. Source: Annals of Internal Medicine. 2003 August 5; 139(3): W-W63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12899609&dopt=Abstract
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Severe prolonged red blood cell aplasia and thrombocytopenia induced by parvovirus B19 infection in a patient with sarcoidosis. Author(s): Viallard JF, Parrens M, Hermine O, Boiron JM, Lafon ME, Marit G, Reiffers J, Pellegrin JL. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 January 15; 36(2): 229-33. Epub 2003 Jan 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12522758&dopt=Abstract
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Severe thrombocytopenia as a presenting symptom of hepatitis C virus infection. Author(s): Beyan C, Cetin T, Kaptan K, Nevruz O, Ural AU, Avcu F, Kubar A, Yalcin A. Source: Haematologia. 2002; 32(3): 277-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12611488&dopt=Abstract
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Specific autoantibodies to platelet glycoproteins in Epstein-Barr virus-associated immune thrombocytopenia. Author(s): Tanaka M, Kamijo T, Koike K, Ueno I, Nakazawa Y, Kurokawa Y, Sakashita K, Komiyama A, Fujisawa K. Source: International Journal of Hematology. 2003 August; 78(2): 168-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12953814&dopt=Abstract
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Spirochete-platelet attachment and thrombocytopenia in murine relapsing fever borreliosis. Author(s): Alugupalli KR, Michelson AD, Joris I, Schwan TG, Hodivala-Dilke K, Hynes RO, Leong JM. Source: Blood. 2003 October 15; 102(8): 2843-50. Epub 2003 July 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12855586&dopt=Abstract
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Spontaneous reports of thrombocytopenia in association with quinine: clinical attributes and timing related to regulatory action. Author(s): Brinker AD, Beitz J. Source: American Journal of Hematology. 2002 August; 70(4): 313-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12210813&dopt=Abstract
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Subacute stent thrombosis associated with a heparin-coated stent and heparininduced thrombocytopenia. Author(s): Cruz D, Karlsberg R, Takano Y, Vora D, Tobis J. Source: Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions. 2003 January; 58(1): 80-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12508203&dopt=Abstract
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Successful treatment of a patient with hairy cell leukemia and pentostatin-induced autoimmune thrombocytopenia with rituximab. Author(s): Hensel M, Ho AD. Source: American Journal of Hematology. 2003 May; 73(1): 37-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12701118&dopt=Abstract
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Successful treatment of thrombocytopenia due to marrow metastases of breast cancer with weekly docetaxel. Author(s): Ballot J, McDonnell D, Crown J. Source: Journal of the National Cancer Institute. 2003 June 4; 95(11): 831-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12783943&dopt=Abstract
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Successful use of Argatroban as a heparin substitute during cardiopulmonary bypass: heparin-induced thrombocytopenia in a high-risk cardiac surgical patient. Author(s): Edwards JT, Hamby JK, Worrall NK. Source: The Annals of Thoracic Surgery. 2003 May; 75(5): 1622-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12735590&dopt=Abstract
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Sudden-onset thrombocytopenia with oxaliplatin. Author(s): Dold FG, Mitchell EP. Source: Annals of Internal Medicine. 2003 July 15; 139(2): E156. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12859182&dopt=Abstract
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T cell receptor VB repertoire diversity in patients with immune thrombocytopenia following splenectomy. Author(s): Fogarty PF, Rick ME, Zeng W, Risitano AM, Dunbar CE, Bussel JB. Source: Clinical and Experimental Immunology. 2003 September; 133(3): 461-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12930375&dopt=Abstract
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Tackling the devastating effects of heparin-induced thrombocytopenia. Author(s): Abraham P, Uber WE, Lazarchick J, Crumbley AJ 3rd. Source: Congestive Heart Failure (Greenwich, Conn.). 2002 November-December; 8(6): 331-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12461323&dopt=Abstract
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The incidence of heparin-induced thrombocytopenia in hospitalized medical patients treated with subcutaneous unfractionated heparin: a prospective cohort study. Author(s): Girolami B, Prandoni P, Stefani PM, Tanduo C, Sabbion P, Eichler P, Ramon R, Baggio G, Fabris F, Girolami A. Source: Blood. 2003 April 15; 101(8): 2955-9. Epub 2002 December 12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12480713&dopt=Abstract
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The pathophysiology of immune-mediated heparin-induced thrombocytopenia. Author(s): Reilly RF. Source: Seminars in Dialysis. 2003 January-February; 16(1): 54-60. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12535302&dopt=Abstract
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The timing of a positive test result for heparin-induced thrombocytopenia relative to the platelet count and anticoagulant therapy in 43 consecutive cases. Author(s): Refaai MA, Van Cott EM, Laposata M. Source: American Journal of Clinical Pathology. 2003 April; 119(4): 497-504. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12710122&dopt=Abstract
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The use of recombinant factor viia in a jehovah's witness with auto-immune thrombocytopenia and post-splenectomy haemorrhage. Author(s): Waddington DP, McAuley FT, Hanley JP, Summerfield GP. Source: British Journal of Haematology. 2002 October; 119(1): 286-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12358947&dopt=Abstract
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Thrombocytopenia after immunization of Canadian children, 1992 to 2001. Author(s): Jadavji T, Scheifele D, Halperin S; Canadian Paediatric Society/Health Cananda Immunization Monitoring Program. Source: The Pediatric Infectious Disease Journal. 2003 February; 22(2): 119-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12586974&dopt=Abstract
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Thrombocytopenia and abdominal mass. Author(s): Salvador-Osuna C, Fernandez-Mosteirin N, Zapater C. Source: British Journal of Haematology. 2003 February; 120(3): 374. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12580950&dopt=Abstract
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Thrombocytopenia and megakaryocyte dysplasia: an adverse effect of valproic acid treatment. Author(s): Gesundheit B, Kirby M, Lau W, Koren G, Abdelhaleem M. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2002 October; 24(7): 589-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12368704&dopt=Abstract
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Thrombocytopenia and Plasmodium falciparum malaria in children with different exposures. Author(s): Moulin F, Lesage F, Legros AH, Maroga C, Moussavou A, Guyon P, Marc E, Gendrel D. Source: Archives of Disease in Childhood. 2003 June; 88(6): 540-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12765928&dopt=Abstract
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Thrombocytopenia associated with levodopa treatment. Author(s): Giner V, Rueda D, Salvador A, Hernandez JC, Esteban MJ, Redon J. Source: Archives of Internal Medicine. 2003 March 24; 163(6): 735-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12639208&dopt=Abstract
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Thrombocytopenia complicating the clinical course of leptospiral infection. Author(s): Turgut M, Sunbul M, Bayirli D, Bilge A, Leblebicioglu H, Haznedaroglu I. Source: J Int Med Res. 2002 September-October; 30(5): 535-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12449525&dopt=Abstract
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Thrombocytopenia during the course of acute poststreptococcal glomerulonephritis. Author(s): Tasic V, Polenakovic M. Source: Turk J Pediatr. 2003 April-June; 45(2): 148-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12921303&dopt=Abstract
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Thrombocytopenia following treatment with platelet glycoprotein IIb/IIIa inhibitors. Author(s): Christopoulos CG. Source: Blood. 2003 February 15; 101(4): 1655; Author Reply 1655. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12560245&dopt=Abstract
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Thrombocytopenia identifies a severe familial phenotype of systemic lupus erythematosus and reveals genetic linkages at 1q22 and 11p13. Author(s): Scofield RH, Bruner GR, Kelly JA, Kilpatrick J, Bacino D, Nath SK, Harley JB. Source: Blood. 2003 February 1; 101(3): 992-7. Epub 2002 September 12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12393658&dopt=Abstract
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Thrombocytopenia in African children can predict the severity of malaria caused by Plasmodium falciparum and the prognosis of the disease. Author(s): Moerman F, Colebunders B, D'Alessandro U. Source: The American Journal of Tropical Medicine and Hygiene. 2003 April; 68(4): 379; Author Reply 380-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12875280&dopt=Abstract
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Thrombocytopenia in patients receiving oral anticoagulant therapy. Author(s): Sottilotta G, Oriana V, Latella C, Lombardo VT. Source: Clinical and Applied Thrombosis/Hemostasis : Official Journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2002 July; 8(3): 213-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12361197&dopt=Abstract
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Thrombocytopenia in patients with 22q11.2 deletion syndrome and its association with glycoprotein Ib-beta. Author(s): Kato T, Kosaka K, Kimura M, Imamura S, Yamada O, Iwai K, Ando M, Joh-o K, Kuroe K, Ohtake A, Takao A, Momma K, Matsuoka R. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2003 March-April; 5(2): 113-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12644781&dopt=Abstract
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Thrombocytopenia in patients with chromosome 22q11.2 deletion syndrome. Author(s): Lawrence S, McDonald-McGinn DM, Zackai E, Sullivan KE. Source: The Journal of Pediatrics. 2003 August; 143(2): 277-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12970648&dopt=Abstract
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Thrombocytopenia in patients with HCV-positive chronic hepatitis: efficacy of leucocyte interferon-alpha treatment. Author(s): Benci A, Caremani M, Tacconi D. Source: Int J Clin Pract. 2003 January-February; 57(1): 17-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12587936&dopt=Abstract
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Thrombocytopenia in patients with malaria: automated analysis of optical platelet counts and platelet clumps with the Cell Dyn CD4000 analyser. Author(s): Scott CS, Van Zyl D, Ho E, Ruivo L, Mendelow B, Coetzer TL. Source: Clinical and Laboratory Haematology. 2002 October; 24(5): 295-302. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12358891&dopt=Abstract
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Thrombocytopenia in pregnancy: differential diagnosis, pathogenesis, and management. Author(s): McCrae KR. Source: Blood Reviews. 2003 March; 17(1): 7-14. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12490206&dopt=Abstract
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Thrombocytopenia in the newborn. Author(s): Roberts IA, Murray NA. Source: Current Opinion in Pediatrics. 2003 February; 15(1): 17-23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12544267&dopt=Abstract
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Thrombocytopenia induced by imatinib mesylate (Glivec) in patients with chronic myelogenous leukemia: is 400 mg daily of imatinib mesylate an optimal starting dose for Japanese patients? Author(s): Miyazawa K, Nishimaki J, Katagiri T, Sashida G, Shoji N, Kawakubo K, Suzuki A, Shimamoto T, Gotoh A, Kuriyama Y, Ito Y, Tauchi T, Kawanishi Y, Kimura Y, Ohyashiki K. Source: International Journal of Hematology. 2003 January; 77(1): 93-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12568307&dopt=Abstract
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Thrombocytopenia or giant platelets? Author(s): Fabry U, Lammert F, Osieka R. Source: Lancet. 2003 March 1; 361(9359): 735. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12620737&dopt=Abstract
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Thrombocytopenia, low molecular weight heparin, and obstetric anesthesia. Author(s): Abramovitz S, Beilin Y. Source: Anesthesiology Clinics of North America. 2003 March; 21(1): 99-109. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12698835&dopt=Abstract
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Thrombocytopenia. Author(s): Baldwin PD. Source: Clinical Journal of Oncology Nursing. 2003 May-June; 7(3): 349-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12793346&dopt=Abstract
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Thrombocytopenia-absent radius syndrome: a clinical genetic study. Author(s): Greenhalgh KL, Howell RT, Bottani A, Ancliff PJ, Brunner HG, VerschuurenBemelmans CC, Vernon E, Brown KW, Newbury-Ecob RA. Source: Journal of Medical Genetics. 2002 December; 39(12): 876-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12471199&dopt=Abstract
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Thrombopoietin concentrations in peripheral blood correlated with platelet numbers in two patients with thrombocytopenia by chronic graft-versus-host disease. Author(s): Hirayama Y, Sakamaki S, Tsuji Y, Sagawa T, Chiba H, Matsunaga T, Kuroda H, Kusakabe T, Akiyama T, Kato J, Niitsu Y. Source: American Journal of Hematology. 2003 August; 73(4): 285-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12879435&dopt=Abstract
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Thrombopoietin is essential for the maintenance of normal hematopoiesis in humans: development of aplastic anemia in patients with congenital amegakaryocytic thrombocytopenia. Author(s): Ballmaier M, Germeshausen M, Krukemeier S, Welte K. Source: Annals of the New York Academy of Sciences. 2003 May; 996: 17-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799278&dopt=Abstract
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Thrombus in harvested marrow from a patient with recent heparin-induced thrombocytopenia. Author(s): Bowers MJ, Jones FG. Source: British Journal of Haematology. 2002 November; 119(2): 294. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12406061&dopt=Abstract
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Transjugular liver biopsy in patients with hematologic malignancy and severe thrombocytopenia. Author(s): Wallace MJ, Narvios A, Lichtiger B, Ahrar K, Morello FA Jr, Gupta S, Madoff DC, Hicks ME. Source: Journal of Vascular and Interventional Radiology : Jvir. 2003 March; 14(3): 323-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12631636&dopt=Abstract
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Traumatic optic neuropathy complicating combined idiopathic thrombocytopenia and neutropenia. Author(s): De S, Gilbertson NJ. Source: Pediatric Hematology and Oncology. 2002 October-November; 19(7): 529-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12217200&dopt=Abstract
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Treatment of drug-induced thrombocytopenia. Author(s): Zondor SD, George JN, Medina PJ. Source: Expert Opinion on Drug Safety. 2002 July; 1(2): 173-80. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12904151&dopt=Abstract
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Two patients with acute thrombocytopenia following gold administration and fiveyear follow-up. Author(s): Levin MD, van t Veer MB, de Veld JC, Markusse HM. Source: The Netherlands Journal of Medicine. 2003 June; 61(6): 223-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13677318&dopt=Abstract
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Two patients with heparin-induced thrombocytopenia followed by idiopathic (immune) thrombocytopenic purpura: case report. Author(s): Waheed F, Naseer N, Ahmed T, Nelson JC. Source: American Journal of Hematology. 2003 August; 73(4): 290-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12879436&dopt=Abstract
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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12221676&dopt=Abstract
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Wilson disease manifested primarily as amenorrhea and accompanying thrombocytopenia. Author(s): Erkan T, Aktuglu C, Gulcan EM, Kutlu T, Cullu F, Apak H, Tumay GT. Source: The Journal of Adolescent Health : Official Publication of the Society for Adolescent Medicine. 2002 October; 31(4): 378-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12359384&dopt=Abstract
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Withdrawal of interferon-alpha results in prompt resolution of thrombocytopenia and hemolysis but not renal failure in hemolytic uremic syndrome caused by interferon-alpha. Author(s): Ohashi N, Yonemura K, Sugiura T, Isozaki T, Togawa A, Fujigaki Y, Yamamoto T, Hishida A. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2003 March; 41(3): E10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12613003&dopt=Abstract
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X-linked thrombocytopenia caused by a mutation in the Wiskott-Aldrich syndrome (WAS) gene that disrupts interaction with the WAS protein (WASP)-interacting protein (WIP). Author(s): Luthi JN, Gandhi MJ, Drachman JG. Source: Experimental Hematology. 2003 February; 31(2): 150-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12591280&dopt=Abstract
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X-linked thrombocytopenia in a girl. Author(s): Inoue H, Kurosawa H, Nonoyama S, Imai K, Kumazaki H, Matsunaga T, Sato Y, Sugita K, Eguchi M. Source: British Journal of Haematology. 2002 September; 118(4): 1163-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12199801&dopt=Abstract
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X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interaction. Author(s): Yu C, Niakan KK, Matsushita M, Stamatoyannopoulos G, Orkin SH, Raskind WH. Source: Blood. 2002 September 15; 100(6): 2040-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12200364&dopt=Abstract
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CHAPTER 2. NUTRITION AND THROMBOCYTOPENIA Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and thrombocytopenia.
Finding Nutrition Studies on Thrombocytopenia 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 “thrombocytopenia” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.
7 Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.
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The following information is typical of that found when using the “Full IBIDS Database” to search for “thrombocytopenia” (or a synonym): •
A comparison of danaparoid and lepirudin in heparin-induced thrombocytopenia. Author(s): Institute for Immunology and Transfusion Medicine, Ernst-Moritz-ArndtUniversity, Greifswald, Germany. Source: Farner, B Eichler, P Kroll, H Greinacher, A Thromb-Haemost. 2001 June; 85(6): 950-7 0340-6245
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Adjunctive therapies in the cath lab. Use of combination glycoprotein IIb/IIIa inhibitor and direct thrombin inhibitor drugs to support percutaneous coronary stent placement in a patient with renal insufficiency and heparin-induced thrombocytopenia. Author(s): Cardiac Catheterization Laboratory, St. Joseph's Hospital, Syracuse, NY, USA.
[email protected] Source: Caputo, R P Giambartolomei, A Simons, A Reger, M Wagner, S Esente, P JInvasive-Cardiol. 2001 September; 13(9): 657-60 1042-3931
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Autoimmune thrombocytopenia in a patient with small cell lung cancer developing after chemotherapy and resolving following autologous peripheral blood stem cell transplantation. Author(s): Dept. of Hematology/Oncology, Ankara University Medical School, Ibn-i Sina Hospital, Turkey. Source: Demirer, T Celebi, H Arat, M Ustun, C Demirer, S Dilek, I Ozcan, M Ilhan, O Akan, H Gurman, G Koc, H Bone-Marrow-Transplant. 1999 August; 24(3): 335-7 02683369
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Carboplatin and paclitaxel interact antagonistically in a megakaryoblast cell line--a potential mechanism for paclitaxel-mediated sparing of carboplatin-induced thrombocytopenia. Author(s): Department of Medical Oncology, Westmead Hospital, Faculty of Medicine, University of Sydney at Westmead Hospital, NSW, Australia.
[email protected] Source: Guminski, A D Harnett, P R deFazio, A Cancer-Chemother-Pharmacol. 2001 September; 48(3): 229-34 0344-5704
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Characterization of autotransplant-related thrombocytopenia by evaluation of glycocalicin and reticulated platelets. Author(s): Hematology and Medical Oncology Institute LA Seragnoli, University of Bologna, Italy. Source: Catani, L Vianelli, N Luatti, S Rizzi, S Castellani, S Valdre, L Lemoli, R M Tura, S Bone-Marrow-Transplant. 1999 December; 24(11): 1191-4 0268-3369
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Current agents for the treatment of patients with heparin-induced thrombocytopenia. Author(s): Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
[email protected] Source: Warkentin, T E Curr-Opin-Pulm-Med. 2002 September; 8(5): 405-12 1070-5287
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Danaparoid thromboprophylaxis in pregnant women with heparin-induced thrombocytopenia. Author(s): West Suffolk Hospital, Bury St Edmund's, UK. Source: Wo, Yin Ling Allard, Shuba Cohen, Hannah Letsky, Elizabeth de Swiet, Michael BJOG. 2002 April; 109(4): 466-8 1470-0328
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H(2) antagonist-induced thrombocytopenia: is this a real phenomenon? Author(s): Department of Pharmacy, University of Pittsburgh Medical Center, 304 Scaife Hall, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
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Source: Wade, Emily E Rebuck, Jill A Healey, Mark A Rogers, Frederick B IntensiveCare-Med. 2002 April; 28(4): 459-65 0342-4642 •
Immune thrombocytopenia after umbilical cord progenitor cell transplant: response to vincristine. Author(s): Department of Pediatrics, UCLA School of Medicine, UCLA Children's Hospital, Los Angeles, CA 90095-1752, USA. Source: Dovat, S Roberts, R L Wakim, M Stiehm, E R Feig, S A Bone-Marrow-Transplant. 1999 August; 24(3): 321-3 0268-3369
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Oxaliplatin-induced haematological emergency with an immediate severe thrombocytopenia and haemolysis. Author(s): Department of Oncology, Haukeland University Hospital, Bergen, Norway.
[email protected] Source: Sorbye, H Bruserud, Y Dahl, O Acta-Oncol. 2001; 40(7): 882-3 0284-186X
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Preventing complications in heparin-induced thrombocytopenia. Alternative anticoagulants are improving patient outcomes. Author(s): Baylor College of Medicine, 6565 Fannin, MS 902, Houston, TX 77030, USA.
[email protected] Source: Rice, L Nguyen, P H Vann, A R Postgrad-Med. 2002 September; 112(3): 85-9 0032-5481
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Severe, isolated thrombocytopenia under polytherapy with carbamazepine and valproate. Author(s): Ludwig Boltzmann Institute for Research in Epilepsy and Neuromuscular Disorders, Postfach 348, 1180 Vienna, Austria.
[email protected] Source: Finsterer, J Pelzl, G Hess, B Psychiatry-Clin-Neurosci. 2001 August; 55(4): 423-6 1323-1316
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Successful management of severe idiopathic thrombocytopenia in the second trimester of pregnancy. Author(s): Division of Maternal Fetal Medicine, First Department of Obstetrics and Gynecology, Alexandra Hospital, School of Medicine, University of Athens, Greece. Source: Antsaklis, A Papageorgiu, I Sindos, M Katsimanis, E Karaiskakis, P Michalas, S Fetal-Diagn-Ther. 1998 Jul-August; 13(4): 233-5 1015-3837
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Thrombocytopenia in an animal model of malaria is associated with an increased caspase-mediated death of thrombocytes. Author(s): Department of Pathology, University of Geneva, CH 1211, Switzerland.
[email protected] Source: Piguet, P F Kan, C D Vesin, C Apoptosis. 2002 April; 7(2): 91-8 1360-8185
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Valproic acid and thrombocytopenia: cross-sectional study. Author(s): Developmental Disabilities Unit, Department of Paediatrics, Caritas Medical Centre, 111 Wing Hong Street, Shamshuipo, Hong Kong. Source: Ko, C H Kong, C K Tse, P W Hong-Kong-Med-J. 2001 March; 7(1): 15-21 10242708
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Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •
healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0
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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov
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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov
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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/
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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/
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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/
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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/
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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/
Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats
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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html
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Google: http://directory.google.com/Top/Health/Nutrition/
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Healthnotes: http://www.healthnotes.com/
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Open Directory Project: http://dmoz.org/Health/Nutrition/
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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/
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WebMDHealth: http://my.webmd.com/nutrition
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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The following is a specific Web list relating to thrombocytopenia; 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: •
Food and Diet Bruising Source: Healthnotes, Inc.; www.healthnotes.com
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CHAPTER 3. ALTERNATIVE THROMBOCYTOPENIA
MEDICINE
AND
Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to thrombocytopenia. 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 thrombocytopenia 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 “thrombocytopenia” (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 thrombocytopenia: •
Carboplatin and paclitaxel interact antagonistically in a megakaryoblast cell line--a potential mechanism for paclitaxel-mediated sparing of carboplatin-induced thrombocytopenia. Author(s): Guminski AD, Harnett PR, deFazio A. Source: Cancer Chemotherapy and Pharmacology. 2001 September; 48(3): 229-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11592345&dopt=Abstract
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Case report. Pseudo pseudothrombocytopenia. Author(s): Jim RT. Source: Hawaii Med J. 2001 April; 60(4): 108. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11383099&dopt=Abstract
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Comparison of platelet count recovery with use of vincristine and prednisone or prednisone alone for treatment for severe immune-mediated thrombocytopenia in dogs. Author(s): Rozanski EA, Callan MB, Hughes D, Sanders N, Giger U. Source: J Am Vet Med Assoc. 2002 February 15; 220(4): 477-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11860242&dopt=Abstract
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Comparisons of the pharmacokinetics and the leukopenia and thrombocytopenia grade after administration of irinotecan and 5-fluorouracil in combination to rats. Author(s): Umezawa T, Kiba T, Numata K, Saito T, Nakaoka M, Shintani S, Sekihara H. Source: Anticancer Res. 2000 November-December; 20(6B): 4235-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11205253&dopt=Abstract
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Detection of multiple accessory spleens in a patient with chronic idiopathic thrombocytopenia purpura. Author(s): Phom H, Dasan J B, Kashyap R, Malhotra A, Choudhry VP, Bal CS. Source: Clinical Nuclear Medicine. 2001 July; 26(7): 593-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11416736&dopt=Abstract
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EDTA-dependent pseudothrombocytopenia confirmed by supplementation of kanamycin; a case report. Author(s): Ahn HL, Jo YI, Choi YS, Lee JY, Lee HW, Kim SR, Sim J, Lee W, Jin CJ. Source: Korean J Intern Med. 2002 March; 17(1): 65-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12014216&dopt=Abstract
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Effect of anti-CD20 (rituximab) on resistant thrombocytopenia in autoimmune lymphoproliferative syndrome. Author(s): Heelan BT, Tormey V, Amlot P, Payne E, Mehta A, Webster AD. Source: British Journal of Haematology. 2002 September; 118(4): 1078-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12199788&dopt=Abstract
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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11154128&dopt=Abstract
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Hepatosplenic gammadelta T-cell lymphoma presenting with immune-mediated thrombocytopenia and hemolytic anemia (Evans' syndrome). Author(s): Motta G, Vianello F, Menin C, De Nicolo A, Agata S, Altavilla G, Pietrogrande F, Girolami A.
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Source: American Journal of Hematology. 2002 April; 69(4): 272-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11921021&dopt=Abstract •
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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11213236&dopt=Abstract
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Olanzapine-induced EDTA-dependent pseudothrombocytopenia. Author(s): Tu CH, Yang S. Source: Psychosomatics. 2002 September-October; 43(5): 421-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12297613&dopt=Abstract
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Platelet size, platelet surface-associated IgG, and reticulated platelets in dogs with immune-mediated thrombocytopenia. Author(s): Wilkerson MJ, Shuman W, Swist S, Harkin K, Meinkoth J, Kocan AA. Source: Vet Clin Pathol. 2001; 30(3): 141-149. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12024314&dopt=Abstract
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Pseudothrombocytopenia as a pitfall in the treatment of essential thrombocythemia. Author(s): Braester A. Source: European Journal of Haematology. 2003 April; 70(4): 251-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12656752&dopt=Abstract
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Pseudothrombocytopenia associated with infectious mononucleosis. Author(s): Hsieh AT, Chao TY, Chen YC. Source: Archives of Pathology & Laboratory Medicine. 2003 January; 127(1): E17-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12562287&dopt=Abstract
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Pseudothrombocytopenia: a report of a new method to count platelets in a patient with EDTA- and temperature-independent antibodies of the IgM type. Author(s): van der Meer W, Allebes W, Simon A, van Berkel Y, de Keijzer MH. Source: European Journal of Haematology. 2002 October; 69(4): 243-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12431244&dopt=Abstract
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Successful treatment of thrombocytopenia due to marrow metastases of breast cancer with weekly docetaxel. Author(s): Ballot J, McDonnell D, Crown J. Source: Journal of the National Cancer Institute. 2003 June 4; 95(11): 831-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12783943&dopt=Abstract
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Thrombocytopenia associated with c7E3 Fab (abciximab). Author(s): Schell DA, Ganti AK, Levitt R, Potti A. Source: Annals of Hematology. 2002 February; 81(2): 76-9. Epub 2002 January 18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11907786&dopt=Abstract
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Thrombocytopenia: an important indicator for the application of partial exchange transfusion in polycythemic newborn infants? Author(s): Acunas B, Celtik C, Vatansever U, Karasalihoglu S. Source: Pediatrics International : Official Journal of the Japan Pediatric Society. 2000 August; 42(4): 343-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10986862&dopt=Abstract
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Tuberculosis and immune thrombocytopenia. Author(s): Madkaikar M, Ghosh K, Jijina F, Gupta M, Rajpurkar M, Mohanty D. Source: Haematologica. 2002 August; 87(8): Elt38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12161383&dopt=Abstract
Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •
Alternative Medicine Foundation, Inc.: http://www.herbmed.org/
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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats
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Chinese Medicine: http://www.newcenturynutrition.com/
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drkoop.com: http://www.drkoop.com/InteractiveMedicine/IndexC.html
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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm
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Google: http://directory.google.com/Top/Health/Alternative/
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Healthnotes: http://www.healthnotes.com/
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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine
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Open Directory Project: http://dmoz.org/Health/Alternative/
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HealthGate: http://www.tnp.com/
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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/
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The following is a specific Web list relating to thrombocytopenia; 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 Capillary Fragility Source: Healthnotes, Inc.; www.healthnotes.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 THROMBOCYTOPENIA Overview In this chapter, we will give you a bibliography on recent dissertations relating to thrombocytopenia. 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 “thrombocytopenia” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on thrombocytopenia, we have not necessarily excluded non-medical dissertations in this bibliography.
Dissertations on Thrombocytopenia 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 thrombocytopenia. 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: •
Intravenous Immunoglobulin Effects in Experimental Models of Immune Thrombocytopenia by Hansen, Ryan John; PhD from State University of New York at Buffalo, 2002, 211 pages http://wwwlib.umi.com/dissertations/fullcit/3052513
•
Physiopathological Study of Thrombocytopenia in Liver Cirrhosis Patients: the Role of Thrombopoietin by Rios Fernandez, Raquel; Dr from Universidad De Navarra (Spain), 2002, 132 pages http://wwwlib.umi.com/dissertations/fullcit/f807793
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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. CLINICAL TRIALS AND THROMBOCYTOPENIA Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning thrombocytopenia.
Recent Trials on Thrombocytopenia The following is a list of recent trials dedicated to thrombocytopenia.8 Further information on a trial is available at the Web site indicated. •
Angiomax in Patients with HIT/HITTS Type II Undergoing Off-Pump Coronary Artery Bypass Grafting (CABG) (CHOOSE) Condition(s): Thrombocytopenia; Thrombosis Study Status: This study is currently recruiting patients. Sponsor(s): The Medicines Company Purpose - Excerpt: The purpose of this study is to examine the safety and efficacy of Angiomax as an anticoagulation in patients with heparin-induced thrombocytopenia (HIT)/heparin-induced thrombocytopenia with thrombosis syndrome (HITTS) undergoing off-pump coronary artery bypass (OPCAB) surgery. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00073580
•
Cancer in Inherited Bone Marrow Failure Syndromes Condition(s): Fanconi's Anemia; Anemia, Diamond-Blackfan; Dyskeratosis Congenital; Thrombocytopenia; Neutropenia Study Status: This study is currently recruiting patients.
8
These are listed at www.ClinicalTrials.gov.
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Sponsor(s): National Cancer Institute (NCI) Purpose - Excerpt: This study will establish a cohort (a group of people followed over time) of patients and families affected by an inherited bone marrow failure syndrome (IBMFS) that may predispose them to leukemia or other cancers. These syndromes include Fanconi's anemia, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, Pearson's syndrome, amegakaryocytic thrombocytopenia, thrombocytopenia absent radii, dyskeratosis congenita, and others. The study will try to identify the types of cancer the patient may be at risk for; measure the rates at which these cancers develop; look for early indicators of cancer; determine what distinguishes family members who develop cancer from those who do not; try to identify new genes that may be involved in causing IBMFS; compare the biology of cancers in patients and family member with IBMFS with the same cancers in people without IBMFS; evaluate the medical condition of affected family members and offer recommendations for future health care and cancer risk reduction; and evaluate whether carriers of just one abnormal gene develop significant health problems. (A carrier is someone who has only one altered gene for a disease that requires two altered genes to cause illness.) This study does not involve treatment. Patients with an IBMFS and their family members are eligible for this study. Participants must provide written permission for the study investigators to 1) obtain medical records and pathology material (tissue samples) from hospitals or clinics where the patient has been treated for blood diseases, tumors, cancer, birth defects, or other illnesses; and 2) obtain medical records and pathology materials from deceased relatives for whom the patient or family member is the legally authorized representative. Participants will complete a family history questionnaire and individual information questionnaire at the start of the study and provide updates annually. In addition, the following tissue samples may be requested: blood or cheek cells, tissue from a scheduled bone marrow procedure, and tumor tissue from prior biopsies or cancer surgeries. Instructions for sending specimens will be provided. Additional samples for research may be requested over time as tests or surgeries are done as part of the patient's standard medical care. Patients who agree to participate in a second part of this study will travel to the NIH Clinical Center for a comprehensive clinical and laboratory evaluation and screening for cancer or pre-cancerous conditions. The evaluation will include a detailed medical history, complete physical examination, cancer screening, and routine tests that are part of the standard medical management of persons with, or at risk of, the particular disorder. These include blood drawing, bone marrow aspirate and biopsy, urinalysis, stool examination, diagnostic X-rays and scans, and biopsies of tumors or pre-cancerous sites. In addition, special consultations may be requested depending on the individual's medical condition. These may include audiology, cardiology, social work, dentistry, dermatology, endocrinology, gastroenterology, gynecology, hematology, nephrology (kidney), neurology, ophthalmology, otorhinolaryngology (ear, nose and throat), physiatry, radiology and nuclear medicine and urology. Finally, patients and family members may choose to participate in a part of the study to identify the specific genetic alteration (mutation) responsible for the IBMFS affecting them in order to learn whether knowing the mutation makes it possible to predict 1) the severity of disease or 2) which medical problems that can arise with the disorder are likely to affect a given patient. Genetic testing will be done on tissue samples already provided for the study, and confirmed on new samples. Patients and family members who want to learn the results of the genetic tests will receive face-toface genetic counseling either at the NIH Clinical Center or from a counselor in their home community. Study Type: Observational Contact(s): see Web site below
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Web Site: http://clinicaltrials.gov/ct/show/NCT00027274 •
Cyclosporine in Treating Patients With Low Blood Counts Caused By Hematologic Cancer Condition(s): Anemia; Thrombocytopenia
Chronic
Lymphocytic
Leukemia;
Neutropenia;
Study Status: This study is currently recruiting patients. Sponsor(s): Cancer and Leukemia Group B; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Cyclosporine may improve low blood counts caused by hematologic cancer. PURPOSE: Phase II trial to study the effectiveness of cyclosporine in treating patients who have low blood counts caused by hematologic cancer. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00031980 •
Daclizumab to Treat Chronic Immune Thrombocytopenia Condition(s): Thrombocytopenia Study Status: This study is currently recruiting patients. Sponsor(s): Warren G Magnuson Clinical Center (CC) Purpose - Excerpt: This study will evaluate the effectiveness of the drug daclizumab for treating patients with chronic immune thrombocytopenia (ITP), a disease in which the immune system destroys platelets (blood cells involved in the clotting process). Patients with ITP have abnormal bruising and bleeding; severe disease can be life-threatening. For many patients, standard drug treatments are not effective, and many of the drugs used may have significant side effects with long-term use. Daclizumab is a genetically engineered antibody that suppresses the immune system and has been used primarily to prevent rejection in patients who have had organ transplants. Daclizumab has fewer side effects than other immune suppressant drugs. Patients with ITP 18 years of age or older who have platelet counts less than 30,000/microliter and have not responded to prednisone treatment may be eligible for this study. Candidates will be screened with a medical history, physical examination, and blood tests. Participants will have a 15minute infusion of daclizumab every 2 weeks for five doses. They will be seen by a physician at least once every 2 weeks while receiving the drug and then at weeks 12, 20, and 32 of the study. Blood will be drawn at the 4- and 8-week visits during treatment for diagnostic tests, and at each follow-up visit after treatment to assess the response to therapy. Patients who respond well to treatment will have their pre-study immunosuppressive medicines tapered gradually one at a time starting with the 1month follow-up visit. If their platelet count falls to pre-treatment levels at any time during the tapering, the dose reduction will stop and pre-study medications will be restarted, if necessary. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00049725
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Evaluation of Argatroban Injection in Pediatric Patients Requiring Anticoagulant Alternatives to Heparin Condition(s): Thrombocytopenia; Thrombosis Study Status: This study is currently recruiting patients. Sponsor(s): GlaxoSmithKline and Encysive Pharmaceuticals Inc. Purpose - Excerpt: The purpose of this study is to evaluate the safe and effective dose of Argatroban for prophylaxis and/or treatment of thrombosis in pediatric patients with current or previous diagnosis of heparin-induced thrombocytopenia (HIT) and thrombosis syndrome (HITTS), or who in the opinion of the investigator require alternative anticoagulation due to an underlying condition. Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00039858
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Phase I Study of T-Cell Large Granular Lymphocytic Leukemia Using the MIK-Beta-1 Monoclonal Antibody Directed Toward the IL-2R-Beta Subunit Condition(s): Agranulocytosis; Thrombocytopenia
Pure
Red
Cell
Aplasia;
T
Cell
Leukemia;
Study Status: This study is currently recruiting patients. Sponsor(s): National Cancer Institute (NCI) Purpose - Excerpt: The purpose of the study is to evaluate the toxicity and clinical response following multiple-dose administration of murine Mik-Beta-1 directed toward IL-2R-Beta in patients with IL-2R-Beta-expressing T-cell large granular lymphocytic (TLGL) leukemia associated with granulocytopenia, thrombocytopenia, or anemia. This study represents an extension of Metabolism Branch IL-2R-directed monoclonal antibody therapy studies for patients with leukemia. The scientific basis for the proposed therapeutic studies is that the monoclonal lymphocytes of patients with TLGL leukemia express large numbers of the IL-2R-Beta subunit identified by Mik-Beta-1 on their cell surfaces, whereas most normal resting cells of patients do not. Furthermore, Mik-Beta-1 prevents IL-2-mediated proliferation and activation into lymphokineactivated killer cells of T-LGL mediated by IL-2 when it is added to T-LGL leukemia cells. We propose to administer murine Mik-Beta-1 at doses of 0.5, 1.0, and 1.5 mg/kg per dose to three groups of five patients with IL-2R-Beta-expressing monoclonal T-LGL leukemia cells and associated granulocytopenia, thrombocytopenia, or anemia. The antibody will be administered intravenously to patients over 18 years of age who fulfill the patient eligibility criteria. The antibody will be administered at the doses indicated above on days 1, 4, 7, and 10 of the study. Clinical response will be evaluated using routine hematological and clinical evaluation, by monitoring the phenotype of circulating IL-2R-expressing leukemic T cells, and by Southern blot analysis of the arrangement of the gene encoding the Beta and Gamma subunits of the T-cell antigen receptor. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below
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Web Site: http://clinicaltrials.gov/ct/show/NCT00001425 •
Rituximab, Carboplatin, Cyclophosphamide, and Etoposide or Etoposide Phosphate Given With Osmotic Blood-Brain Barrier Disruption Plus Sodium Thiosulfate and Cytarabine in Treating Patients With Refractory or Recurrent Primary CNS Lymphoma Condition(s): Drug Toxicity; Thrombocytopenia; intraocular lymphoma; primary central nervous system lymphoma Study Status: This study is currently recruiting patients. Sponsor(s): Cancer Institute at Oregon Health and Science University; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Monoclonal antibodies, such as rituximab, can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as carboplatin, cyclophosphamide, etoposide, etoposide phosphate, and cytarabine, use different ways to stop cancer cells from dividing so they stop growing or die. Osmotic blood-brain barrier disruption uses certain drugs to open the blood vessels around the brain and allow anticancer substances to be delivered directly to the brain. Chemoprotective drugs such as sodium thiosulfate may protect normal cells from the side effects of carboplatinbased chemotherapy. Combining rituximab with chemotherapy given with osmotic blood-brain barrier disruption plus sodium thiosulfate may kill more cancer cells. PURPOSE: Phase II trial to study the effectiveness of combining rituximab with combination chemotherapy given with osmotic blood-brain barrier disruption plus sodium thiosulfate in treating patients who have refractory or recurrent primary CNS lymphoma. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00074165
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Screening for Hematology Branch Protocols Condition(s): Anemia; Thrombocytopenia
Hematologic
Neoplasm;
Neutropenia;
Pancytopenia;
Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: This study allows the evaluation of subjects in order to determine their ability to safely participate in other active research studies. After subjects complete the screening process, they will be offered the opportunity to participate in an active research study, or if no appropriate studies are available information and recommendations will be provided for other treatment options. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001620
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Treatment of Autoimmune Thrombocytopenia (AITP) Condition(s): Autoimmune Thrombocytopenia
Disease;
Autoimmune
Hemolytic
Anemia;
Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Platelets are particles found along with red and white blood cells in the blood that play a role in the process of blood clotting. Disorders affecting the platelets can lower the amount of platelets in the blood and put patients at risk of bleeding. The condition of low platelets is referred to as thrombocytopenia. Thrombocytopenia can be associated with a variety of diseases including cancer, leukemia, tuberculosis, or as a result of an autoimmune reaction. Autoimmune reactions are disorders in which the normal immune system begins attacking itself. Autoimmune thrombocytopenia (AITP) is a disorder of low blood platelet counts in which platelets are destroyed by antibodies produced by the immune system. Unfortunately, many patients with AITP do not respond to standard treatments for thrombocytopenia. Cyclophosphamide is a drug that works to suppress the activity of the immune system. Researchers believe that combining this drug with transplanted rescued blood stem cells may provide effective treatment for AITP. The purpose of this study is to explore the affordability and safety of this therapy for the treatment of AITP. The effectiveness of the therapy will be measured by the number of patients whose platelet levels rise greater than 100,000/m3. If this treatment approach appears affordable, this study will form the basis for a larger study to compare alternate treatment approaches. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001630
Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “thrombocytopenia” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •
For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/
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•
For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html
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For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/
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For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm
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For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm
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For trials on aging, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm
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For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp
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For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm
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For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/
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For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm
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For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm
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For trials on diseases of the digestive system and kidneys, and diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases: http://www.niddk.nih.gov/patient/patient.htm
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For drug abuse trials, visit and search the Web site sponsored by the National Institute on Drug Abuse: http://www.nida.nih.gov/CTN/Index.htm
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For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm
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For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials
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CHAPTER 6. PATENTS ON THROMBOCYTOPENIA Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.9 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “thrombocytopenia” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on thrombocytopenia, we have not necessarily excluded non-medical patents in this bibliography.
Patents on Thrombocytopenia By performing a patent search focusing on thrombocytopenia, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. 9Adapted from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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The following is an example of the type of information that you can expect to obtain from a patent search on thrombocytopenia: •
Administration of thrombopoietin on a single day only Inventor(s): Thomas; Griffith Roger (Burlingame, CA) Assignee(s): Genentech, Inc. (South San Francisco, CA) Patent Number: 5,879,673 Date filed: August 28, 1996 Abstract: The present invention is directed to the surprising and unexpected finding that biologically active thrombopoietin materials can be administered with substantial therapeutic effect at dosage rates commensurate with previously reported administration of such materials, but in a single or low-multiple daily administration. Thus, the predicate of the present invention relates to the reversal of thrombocytopenia by administering to a patient having or in need of such treatment a single or lowmultiple daily dose of a therapeutically effective amount of a thrombopoietin. The preferable dose of the active material ranges from about 1 to about 10.mu.g/kg body weight. Excerpt(s): The present application, and the subject matter contained therein, is related to the following patent applications and their contents: International Patent Application PCT/US94/14553, filed 28 Dec. 1994 (published under number WO95/18858 on 13 Jul. 1995) and the several patent applications referenced therein, namely, U.S. Ser. No. 08/176,553, filed 3 Jan. 1994; 08/185,607, filed 21 Jan. 1994; 08/196,689 filed 15 Feb. 1994; 08/223,263 filed 4 Apr. 1994; 08/249,376 filed 25 May 1994; 08/348,657 filed 2 Dec. 1994 and 08/348,658 filed 2 Dec. 1994. The present invention relates to a new method of using thrombopoietin, and biologically active derivatives and isoforms thereof, for the treatment of immune and/or hematopoietic disorders including thrombocytopenia. The use contemplates the co-administration of such materials together with a cytokine, especially a colony stimulating factor or interleukin. The use includes and is included within a method for treating a mammal having or at risk for thrombocytopenia by administering to said mammal in need of such treatment a therapeutically effective amount of said material(s). The hematopoietic system produces the mature highly specialized blood cells known to be necessary for survival of all mammals. These mature cells include erythrocytes, specialized to transport oxygen and carbon dioxide, T- and Blymphocytes, responsible for cell- and antibody-mediated immune responses, platelets or thrombocytes, specialized to form blood clots, and granulocytes and macrophages, specialized as scavengers and as accessory cells to combat infection. All of these specialized mature blood cells are derived from a single common primitive cell type referred to as the pluripotent stem cell found primarily in bone marrow. Web site: http://www.delphion.com/details?pn=US05879673__
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Agonist antibodies Inventor(s): Adams; Camellia W. (Mountain View, CA), Carter; Paul J. (San Francisco, CA), Fendly; Brian M. (Half Moon Bay, CA), Gurney; Austin L. (Belmont, CA) Assignee(s): Genentech, Inc. (South San Francisco, CA) Patent Number: 6,342,220 Date filed: August 25, 1997 Abstract: Various forms of c-mpl agonist antibodies are shown to influence the replication, differentiation or maturation of blood cells, especially megakaryocytes and megakaryocyte progenitor cells. Accordingly, these compounds may be used for treatment of thrombocytopenia. Excerpt(s): This invention relates to the recombinant synthesis and purification of protein antibodies that influence survival, proliferation, differentiation or maturation of hematopoietic cells, especially platelet progenitor cells and to antibodies that influence the growth and differentiation of cells expressing a protein kinase receptor. This invention also relates to the cloning and expression of nucleic acids encoding antibody ligands (thrombopoietin receptor agonist antibodies) capable of binding to and activating a thrombopoietin receptor such as c-mpl, a member of the cytokine receptor superfamily. This invention further relates to the use of these antibodies alone or in combination with other cytokines to treat immune or hematopoietic disorders including thrombocytopenia and to uses in assays. In 1994 several groups reported the isolation and cloning of thrombopoietin (F. de Sauvage et al., Nature 369:533 (1994); S. Lok et al., Nature 369:565 (1994); T D. Bartley et al., Cell 77:1117 (1994); Y. Sohma et al., FEBS Letters 353:57 (1994); D J. Kuteret al., Proc. Natl. Acad. Sci. 91:11104 (1994)). This was the culmination of more than 30 years of research initiated in the late 50's when Yamamoto (S. Yamamoto, Acta Haematol Jpn. 20:163-178. (1957)) and Kelemen (E. Kelemen et al., Acta Haematol (Basel). 20:350-355 (1958)) proposed that physiological platelet production is controlled by a humoral factor termed "thrombopoietin" (TPO). Although routinely detected in urine, plasma and serum from thrombocytopenic animals and patients, as well as kidney cell conditioned media, purification of TPO proved to be a daunting task (for a review see MS. Gordon et al., Blood 80:302 (1992); W. Vainchenker et al., Critical Rev. Oncology/Hematology 20:165 (1995)). In the absence of purified TPO and the apparent fact that numerous plieotrophic cytokines affected megakaryocytopoiesis (M S. Gordon et al., Blood 80:302 (1992); W. Vainchenker et al., Critical Rev. Oncology/Hematology 20:165 (1995)), the existence of a lineage specific factor that regulated platelet production was doubted until the discovery of the orphan cytokine receptor c-Mpl in 1990 (M. Souyri et al., Cell 63:1137 (1990); I. Vigon et al., Proc. Natl Acad. Sci. 89:5640 (1992)). The expression of c-Mpl was found to be restricted to progenitor cells, megakaryocytes and platelets, and c-Mpl antisense oligonucleotides selectively inhibited in vitro megakaryocytopoiesis (M. Methia et al., Blood 82:1395 (1993)). From this it was postulated that c-Mpl played a critical role in regulating megakaryocytopoiesis and that its putative ligand may be the long sought TPO (M. Methia et al., supra). Following this discovery several groups utilizing c-Mpl ligand specific cell proliferation assays and c-Mpl as a purification tool isolated and cloned the ligand for c-Mpl (F. de Sauvage et al., supra; S. Lok et al., supra; T D. Bartley et al., supra). In addition two other groups independently reported the purification of the Mpl-ligand using standard chromatography techniques and megakaryocyte assays (Y. Sohma et al., supra; D J. Kuteret al., supra). In the years since its reported discovery numerous studies clearly indicate that the Mpl-ligand possess all the characteristics that have long been attributed to the purported regulator of megakaryocytopoiesis and
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thrombopoiesis and consequently, is now referred to as TPO. The Mpl ligand is currently referred to as either TPO or as megakaryocyte growth and differentiation factor (MGDF). Human TPO consists of 332 amino acids that can be divided into 2 domains; an amino terminal domain of 153 amino acids showing 23% identity (50% similarity) to erythropoietin (EPO) and a unique 181 amino acid C-terminal domain that is highly glycosylated ((F. de Sauvage et al., supra; S. Lok et al., supra; T D. Bartley et al., supra). The EPO-like domain of TPO contains 4 cysteines, 3 of which are conserved with EPO. The first and last and the two middle cysteines form two disulfide bridges, respectively, which are both required for activity (T. Kato et al., Blood 86 (suppl 1):365 (1995)). None of the Asn-linked glycosylation sites present in EPO are conserved in the EPO-like domain of TPO, however, the EPO-like domain of recombinant TPO (rTPO) contains 2-3O-linked glycosylations (M. Eng et al., Protein Science 5(suppl 1): 105 (1996)). A recombinant truncated form of TPO (rTPO153), consisting of only the EPOlike domain, is fully functional in vitro, indicating that this domain contains all the required structural elements to bind and activate Mpl (F. de Sauvage et al., supra; D L. Eaton et al., Blood 84(suppl 1):241 (1994)). The carboxy terminal domain of TPO contains 6 N-linked and 18 O-linked glycosylate sites and is rich in proline, serine and threonine (M. Eng et al., supra). The function of this domain remains to be elucidated. However, because of its high degree of glycosylation this region may act to stabilize and increase the half life of circulating TPO. This is supported by the observation that rTPO153 has a half life of 1.5 hours compared to 18-24 hours for full length glycosylated rTPO (GR. Thomas et al., Stem Cells 14(suppl 1) (1996). Web site: http://www.delphion.com/details?pn=US06342220__ •
Agonist murine monoclonal antibody as a stimulant for megakaryocytopoiesis Inventor(s): Avraham; Hava (Brookline, MA), Groopman; Jerome E. (Brookline, MA) Assignee(s): Beth Israel Deaconess Medical Center, Inc. (Boston, MA) Patent Number: 5,980,893 Date filed: July 17, 1997 Abstract: A class of murine monoclonal antibodies that is capable of stimulating megakaryocytopoiesis in vitro has been raised against human megakaryocytic cells. The monoclonal antibody BAH-1 specifically recognizes and demonstrates agonist activity against the c-Mpl receptor on the megakaryocytic cell surface. In therapeutic applications, the BAH-1 and M4 monoclonal antibodies identified to date and similar antibodies (or active portions and chimeric combinations thereof) can stimulate proliferation of primary bone marrow megakaryocytes. Thus, the antibodies of the invention can be used to prepare a composition for treating, e.g., thrombocytopenia. A typical composition comprises a therapeutically effective amount of the BAH-1 monoclonal antibody in association with a pharmaceutically acceptable carrier vehicle. Excerpt(s): This invention relates to the treatment of thrombocytopenia, and more particularly to the use of an agonist antibody capable of stimulating megakaryocytopoiesis for such treatment. The development of specialized blood cells, including platelets, via the hematopoietic system requires the interplay of pluripotent cells found in bone marrow and polypeptide cytokines (5). When a patient's levels of circulating platlets are depleted to less than 150.times.10.sup.9 platlets per liter, a condition known as thrombocytopenia can follow. In general, patients with platelet counts between 20 and 100.times.10.sup.9 per liter are at risk of excessive post traumatic bleeding, while those with platelet counts below 20.times.10.sup.9 may bleed
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spontaneously. These latter patients are candidates for platelet transfusion with associated immune and viral risk. The major regulator of circulating levels of platelets in the blood is believed to be the recently cloned cytokine thrombopoietin (TPO), the cognate ligand for the receptor encoded by the c-mpl proto-oncogene (c-Mpl) (1-16). TPO has been determined to have both direct proliferative and differentiative activities on human megakaryocyte progenitors. Furthermore, TPO hastens the restoration of platelet counts following cytoreductive therapies and has been associated with improved survival in certain murine models. Treatment of patients suffering from thrombocytopenia with TPO should have therapeutic importance in augmenting megakaryocytopoiesis and circulating blood platelet numbers. The availability of additional agents, capable of stimulating platelet production would be desirable. Web site: http://www.delphion.com/details?pn=US05980893__ •
Compositions and methods of treating thrombocytopenia with IL-15 Inventor(s): Shimonaka; Yasushi (Gotemba, JP) Assignee(s): Chugai Seiyaku Kabushiki Kaisha (JP) Patent Number: 6,258,352 Date filed: December 17, 1997 Abstract: It has been revealed that human interleukin-15 (hIL-15) acts on the megakaryocyte-thrombocyte system to accelerate its differentiation, maturation and/or proliferation, thereby accelerating the formation of thrombocytes. The present invention provides a treatment using IL-15 for thrombocytopenia and diseases accompanied by thrombocyte dysfunctions. Excerpt(s): The present invention relates to a pharmaceutical composition for treating thrombocytopenia which comprises as an active ingredient human interleukin-15 (to be described hereinafter as "hIL-15") having activity to promote the differentiation, maturation and/or proliferation of megakaryocyte-thrombocyte cells and the production of platelets through actions on the cells. Since hIL-15 of this invention acts on the megakaryocyte-thrombocyte system to accelerate the differentiation, maturation and/or proliferation thereof to thereby accelerate the formation of thrombocytes, it is useful especially in the field of medical care as an active ingredient of therapeutic and preventive agents for thrombocytopenia and for thrombocytopenic purpura associated with chemotherapy and bone marrow transplantation and for various diseases characterized by the tendency for bleeding attributable to thrombocytopenia and the like. Blood, which is an indispensable medium for somatic cells constituting the living body, contains blood cells such as erythrocytes, leucocytes, lymphocytes, and thrombocytes. These cells have their own functions and contribute to the maintenance of homeostasis of the living body. It has been a longtime subject of research in the field of hematology to clarify the essential features of differentiation, maturation and proliferation of the blood cells in vivo. It has become recently apparent that the various blood cells are differentiated and maturated from hematopoietic stem cells of the bone marrow and various types of humoral factors in vivo participate in the processes of differentiation and maturation. From these findings, the humoral factors are expected to be used as a medicament for curing diseases with decreases in blood cells, and the like. Until now there were found various humoral factors including erythropoietin (EPO), GCSF, GM-CSF, M-CSF, and interleukin (IL) and some of them have been used practically as medical agents which are capable of promoting the differentiation and maturation of blood cells such as erythrocyte, leucocyte, lymphocyte lineages, or the like.
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Compositions, kits, and methods for modulating survival and differentiation of multi-potential hematopoietic progenitor cells Inventor(s): Cohen; Isaac (Wilmette, IL), Lefebvre; Phil (Chicago, IL), Lin; Jiandie (Evanston, IL), Linzer; Daniel (Evanston, IL) Assignee(s): The Board of Trustees of Northwestern University (Evanston, IL) Patent Number: 6,261,841 Date filed: June 23, 2000 Abstract: The invention includes compositions, kits, and methods for modulating survival and differentiation of mammalian multi-potential hematopoietic progenitor cells using a placental glycoprotein hormone of the murine prolactin family, namely either murine prolactin-like protein E or murine prolactin-like protein F. The compositions, kits, and methods described herein can be used, for example, for in vitro or ex vivo expansion of hematopoietic precursor cells or to treat a disorder associated with aberrant hematopoiesis (e.g., pre-eclampsia and thrombocytopenia). Excerpt(s): The invention relates generally to the field of maintaining and expanding populations of hematopoietic cells ex vivo. Blood cells of all types derive from hematopoietic progenitor cells, which are multipotential (i.e., capable of differentiating into any of a variety of types of blood cells) at early stages of development. At later stages of development, a hematopoietic progenitor cell can become one of only certain types of cells, depending on the developmental path the cell has undergone. By way of example, a hematopoietic stem cell can differentiate to become either a myelo-erythroid progenitor cell or a lymphoid stem cell. If the cell becomes a myelo-crythroid progenitor cell, it can become an erythroid progenitor (and subsequently an erythrocyte) or a myeloid progenitor cell. A myeloid progenitor cell, in turn, can differentiate to become a megakaryocyte (MK), or one of several other types of blood cells. Platelets are derived from MKs. Thus, MKs and the physiological processes by which hematopoietic progenitor cells differentiate into MKs are involved in disorders associated with aberrant formation and activation of platelets. Many pregnancy-associated diseases (e.g., pregnancy-induced hypertension, pre-eclampsia, and diabetes) result from aberrant modulation of maternal physiology. For example, although the platelet count has been observed to decrease slightly during human pregnancy in some studies (Fay et al., 1983, Obst. Gynecol. 61:238-240), the rate of platelet production apparently increases to compensate for the dramatic increase in blood volume during pregnancy (Davison et al., 1989, Baillieres Clin. Endocrinol. Metab. 3:451-472). Aberrantly high rates of platelet activation in plasma have been clinically associated with pre-eclampsia, and antiplatelet treatment is widely used to treat pregnant women afflicted with this disorder (Beaufils et al., 1985, Lancet 1:840-842; Steyn et al., 1997, Lancet 350:1267-1271; Konijnenberg et al., 1997, Am. J. Obst. Gynecol. 176:461-469). Disorders associated with aberrantly low rates of platelet production include thrombocytopenia (e.g., that associated with leukemia and alcohol-induced thrombocytopenia). Web site: http://www.delphion.com/details?pn=US06261841__
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Detection of patients at risk for developing integrin antagonist/agonist mediated disease states Inventor(s): Billheimer; Jeffrey T. (West Chester, PA), Breth; Leah A. (Newark, DE), Burn; Timothy C. (Hockessin, DE), Dicker; Ira B. (Wilmington, DE), George; Henry J. (Newark, DE), Hollis; Gregory F. (Wilmington, DE), Hollis; Jeannine M. (Wilmington, DE), Kochie; Jennifer E. (Hockessin, DE), O'Neil; Karyn T. (Kennett Square, PA), Seiffert; Dietmar A. (Boothwyn, PA) Assignee(s): Bristol-Myers Squibb Company (Princeton, NJ) Patent Number: 6,623,981 Date filed: January 26, 1999 Abstract: This invention relates to the detection of patients at risk for developing integrin antagonist/agonist mediated disease states. This invention relates to assays useful for the detection in a patient bodily fluid sample of drug-dependent antibodies which bind to integrins, or intergrin-associated proteins or complexes thereof in the presence of an integrin antagonist/agonist. This invention also relates to assays useful for the detection in a patient bodily fluid sample of drug-dependent antibodies (DDABS) that bind to integrins, including the platelet glycoprotein IIb/IIIa (GPIIb/IIIa), in the presence of a integrin agonist and/or antagonist. This invention also relates to procedures for identifying integrin antagonists/agonists that are less prone to elicit integrin antagonist/agonist mediated disease states.This invention also relates to procedures which increase the recovery of integrin-directed antibodies in body fluids, resulting in an increased sensitivity and specificity of DDAB detection assays. This invention also relates to procedures for treating blood samples, which dissociate antibodies to GPIIb/IIIa from the platelet surface, thereby increasing the recovery from the platelet supernatant. This invention also relates to the use of different GPIIb/IIIa preparations to identify patients at risk for early-onset thrombocytopenia upon treatment with GPIIb/IIIa antagonist/agonists, thereby increasing the specificity of antibody detection.This invention also relates to the use of DDABs as a positive control and calibration standard for DDAB assays.Such methods, procedures and assays are useful for identifying patients who may be at risk to develop disease states mediated by treatment with integrin antagonists/agonists. Excerpt(s): This invention also relates to procedures which increase the recovery of integrin-directed antibodies in body fluids, resulting in an increased sensitivity and specificity of DDAB detection assays. This invention also relates to procedures for treating blood samples, which dissociate antibodies to GPIIb/IIIa from the platelet surface, thereby increasing the recovery from the platelet supernatant. This invention also relates to the use of different GPIIb/IIIa preparations to identify patients at risk for early-onset thrombocytopenia upon treatment with GPIIb/IIIa antagonist/agonists, thereby increasing the specificity of antibody detection. This invention also relates to the use of DDABs as a positive control and calibration standard for DDAB assays. Web site: http://www.delphion.com/details?pn=US06623981__
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Human stromal derived factor 1.alpha. and 1.beta. Inventor(s): Honjo; Tasuku (Kyoto, JP), Shirozu; Michio (Kyoto, JP), Tada; Hideaki (Osaka, JP) Assignee(s): Ono Pharmaceutical Co., Ltd. (Osaka, JP) Patent Number: 5,756,084 Date filed: July 1, 1996 Abstract: The polypeptides of the present invention are produced and secreted in pro-B cells, so they may be used for diseases relating to undergrown or abnormal proliferation of hematopoietic cells, neuronal enhancement or depression, immunological enhancement and depression, for example, inflammatory diseases (rheumatoid arthritis, ulcerative colitis etc.), hematopoietic stemcytopenia after bone marrow transplantation, leukocytopenia, thrombocytopenia, B lymphopenia and T lymphopenia after chemotherapy, anemia, infectious diseases, cancer, leukocytosis, AIDS, neurodegenerative diseases (Alzheimer, multiple sclerosis etc.), prevention of treatment of neuronal injury, prevention of treatment of disorder of bone metabolism (osteoporosis etc.) or tissue repair. The DNA of the present invention may be utilized as an important and essential template in preparing the polypeptides of the present invention which are expected to possess various use or for diagnosis of an in the treatment of gene diseases. Excerpt(s): The present invention is related to novel polypeptides produced by human pro-B cell line and DNAs encoding them. The present invention is related to novel polypeptides produced by hematopoietic cells and DNAs encoding them. It is known that many kinds of growth and differentiation factors, such as interleukin (IL), are secreted from hematopoietic cells. This fact suggests that factors having similar or novel functions might be secreted therefrom in addition to the known factors already found. Web site: http://www.delphion.com/details?pn=US05756084__
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Hybridization and amplification of nucleic acids encoding mpl ligand Inventor(s): de Sauvage; Frederic J. (Foster City, CA), Eaton; Dan L. (San Rafael, CA) Assignee(s): Genentech, Inc. (South San Francisco, CA) Patent Number: 5,830,647 Date filed: April 26, 1995 Abstract: Isolated mpl ligand, isolated DNA encoding mpl ligand, and recombinant methods of preparing mpl ligand are disclosed. These mpl ligands are shown to influence the replication, differentiation or maturation of blood cells, especially megakaryocyte progenitor cells. Accordingly, these compounds are used for treatment of thrombocytopenia. Excerpt(s): This invention relates to the isolation, purification and characterization of proteins that influence the replication, differentiation or maturation of primitive stem cells, especially hematopoietic cells, including platelet progenitor cells. This invention further relates to the cloning and expression or chemical synthesis of a protein ligand capable of binding to and activating mpl, a member of the cytokine receptor superfamily. This application further relates to the use of these proteins alone or in combination with other cytokines to treat immune or hematopoietic disorders including thrombocytopenia. It is known that bone marrow pluripotent stem cells differentiate
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into megakaryocytic, erythrocytic, and myelocytic cell lines. It is believed there is also a line of committed cells between stem cells and megakaryocytes. The earliest recognizable member of the megakaryocyte (meg) family are the megakaryoblasts. These cells are initially 20 to 30.mu.m in diameter having basophilic cytoplasm and a slightly irregular nucleus with loose, somewhat reticular chromatin and several nucleoli. Later, megakaryoblasts may contain up to 32 nuclei, but the cytoplasm remains sparse and immature. As maturation proceeds, the nucleus becomes more lobulate and pyknotic, the cytoplasm increases in quantity and becomes more acidophilic and granular. The most mature cells of this family may give the appearance of releasing platelets at their periphery. Normally, less than 10% of megakaryocytes are in the blast stage and more than 50% are mature. Arbitrary morphologic classifications commonly applied to the megakaryocyte series are megakaryoblast for the earliest form; promegakaryocyte or basophilic megakaryocyte for the intermediate form; and mature (acidophilic, granular, or platelet-producing) megakaryocyte for the late forms. The mature megakaryocyte extends filaments of cytoplasm into sinusoidal spaces where they detach and fragment into individual platelets (Williams et al., Hematology, 1972). Megakaryocytopoiesis is believed to involve several regulatory factors (Williams et al., Br. J. Haematol., 52:173 ›1982! and Williams et al., J. Cell Physiol. 110:101 ›1982!). The early level of megakaryocytopoiesis is postulated as being mitotic, concerned with cell proliferation and colony initiation from CFU-meg but is not affected by platelet count (Burstein et al., J. Cell Physiol. 109:333 ›1981! and Kimura et al., Exp. Hematol. 13:1048 ›1985!). The later stage of maturation is non-mitotic, involved with nuclear polyploidization and cytoplasmic maturation and is probably regulated in a feedback mechanism by peripheral platelet number (Odell et al., Blood 48:765 ›1976! and Ebbe et al., Blood 32:787 ›1968!). The existence of a distinct and specific megakaryocyte colonystimulating factor (meg-CSF) has been disputed (Mazur, E., Exp. Hematol. 15:340-350 ›1987!). Although meg-CSF's have been partly purified from experimentally produced thrombocytopenia (Hill et al., Exp. Hematol. 14:752 ›1986!) and human embryonic kidney conditioned medium ›CM! (McDonald et al., J. Lab. Clin. Med. 85:59 ›1975!) and in man from aplastic anemia and idiopathic thrombocytopenic purpura urinary extracts (Kawakita et al., Blood 6:556 ›1983!) and plasma (Hoffman et al., J. Clin. Invest. 75:1174 ›1985!), their physiological function is as yet unknown in most cases. The conditioned medium of pokeweed mitogen-activated spleen cells (PWM-SpCM) and the murine myelomonocyte cell line WEHI-3 (WEHI-3CM) have been used as megakaryocyte potentiators. PWM-SpCM contains factors enhancing CFU-meg growth (Metcalf et al., Pro. Natl. Acad. Sci., USA 72:1744-1748 ›1975!; Quesenberry et al., Blood 65:214 ›1985!; and Iscove, N. N., in Hematopoietic Cell Differentiation, ICN-UCLA Symposia on Molecular and Cellular Biology, Vol. 10, Golde et al., eds. ›New York, Academy Press! pp 37-52 ›1978!), one of which is interleukin-3 (IL-3), a multilineage colony stimulating factor (multi-CSF ›Burstein, S. A., Blood Cells 11:469 ›1986!). The other factors in this medium have not yet been identified and isolated. WEHI-3 is a murine myelomonocytic cell line secreting relatively large amounts of IL-3 and smaller amounts of GM-CSF. IL-3 has been recently purified and cloned (Ihle et al., J. Immunol. 129:2431 ›1982!) and has been found to potentiate the growth of a wide range of hemopoietic cells (Ihle et al., J. Immunol. 13:282 ›1983!). IL-3 has also been found to synergize with many of the known hemopoietic hormones or growth factors (Bartelmez et al., J. Cell Physiol. 122:362-369 ›1985! and Warren et al., Cell 46:667-674 ›1988!), including both erythropoietin (EPO) and H-1 (later known as interleukin-1 or IL-1), in the induction of very early multipotential precursors and the formation of very large mixed hemopoietic colonies. Web site: http://www.delphion.com/details?pn=US05830647__
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IL-1.alpha. derivatives Inventor(s): Aihara; Koutoku (Tokushima, JP), Hirai; Yoshikatsu (Tokushima-ken, JP), Kamogashira; Takashi (Tokushima, JP), Kaneta; Mayumi (Tokushima-ken, JP), Kawai; Kazuyoshi (Tokushima-ken, JP), Masui; Yoshihiro (Tokushima-ken, JP), Nakai; Satoru (Tokushima-ken, JP) Assignee(s): Otsuka Pharmaceutical Co., Ltd. (Tokyo-To, JP) Patent Number: 5,756,675 Date filed: June 6, 1994 Abstract: The present invention provides a medicament for treating thrombocytopenia comprising as an active component at least one polypeptide selected from IL-1 and derivative thereof and a Il-1.alpha. derivative having an amino acid sequence of the formula (.alpha.) which is so modified as to fulfill at least one of the requirements of: deletion of the 16-position Arg; replacement of the 16-position Arg by another amino acid residue; deletion of the sequence of the 1-position Ser to the 14-position Phe and deletion of the amino acid sequence of the 1-position Ser to the 15-position Met. Excerpt(s): The present invention relates to a medicament for treating thrombocytopenia, and more particularly to a medicament comprising as an active component at least one selected from interleukin-1 (IL-1) and derivatives thereof and to novel IL-1.alpha. derivatives useful as an active component of said medicament. The technology of cancer therapy has been advanced in recent years. Remarkable advances have been made not only in conventional surgical operations but also in chemotherapy, radiotherapy and immunotherapy. However, the advantages of chemotherapy and radiotherapy in particular are liable to be accompanied by severe side effects. The ideal chemotherapeutic agent is such that it displays a carcinostatic effect but little or no adverse affect on normal tissues. However, since conventional chemotherapeutic agents induce strong inhibition of the bone marrow accompanied by decreases in leukocytes and platelets, it is impossible to administer them consecutively over a long period, and the medication must be interrupted due to these side effects. The irradiation of X-ray or.gamma.-ray for radiotherapy likewise causes adverse effects on hematogenic tissues such as the bone marrow. Particularly if leukocytes, platelets, etc. are markedly decreased, the irradiation should be discontinued. Web site: http://www.delphion.com/details?pn=US05756675__
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Method and kit for detecting heparin induced thrombocytopenia Inventor(s): Aster; Richard H. (Milwaukee, WI), Visentin; Gian (Shorewood, WI) Assignee(s): The Blood Center Research Foundation, Inc. (Milwaukee, WI) Patent Number: 5,972,717 Date filed: November 19, 1997 Abstract: A method of detecting heparin-induced antibodies to complete a diagnosis of heparin-induced thrombocytopenia (HITP) is disclosed. This method comprises the first step of attaching a glycosaminoglycan to a solid support, wherein the glycosaminoglycan is attached to the solid support only at the reducing end of the molecule (unidirectionally). Platelet factor 4 is then bound to the glycosaminoglycan forming a complex having an epitope recognizable by antibodies generated in an HITP immune response. Human blood plasma or serum from a patient suspected of having
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HITP is exposed to the complex and the complex is analyzed to determine if HITPrelated antibodies are present. A device and kit used in performing the diagnostic assay are also disclosed. Excerpt(s): In general, the present invention relates to heparin-induced thrombocytopenia/thrombosis (HITP) and its detection. Specifically, the invention includes a method for diagnostic uses relating to anchored heparin/PF4 (platelet factor 4) complexes which are recognized by a heparin-induced antibody. Thrombocytopenia (low blood platelet levels) is most often caused either by defective platelet production or excessive platelet destruction. Defective platelet production is a common manifestation of many toxic, nutritional, and neoplastic disturbances of the bone marrow. Increased peripheral destruction of platelets is characterized by shortened platelet survival and increased proliferation of bone marrow megakaryocytes in an effort to compensate for the low platelet levels. Frequently, this process is immunologically mediated. Certain drugs and their metabolites induce antibodies in some individuals which can cause immune platelet destruction. Implicated drugs include quinidine and quinine (stereoisomers of each other), sulfonamide antibiotics and many others (R. H. Aster, in Platelet Immunobiology: Molecular and Clinical Aspects. T. J. Kunicki and J. N. George eds., Lippincott, Philadelphia, pp. 387-435, 1989; N. R. Shulman, et al., "Platelet Immunology" in Hemostasis and Thrombosis: Basic Principles and Clinical Practice. R. W. Culman, J. Hirsh, V. J. Marder, E. W. Salzman, eds. Lippincott, Philadelphia, 2nd ed., pp. 452-529, 1989). A few of these drugs, such as penicillin, appear to bind covalently to platelet proteins and stimulate the formation of antibodies specific for the drug-protein complex (hapten-dependent antibodies) (D. J. Salamon, et al., Transfusion 24: 395, 1984). More often, however, the sensitizing drug or one of its metabolites induces the formation of antibody by an unknown mechanism (Aster, supra, 1989; A. Salama, et al., Sem. Hematol. 29: 54-63, 1992). The resulting antibodies bind to platelets only in the presence of drug to cause platelet destruction. Evidence obtained by the Applicants (D. J. Christie, et al., J. Clin. Invest. 75: 310, 1985; D. J. Christie, et al., J. Clin. Invest. 70: 989, 1982) and others (C. Mueller-Eckhardt, et al., Trans. Med. Rev. 4: 69, 1990; A. Salama, et al., Semin. Hematol. 29: 54, 1992) indicates that in such cases, the drug binds noncovalently and reversibly to selected platelet membrane proteins to induce conformational changes or form compound epitopes that are recognized by the antibodies. Drug-dependent binding of the antibodies to platelets causes the platelets to be destroyed. In the several forms of drug-induced immune thrombocytopenia, platelet counts are often very low and bleeding complications are frequently severe. Web site: http://www.delphion.com/details?pn=US05972717__ •
Method for the treatment of thrombocytopenia and pharmaceutical compositions useful therefor Inventor(s): Metcalf; Donald (Balwyn, AU) Assignee(s): Amrad Corporation Limited (Victoria, AU) Patent Number: 5,571,508 Date filed: July 27, 1992 Abstract: The present invention relates generally to a method for, and pharmaceutical compositions useful in, the treatment of thrombocytopenia in a mammal by the administration of an effective amount of leukaemia inhibitory factor (LIF) and/or its derivatives and optionally in combination with one or more other cytokines.
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Excerpt(s): Leukaemia inhibitory factor (LIF) was purified (1, 2) and cloned (3) on the basis of its capacity to induce differentiation in and suppress clonogenecity of the M1 mouse myeloid leukaemic cell line (see International Patent Application No. PCT/AU88/00093). LIF has comparable effects on human HL60 and U937 cells, particularly when acting in collaboration with colony stimulating factors (4). In conventional semisolid cultures, LIF has no colony stimulating activity for normal murine haemopoietic cells (5) although it stimulates the proliferation of the continuous haemopoietic cell line DA1.1a (6) and erythroid cell lines from myc-transformed mouse fetal liver cells. Receptors for LIF are present on monocytemacrophages (7) and some non-haemopoietic cells including osteoblasts, placental and liver cells (8). LIF has been shown to possess a remarkable variety of actions: it releases calcium from bone tissue (9), is the factor preventing spontaneous differentiation in normal embryonic stem cells (10, 11), is a molecule stimulating DA1.1a (6) cell proliferation, stimulates liver cells to produce acute phase proteins (12, 13), and is a lipoprotein lipase inhibitor (14). Web site: http://www.delphion.com/details?pn=US05571508__ •
Method of stimulating hematopoiesis with hemoglobin Inventor(s): Gerber; Michael J. (Denver, CO), Rosenthal; Gary J. (Boulder, CO) Assignee(s): Somatogen, Inc. (Boulder, CO) Patent Number: 5,631,219 Date filed: March 8, 1994 Abstract: The present invention relates to a method for stimulating hematopoiesis in a mammal comprising administration of a therapeutically effective amount of a hemoglobin, including recombinant hemoglobin, and methods for treating cytopenias. These cytopenias include anemia, thrombocytopenia, lymphopenia, neutropenia and the like. The stimulation of hematopoiesis can occur both in vivo and ex vivo, as in the treatment of cytopenias associated with disease states, in cell culture or ex vivo expansion of bone marrow cells. Excerpt(s): The present invention relates to a novel method of stimulating hematopoiesis by administration of a suitable amount of hemoglobin. Hematopoiesis is the process of blood cell production which takes place in the bone marrow. Stem cells in the bone marrow are the progenitor cells for all of the various cell types found in the circulating blood. These stem cells are functionally defined by their capacity to repopulate, on a long-term basis, all of the hematopoietic cell lineages in a lethally irradiated animal [Nicola, N. A. (1993) in Application of Basic Science to Hematopoiesis and the Treatment of Disease, E. D. Thomas and S. K. Carter (ed), Raven Press, New York]. Through a complex series of regulatory events, stem cells differentiate into a number of types of cells including at least red blood cells, leukocytes, lymphocytes, platelets (thrombocytes), monocytes, macrophages, mast cells, basophils, eosinophils,.beta.lymphocytes and T-lymphocytes. Millions of each type of new blood cells are produced daily and are released into the circulating blood to replace destroyed blood cells and maintain homeostasis. (Nathan, D. G. (1992) in Cecil Textbook of Medicine, L. B. Wyngaarden, L. H. Smith and J. C. Bennett, ed., W. B. Saunders Co, Philadelphia, pages 817-836). The production of the different cell types can be modulated in response to exogenous stimuli such as infection or blood loss. For example, during infection white blood cells (leukocytes) are mobilized from peripheral stores, e.g. along the margins of vascular walls (the so-called process of de-marginalization) and there is a concomitant increase of leukocyte production in the bone marrow (Bagby, G. C. (1992) in Cecil
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Textbook of Medicine, J. B. Wyngaarden, L. H. Smith and J. C. Bennett, ed., W. B. Saunders Co., Philadelphia, pages 914-920). Acute blood losses such as menstruation, trauma or surgical blood loss may result in anemia wherein the blood is deficient in red blood cells, in hemoglobin or in total volume (hematocrit<40%, hemoglobin<12 grams/dl, red blood cells<4.times.10.sup.6 /ul, or mean cell volume<80 fl; Nathan, D. G. (1992) in Cecil Textbook of Medicine, J. B. Wyngaarden, L. H. Smith and J. C. Bennett, ed., W. B. Saunders Co., Philadelphia, pages 817-836). The red cell mass (total red blood cells, either total number, weight or volume) acts as an organ that delivers oxygen to tissues. Red cell mass and the rate of red blood cell production are closely coupled to the supply and demand for oxygen in body tissues. Red blood cell production is stimulated by low tissue tension of oxygen. Anemic conditions result in reduced oxygen levels in tissues (hypoxia). Hypoxia in the kidney is sensed by the renal parenchyma which stimulates the release of erythropoietin from the kidney. Erythropoietin is the major regulatory hormone of erythropoiesis produced in response to hypoxia resulting from alterations in the red cell mass. (Erslev, A. J. (1990) in Hematology, W. J. Williams, E. Beutler, A. J. Erslev and M. A. Lichtman eds, McGraw-Hill, Inc. New York, pp 389-407). Web site: http://www.delphion.com/details?pn=US05631219__ •
Methods and compositions for treating thrombocytopenia Inventor(s): McDonald; Ted P. (Knoxville, TN) Assignee(s): The University of Tennessee Research Corp. (Knoxville, TN) Patent Number: 5,593,666 Date filed: October 27, 1994 Abstract: A method and composition utilizing thrombopoietin for increasing platelet cell counts in thrombocytopenia is disclosed. The method and composition are suitable for treatments of patients suffering from medical conditions, such as HIV/AIDS or chemotherapy, which result in low platelet cell numbers. Also disclosed are the active moieties or domains of the thrombopoietin molecule. Excerpt(s): This invention relates to therapies employing thrombopoietin, and especially those which include the treatment of thrombocytopenia in immunodeficient and chemotherapy patients. Thrombopoietin (TPO) protein, a cytokine, stimulates the creation and maturation of megakaryocytes. TPO is also referred to as thrombocytopoiesis-stimulating factor (TSF). TPO plays a major role in stimulating thrombocytopoiesis (platelet production). For a comprehensive review of TPO, see McDonald, The Amer. J. of Ped. Hem./Onc. 14 (1): 8-21 (1992), which is incorporated herein by reference. All references cited are incorporated hereinby reference. Platelets are the blood cells responsible for clotting and low platelet counts can lead directly to excessive internal bleeding. Platelets--small blood cell fragments that break off from a relatively huge parent cell (the megakaryocyte)--are key to normal blood clotting. They routinely serve as patches for small defects in blood vessels to confine hemorrhage and encourage ordinary coagulation. Vast numbers of platelets aggregate to form a thrombus that stops excessive bleeding at wound sites. Web site: http://www.delphion.com/details?pn=US05593666__
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Methods and kits using macrophage stimulating protein Inventor(s): Avraham; Hava Karsenty (Brookline, MA), Godowski; Paul J. (Burlingame, CA) Assignee(s): Beth Israel Deaconess Medical Center, Inc. (Boston, MA), Genentech, Inc. (South San Francisco, CA) Patent Number: 5,696,086 Date filed: November 3, 1994 Abstract: The invention provides methods for stimulating megakaryocyte maturation and thrombocyte production using macrophage stimulating protein ("MSP"). In the methods, an effective amount of MSP can be administered in vivo, or alternatively, be used to stimulate maturation of megakaryocytes and produce thrombocytes in vitro. Methods for treating thrombocytopenia in a mammal with MSP are also provided. Kits and articles of manufacture which include MSP are further provided. Excerpt(s): The invention relates generally to methods of stimulating megakaryocytopoiesis and thrombocytopoiesis. More particularly, the invention relates to methods of stimulating megakaryocyte maturation and thrombocyte production using macrophage stimulating protein. The invention also relates to methods of treating certain hematopoietic disorders, such as thrombocytopenia, and to kits containing macrophage stimulating protein. Hepatocyte growth factor ("HGF") functions as a growth factor for particular tissues and cell types. HGF was identified initially as a mitogen for hepatocytes ›Michalopoulos et al., Cancer Res., 44: 4414-4419 (1984); Russel et al., J. Cell. Physiol., 119: 183-192 (1984); Nakamura et al., Biochem. Biophys. Res. Comm., 122: 1450-459 (1984)!. Nakamura et al., supra, reported the purification of HGF from the serum of partially hepatectomized rats. Subsequently, HGF was purified from rat platelets, and its subunit structure was determined ›Nakamura et al., Proc. Natl. Acad. Sci. USA, 83: 6489-6493 (1986); Nakamura et al., FEBS Letters, 224: 311-316 (1987)!. The purification of human HGF ("huHGF") from human plasma was first described by Gohda et al., J. Clin. Invest., 81: 414-419 (1988). Both rat HGF and huHGF have been molecularly cloned, including the cloning and sequencing of a naturally occurring variant lacking 5 amino acids designated "delta5 HGF" ›Miyazawa et al., Biochem. Biophys. Res. Comm., 163: 967-973 (1989); Nakamura et al., Nature, 342: 440-443 (1989); Seki et al, Biochem. Biophys. Res. Commun., 172: 321-327 (1990); Tashiro et al., Proc. Natl. Acad. Sci. USA, 87: 3200-3204 (1990); Okajima et al., Eur. J. Biochem., 193: 375-381 (1990)!. Web site: http://www.delphion.com/details?pn=US05696086__
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Methods for stimulating erythropoiesis using hematopoietic proteins Inventor(s): Kaushansky; Kenneth (Woodinville, WA) Assignee(s): University of Washington (Seattle, WA), ZymoGenetics, Inc. (Seattle, WA) Patent Number: 6,099,830 Date filed: September 12, 1997 Abstract: Methods for stimulating erythropoiesis using the hematopoietic protein thrombopoietin, optionally in combination with erythropoietin, are provided. The methods provided may be used to stimulate erythropoiesis in bone marrow and
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peripheral blood cells and in vitro and in vivo. In addition, methods for treatment of thrombocytopenia and anemia in patients are disclosed. Excerpt(s): Hematopoiesis is the process by which blood cells develop and differentiate from pluripotent stem cells in the bone marrow. This process involves a complex interplay of polypeptide growth factors (cytokines) acting via membrane-bound receptors on the target cells. Cytokine action results in cellular proliferation and differentiation, with response to a particular cytokine often being lineage-specific and/or stage-specific. Development of a single cell type, such as a platelet or erythrocyte, from a stem cell may require the coordinated action of a plurality of cytokines acting in the proper sequence. The known cytokines include the interleukins, such as IL-1, IL-2, IL-3, IL-6, IL-8, etc.; and the colony stimulating factors, such as G-CSF, M-CSF, GM-CSF, erythropoietin (EPO), etc. In general, the interleukins act as mediators of immune and inflammatory responses. The colony stimulating factors stimulate the proliferation of marrow-derived cells, activate mature leukocytes, and otherwise form an integral part of the host's response to inflammatory, infectious, and immunologic challenges. Various cytokines have been developed as therapeutic agents. Several of the colony stimulating factors have been used in conjunction with cancer chemotherapy to speed the recovery of patients' immune systems. Interleukin-2,.alpha.-interferon.beta.interferon and.gamma.-interferon are used in the treatment of certain cancers. EPO, which stimulates the development of erythrocytes, is used in the treatment of anemia arising from renal failure. Factors responsible for stimulation of megakaryocytopoiesis and thrombocytopoiesis resisted definitive characterization, due in part to lack of a good source, a lack of good assays, and a lack of knowledge as to the site(s) of production until recently, despite three decades of work to isolate and characterize them. The megakaryocytopoietic factor referred to in the literature as "thrombopoietin" (recently reviewed by McDonald, Exp. Hematol. 16:201-205, 1988; and McDonald, Am. J. Ped. Hematol. Oncol. 14:8-21, 1992) has now been identified and isolated (see copending U.S. patent application Ser. No. 08/252,491; Lok et al., Nature 369:565-568, 1994; and Kaushansky et al., Nature 369:568-571, 1994; all herein incorporated by reference). Web site: http://www.delphion.com/details?pn=US06099830__ •
Methods for treating autoimmune diseases with 5C8-specific antibodies Inventor(s): Chess; Leonard (Scarsdale, NY), Lederman; Seth (New York, NY), Yellin; Michael J. (Riverdale, NY) Assignee(s): The Trustees of Columbia University in the City of New York (New York, NY) Patent Number: 6,592,868 Date filed: June 7, 1995 Abstract: This invention provides methods of treating autoimmune diseases, including those selected from the group consisting of rheumatoid arthritis, Myasthenia gravis, systemic lupus erythematosus, Graves' disease, idiopathic thrombocytopenia purpura, hemolytic anemia and diabetes mellitus with 5C8-specific antibodies. Excerpt(s): Throughout this application, various publications are referenced by Arabic numerals within parenthesis. Full citations for these publications may be found at the end of the specification, immediately preceding the claims. The disclosures of these publications are hereby incorporated by reference into this application in order to more full describe the state of the art as one skilled therein as of the date of the invention
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described and claimed herein. In a contact-dependent process termed "T cell helper function," CD4.sup.+ T lymphocytes direct the activation and differentiation of B lymphocytes and thereby regulate the humoral immune response by modulating the specificity, secretion and isotype-encoded functions of antibody molecules (1-8). The T cell surface molecules that mediate the contact-dependent elements of T cell helper function are not yet fully known (9). The process by which T cells help B cells to differentiate has been divided into two distinct phases: the inductive and effector phases (10,11). In the inductive phase, resting T cells contact antigen-primed B cells and this association allows clonotypic T cell receptor (TCR)-CD4 complexes to interact with Ia/Ag complexes on B cells (5, 12-19). TCR/CD4 recognition of Ia/Ag results in the formation of stable T-B cognate pairs and bidirectional T and B cell activation (20-26). In the effector phase, activated T cells drive B cell differentiation by secreting lymphokines (27-30) and by contact-dependent stimuli (24,31-38), both of which are required for T cells to drive small, resting B cells to terminally differentiate into Ig secreting cells (31, 39-42). Web site: http://www.delphion.com/details?pn=US06592868__ •
Methods of treating thrombocytopenia Inventor(s): Lamb; Peter I. (San Diego, CA), Luengo; Juan I. (Audubon, PA) Assignee(s): Ligan Pharmaceuticals (San Diego, CA), SmithKline Beecham Corporation (Philadelphia, PA) Patent Number: 6,498,155 Date filed: July 24, 2001 Abstract: Invented are non-peptide TPO mimetics. Also invented is a method of treating thrombocytopenia, in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a linked cyclic polyamine derivative. Excerpt(s): This invention relates to TPO receptor ligands and their use as agonists of the TPO receptor. Megakaryocytes are bone marrow-derived cells, which are responsible for producing circulating blood platelets. Although comprising <0.25% of the bone marrow cells in most species, they have >10 times the volume of typical marrow cells. See Kuter et al. Proc. Natl. Acad. Aci. USA 91: 11104-11108 (1994). Megakaryocytes undergo a process known as endomitosis whereby they replicate their nuclei but fail to undergo cell division and thereby give rise to polypoid cells. In response to a decreased platelet count, the endomitotic rate increases, higher ploidy megakaryocytes are formed, and the number of megakaryocytes may increase up to 3-fold. See Harker J. Clin. Invest. 47: 458465 (1968). In contrast, in response to an elevated platelet count, the endomitotic rate decreases, lower ploidy megakaryocytes are formed, and the number of megakaryocytes may decrease by 50%. The exact physiological feedback mechanism by which the mass of circulating platelets regulates the endomitotic rate and number of bone marrow megakaryocytes is not known. The circulating thrombopoietic factor involved in mediating this feedback loop is now thought to be thrombopoietin (TPO). More specifically, TPO has been shown to be the main humoral regulator in situations involving thrombocytopenia. See, e.g., Metcalf Nature 369:519-520 (1994). TPO has been shown in several studies to increase platelet counts, increase platelet size, and increase isotope incorporation into platelets of recipient animals. Specifically, TWO is thought to affect megakaryocytopoiesis in several ways: (1) it produces increases in megakaryocyte size and number; (2) it produces an increase in DNA content, in the form of polyploidy,
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in megakaryocytes; (3) it increases megakaryocyte endomitosis; (4) it produces increased maturation of megakaryocytes; and (5) it produces an increase in the percentage of precursor cells, in the form of small acetylcholinesterase-positive cells, in the bone marrow. Web site: http://www.delphion.com/details?pn=US06498155__ •
Remedies for thrombocytopenia Inventor(s): Oda; Yasuhiro (Nagano-ken, JP), Tamura; Masahiko (Shizuoka-ken, JP) Assignee(s): Chugai Seiyaku Kabushiki Kaisha (Tokyo, JP) Patent Number: 6,342,477 Date filed: July 29, 1998 Abstract: Agents for preventing and treating thrombocytopenia, thrombocytopenic purpura and various diseases that tend to cause bleeding due, presumably, to thrombocytopenia contain a parathyroid hormone (PTH) or at least one PTH derivative as an active ingredient. Excerpt(s): This invention relates to agents for preventing and treating thrombocytopenia that contain a parathyroid hormone (PTH) or a derivative thereof as an active ingredient. Platelets, as well as erythrocytes and neutrophils which are also in the class of mature corpuscles, originate from hematopoietic stem cells and are produced by the differentiation and proliferation of these cells. In the early stage of the hematopoietic process, hematopoietic stem cells differentiate and proliferate to megakaryocytes via their precursor cells. Mature magakaryocytes form proplatelets which would eventually be released into peripheral blood as platelets. It has been found that various hematopoietic factors and cytokines are involved in the series of steps in the above-described platelet production process. For example, it has been shown experimentally that interleukin-3 is involved in the stage from stem cells to megakaryocytes, interleukin-6 in the maturing of megakaryocytes and thrombopoietin in the stage from stem cells to the maturing of megakacyocytes. It is speculated that a certain factor is also involved in the process of platelet production and release from mature magakacyocytes but no such factors are yet to be identified. Thrombocytopenia manifests itself if either one of the steps in the above-described thrombpoletic process is interfered with and there are two major causes of such interference, abnormality in hematopoietic cells and abnormality in hematopoietic factors. In the first case, the differentiation and proliferation of hematopoietic cells are interfered with by either congenital or acquired causes. Aplastic anemia and osteomyelodysplasia syndrome are known to occur by congenital causes and bone marrow transplantation and the administration of chemotherapeutics are two known acquired causes. As for the abnormality in hematopoietic factors, cyclic thrombocytopenia is known to be caused by this reason. Web site: http://www.delphion.com/details?pn=US06342477__
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Thrombocytopoiesis stimulating factor Inventor(s): Higuchi; Masato (Shizuoka, JP), Kawakita; Makoto (Kumamoto, JP), Matsuzaki; Hiromitsu (Kumamoto, JP), Shibuya; Kazushi (Tokyo, JP), Takatsuki; Kiyoshi (Kyoto, JP) Assignee(s): Chugai Seiyaku Kabushiki Kaisha (Tokyo, JP) Patent Number: 5,856,444 Date filed: July 18, 1997 Abstract: An object of the present invention is to provide a physiologically active substance having activity in acting on the megakaryocyte-platelet system, in promoting the differentiation and maturation of megakaryocytes, and in promoting the formation of platelets. The present invention relates to a thrombocytopoiesis stimulating factor, characterized in having the following amino acid sequence in its molecule, and to a medicinal composition for treating thrombocytopenia, characterized in containing thrombocytopoiesis stimulating factor as an active component: Xaa Gly Asn Asn Asp Glu Ser Asn Ile Ser Phe Lys Glu Lys Asp Ile (where Xaa indicates that the amino acid is unspecified). The physiologically active substance is useful as an active component or the like in therapeutics and preventives for thrombocytopenia and thrombocytopenic purpura associated with chemotherapy and marrow grafts, and for various other diseases which are prone to bleeding attributed to thrombocytopenia. Excerpt(s): The present invention relates to a novel physiologically active substance (thrombocytopoiesis stimulating factor) having activity in acting on cells in the megakaryocyte system, in promoting their differentiation and maturation, and in promoting the formation of platelets, as well as to a medicinal composition containing this physiologically active substance as an active component for the treatment of thrombocytopenia. Since the physiologically active substance (thrombocytopoiesis stimulating factor) of the present invention has activity in acting on the megakaryocyteplatelet system, in promoting differentiation and maturation therein, and in promoting the formation of platelets, it is particularly useful in the medical field as an active component or the like in therapeutics and preventives for thrombocytopenia and thrombocytopenic purpura associated with chemotherapy and marrow grafts, and for various other diseases which are prone to bleeding attributed to thrombocytopenia. Blood cells such as erythrocytes, leukocytes, lymphocytes, and platelets are present as material components in the blood, which is an indispensable medium for the somatic cells constituting the body, and these blood cells each have an inherent function in the continual maintenance of the body. Understanding the phenomenon of the differentiation, maturation, proliferation, and the like of these blood cells in the body has long been the subject of research in the field of hematology, but the differentiation and maturation of various blood cells from one type of multifunctional hematopoietic stem cell in the marrow, the roles played by various endogenous humoral factors during the process of differentiation and maturation, and, other facts have recently been elucidated. In light of such facts, these endogenous humoral factors hold promise as medicinal products such as drugs for the treatment of diseases associated with decreases in the blood cells of the blood cell systems, and a variety of humoral factors, such as erythropoietin, G-CSF, GM-CSF, M-CSF, and interleukin, have thus far been discovered, some of which have been put to actual use as drugs having action in promoting the differentiation and maturation of blood cells such as those in the erythrocyte, leukocyte, and lymphocyte systems. Web site: http://www.delphion.com/details?pn=US05856444__
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Use of polypeptides for treating thrombocytopenia Inventor(s): Forssmann; Wolf-Georg (Blucherstrasse 5, D-30175, Hannover, DE), Opitz; Hans-Georg (Weinheim, DE), Schmitt; Joachim (Viernheim, DE), Schultz-Knappe; Peter (Hemmingen, DE) Assignee(s): Forssmann; Wolf-Georg (Hannover, DE) Patent Number: 6,403,553 Date filed: January 11, 2000 Abstract: The present invention relates to the use of polypeptides of the MIP (macrophage inflammatory proteins) class for the treatment of diseases involving a pathological change of thrombocytopolesis, especially for the treatment of thrombocytopenia. Excerpt(s): The present invention relates to the use of polypeptides of the MIP (macrophage inflammatory proteins) class for the treatment of diseases involving a pathological reduction of thrombocytopoiesis. Thrombocytes (platelets) play a key role in blood clotting and wound healing. Therefore, thrombocytic diseases can lead to hemostatic disorders and thus to massive hemorrhages. It is generally distinguished between thrombocytopenias, in which the platelet count is reduced, and thrombocytic dysfunctions, in which the function of platelets is impaired, in spite of normal counts. Possible causes of thrombocytopenia include reduced or lacking megakaryocytes in the bone marrow, reduced platelet production, sequestration of platelets in the spleen, increased thrombocytolysis, increased platelet consumption or dilution of the platelet pool. Irrespective of the etiology, severe thrombocytopenia results in skin hemorrhages in the form of multiple petechiae, which are usually most pronounced at the lower legs, and isolated little ecchymoses following trivial traumata. More serious are mucosal hemorrhages (nosebleeding; bleedings in the gastrointestinal tract, in the urogenital tract and in the vagina) and bleedings following surgical interventions. Depending on the extent of thrombocytopenia, severe gastrointestinal bleedings and bleedings into the central nervous system with life-threatening consequences can occur. Web site: http://www.delphion.com/details?pn=US06403553__
Patent Applications on Thrombocytopenia As of December 2000, U.S. patent applications are open to public viewing.10 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to thrombocytopenia:
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This has been a common practice outside the United States prior to December 2000.
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Acetylcholinesterase-derived peptides and uses thereof Inventor(s): Deutch, Varda; (Jerusalem, IL), Eldor, Amiram; (US), Eldor, Sofia; ( Tel Aviv, IL), Grisaru, Dan; (Hertzlia, IL), Soreq, Hermona; (Jerusalem, IL) Correspondence: Cooper & Dunham Llp; 1185 Avenue OF The Americas; New York; NY; 10036; US Patent Application Number: 20030036632 Date filed: November 30, 2001 Abstract: The invention relates to a cell growth and/or differentiation regulatory peptide comprising a sequence of about 9 to about 150 amino acids derived from acetylcholinesterase amino acid sequence, preferably from the C-terminal region of acetylcholinesterase. The invention also relates to pharmaceutical compositions comprising the peptides, particularly for use in promoting survival of stem cells, promoting differentiation of stem cells, promoting growth of stem cells and/or promoting the growth-enhancing effect of a growth factor on stem cells, alone, or in combination with other growth factors. Of particular interest is the use of the peptides in the treatment of thrombocytopenia, post-irradiation conditions, post-chemotherapy conditions, or conditions following massive blood loss and promotion of neural progenitors in use for cell therapies aimed at restoring neural functions in diseased individuals. Further, the invention relates to antibodies against the peptides, inter alia for diagnostic use, for example, the diagnosis of stress-induced male infertility. The invention also relates to in vitro and in vivo methods for screening of drugs that affect the central nervous system, and are potential modulators of interactions between the "readthrough" form of acteylcholinesterase, AChE-R, the intracellular receptor RACK1 and the kinase PKC. Excerpt(s): This application is a continuation-in-part application of international patent application PCT/IL00/00311. The invention is directed to the field of stem cell survival and expansion. Specifically, the invention is directed at the stem cell survival and expansion effects of peptides derived from acetylcholinesterase. In addition, the invention relates to a system for screening of nervous system drugs that are directed to central nervous system conditions or disorders. More specifically, the invention relates to the screening of modulators of the AChE-R-PKC.beta.II-RACK1 complex. Stress insults evoke a plethora of responses in the organism, affecting the functioning of various systems. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Acid-modified arabinogalactan protein composition Inventor(s): An, Jinhua; (Palo Alto, CA), Lennox, Edwin S.; (Stanford, CA), Leu, Karen S.; (Saratoga, CA), Musser, John H.; (San Carlos, CA) Correspondence: Heller Ehrman White & Mcauliffe Llp; 275 Middlefield Road; Menlo Park; CA; 94025-3506; US Patent Application Number: 20030211077 Date filed: November 27, 2002 Abstract: An acid-modified arabinogalactan protein composition, having an arabinosegalactose ratio of less than 3.5:1 or less than 80% of the arabinose:galactose ratio of the arabinogalactan protein component of the composition prior to acid modification,
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prepared from Astragalus membranaceus, especially from the roots of Atragalus membranaceus, is capable of reconstitution into an aqueous intravenously injectable formulation; and is useful for stimulating hematopoiesis, inducing the proliferation or maturation of megakaryocytes, stimulating the production of IL-1.beta., Il-6, TNF.alpha., IFN-.gamma., GM-CSF, or G-CSF, stimulating the production or action of neutrophils, treating neutropenia, anemia, or thrombocytopenia, accelerating recovery from exposure (e.g. accidental or non-therapeutic exposure, as well as therapeutic exposure) to cytotoxic agents or radiation, treating cachexia, emesis, or drug withdrawal symptoms, or modifying biological responses or protecting hepatic cells in hepatitis B, in a mammal when intravenously administered to the mammal. Excerpt(s): This invention relates to arabinogalactans. In particular, this invention relates to an acid-modified arabinogalactan protein composition, having an arabinose:galactose ratio of less than 3.5:1 or less than 80% of the arabinose:galactose ratio of the arabinogalactan protein component of the composition prior to acid modification, prepared from Astragalus membranaceus, especially from the roots of Astragalus membranaceus. Huang-qi, Radix Astragali, is the dried root of Astragalus membranaceus Bge. var. mongholicus (Bge.) Hsiao or A. membranaceus (Fisch.) Bge. (Fabaceae). Huang-qi is a very old and well known drug in traditional Chinese medicine. It is officially listed in the Chinese Pharmacopoeia and used mainly as a tonic and for treatment of nephritis and diabetes. It is commonly used as a decoction or "tea" alone or with other plants in the traditional medicines Shi-ka-ron (a combination with herbs Lithosperium erythrorhizon and Ligusticum wallachii) and Ren-shen-yang-rongtang (a combination of twelve herbs including Radix Astragali) [The section entitled "Astragalus membranaceus (Fisch.) Bge.", Section 26, pages 191-197, of "Chinese Drugs of Plant Origin", W. Tang and G. Eisenbrand, eds., Springer Verlag, Berlin, 1992]. Huang-qi decoctions, and solutions prepared from the alcohol-precipitated decoction, have also been administered by injection, and are reported to give improvement in the symptoms of gastric and duodenal ulcers and increase the white blood cell count in chronic leukopenia [The section entitled "Huangqi", pages 1041-1046, of "Pharmacology and Applications of Chinese Materia Medica", H.-M. Chang and P. P.-H. But, eds., World Scientific Publishing Co., Singapore, 1987]. Huang-qi decoctions, purified low molecular weight fractions (e.g. 25,000-35,000 MW), and decoctions of herb mixtures containing huang-qi, have also shown activity in restoring the immune system in local xenogeneic graft-versus-host reaction [D.-T. Chu et al., "Immunotherapy with Chinese medicinal herbs. I. ", J. Clin. Lab. Immunol., 25, 119-123 (1988)], reversing cyclophosphamide-induced immune suppression [D.-T. Chu et al., "Immunotherapy with Chinese medicinal herbs. II. ", J. Clin. Lab. Immunol., 25, 125-129 (1988)], potentiating LAK cell cytotoxicity generated by rIL-2 [D.-T. Chu et al., "Fractionated extract of Astragalus membranaceus. ", J. Clin. Lab. Immunol., 25, 183-187 (1988)], enhancing the immune response in immunodepressed mice [K. S. Zhao et al., "Enhancement of the immune response in mice by Astragalus membranaceus extracts", Immunopharmacology, 20, 225-234 (1990)], stimulating responses in mononuclear cells [Y. Sun et al., "Preliminary observations on the effects of the Chinese medicinal herbs. ", J. Biol. Response Modifiers, 2, 227-237 (1983)], and stimulating bone marrow hematopoiesis in mice [M. Rou et al., "The effect of radix astragali on mouse marrow hemopoiesis", J. Trad. Chin. Med., 3(3), 199-204 (1983); S.-I. Miura et al., "Effect of a traditional Chinese herbal medicine. ", Int. J Immunopharmacol., 7(11), 771-780 (1989); and Y. Ohnishi et al., "Effects of Juzen-taiho-toh (TJ-48). ", Exp. Hematol., 18, 18-22 (1990)]. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Agents for preventing and treating thrombocytopenia Inventor(s): Oda, Yasuhiro; (Nagano-ken, JP), Tamura, Masahiko; (Shizuoka-ken, JP) Correspondence: Browdy And Neimark, P.L.L.C.; 624 Ninth Street, NW; Suite 300; Washington; DC; 20001-5303; US Patent Application Number: 20020058626 Date filed: December 27, 2001 Abstract: Method of increasing blood platelet formation by administering a parathyroid hormone (PTH) or at least one PTH derivative as an active ingredient. Excerpt(s): This is a division of co-pending parent application Ser. No. 09/117,379, the national stage under 35 U.S.C.sctn.371 of international application PCT/JP97/00255, which designated the United States, was nationalized Jul. 29, 1998, and was not published in English. This invention relates to agents for preventing and treating thrombocytopenia that contain a parathyroid hormone (PTH) or a derivative thereof as an active ingredient. Platelets, as well as erythrocytes and neutrophils which are also in the class of mature corpuscles, originate from hematopoietic stem cells and are produced by the differentiation and proliferation of these cells. In the early stage of the hematopoietic process, hematopoietic stem cells differentiate and proliferate to megakaryocytes via their precursor cells. Mature magakaryocytes form proplatelets which would eventually be released into peripheral blood as platelets. It has been found that various hematopoietic factors and cytokines are involved in the series of steps in the above-described platelet production process. For example, it has been shown experimentally that interleukin-3 is involved in the stage from stem cells to megakaryocytes, interleukin-6 in the maturing of megakaryocytes and thrombopoietin in the stage from stem cells to the maturing of megakacyocytes. It is speculated that a certain factor is also involved in the process of platelet production and release from mature magakacyocytes but no such factors are yet to be identified. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Anticoagulant test Inventor(s): Bednar, Bohumil; (North Wales, PA), Bollag, Daniel M.; (Wyncote, PA), Gould, Robert J.; (Green Lane, PA) Correspondence: Merck And CO Inc; P O Box 2000; Rahway; NJ; 070650907 Patent Application Number: 20020009753 Date filed: March 30, 2001 Abstract: The present invention is a method for diagnosing a patient at risk to thrombocytopenia induced by administration of a GP IIb/IIIa receptor antagonist, which comprises combiningi) a plasma sample of the patient;ii) detectable monoclonal antibody which recognizes induced binding sites formed on the GP IIb/IIIa receptor following association of a fibrinogen receptor antagonist with the GP IIb/IIIa receptor; andiii) GP IIb/IIIa receptor:GP IIb/III receptor antagonist complex,and determining association of the detectable monoclonal antibody with the complex in the presence of the plasma. Excerpt(s): Drug-induced thrombocytopenia contributes to morbidity and, occasionally, mortality in patients treated with a wide range of medications (Karpatkin, (1971) Am. J. Med. Sci. 262, p. 68). More than 100 different medications have been implicated in drug-
Patents 147
induced thrombocytopenia, including heparin, quinine, quinidine and sulfonamide antibiotics (Shulman et al. "Hemostasis and Thrombosis" (ed 2) Philadelphia, Pa., Lippincott (1987) p.452, and Kracke et al. (1943) JAMA 122, p. 168. Drug-dependent antibodies reactive with platelets have been identified in only a few instances. Curtis et al., (1984) Blood v. 84, n.1, 176-183, applied flow cytometry to the detection of such antibodies induced by sulfonamide antibiotics. Visentin et al. (1990) Transfusion Oct. v. 30 n. 8, 694-700 describes detection of drug-dependent, platelet-reactive antibodies by antigen-capture ELISA and flow cytometry. The occurrence of fibrinogen receptor antagonist induced-thrombocytopenia has prompted a search for monoclonal antibodies (mAbs) specific for GP IIb/IIIa receptor:receptor antagonist complexes. Monoclonal antibodies capable of detecting alterations in glycoprotein IIb/IIIa upon binding of fibrinogen receptor antagonists to glycoprotein IIb/IIIa are useful in diagnosing patients at risk to developing fibrinogen receptor antagonist-induced thrombocytopenia. The monoclonals can be tagged with fluorescent or radioactive tracers for ease in diagnosis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Blood cell deficiency treatment method Inventor(s): Ahlem, Clarence N.; (San Diego, CA), Frincke, James; (San Diego, CA), Lardy, Henry A.; (Madison, WI), Marwah, Ashok; (Middleton, WI), Marwah, Padma; (Middleton, WI), Prendergast, Patrick T.; (Straffan, IE), Reading, Christopher; (San Diego, CA), Stickney, Dwight; (Granite Bay, CA) Correspondence: Hollis-eden Pharmaceuticals, INC.; 4435 Eastgate Mall; Suite 400; San Diego; CA; 92121; US Patent Application Number: 20030083231 Date filed: March 1, 2002 Abstract: The invention relates to the use of compounds to treat a number of conditions, such as thrombocytopenia, neutropenia or the delayed effects of radiation therapy. Compounds that can be used in the invention include methyl-2,3,4-trihydroxy-1-O(7,17-dioxoandrost-5-ene-3.beta.-yl)-.beta.-D-glucopyranosiduronate, 16.alpha.,3.alpha.-dihydroxy-5.alpha.-androstan-17-one or 3,7,16,17tetrahydroxyandrost-5-ene, 3,7,16,17-tetrahydroxyandrost-4-ene,3,7,16,17tetrahydroxyandrost-1-ene or 3,7,16,17-tetrahydroxyandros- tane that can be used in the treatment method. Excerpt(s): This application is a continuation-in-part of: (1) pending U.S. application Ser. No. 09/675,470, filed Sep. 28, 2000, which is a continuation-in-part of abandoned U.S. provisional application Ser. No. 60/161,453, filed Oct. 25, 1999, and (2) pending U.S. provisional application Ser. No. 60/272,624, filed Mar. 1, 2001, and (3) pending U.S. provisional application Ser. No. 60/323,016, filed Sep. 10, 2001, and (4) pending U.S. provisional application Ser. No. 60/340,045, filed Nov. 1, 2001, and (5) pending U.S. provisional application Ser. No. 60/328,738, filed Oct. 11, 2001, and (6) pending U.S. provisional application Ser. No. 60/338,015, filed Nov. 8, 2001, and (7) pending U.S. provisional application Ser. No. 60/343,523, filed Dec. 20, 2001, and (8) pending U.S. application Ser. No. 09/820,483, filed Mar. 29, 2001, which is a continuation-in-part of pending U.S. application Ser. No. 09/535,675, filed Mar. 23, 2000, which is a continuation-in-part of abandoned U.S. provisional application Ser. No. 60/126,056, filed Mar. 23, 1999, and abandoned U.S. provisional application Ser. No. 60/124,087, filed Mar. 11, 1999 and which is a continuation-in-part of abandoned U.S. application Ser. No. 09/449,004, filed Nov. 24, 1999, which is a continuation-in-part of abandoned
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U.S. provisional application Ser. No. 60/109,923, filed Nov. 24, 1998, and which is a continuation-in-part of abandoned U.S. application Ser. No. 09/449,184, filed Nov. 24, 1999, which is a continuation-in-part of abandoned U.S. provisional application Ser. No. 60/109,924, filed Nov. 24, 1998, and which is a continuation-in-part of abandoned U.S. application Ser. No. 09/449,042, filed Nov. 24, 1999, which is a continuation-in-part of abandoned U.S. provisional application Ser. No. 60/110,127, filed Nov. 27, 1998, and which is a continuation-in-part of pending U.S. application Ser. No. 09/461,026, filed Dec. 15, 1999, which is a continuation-in-part of abandoned U.S. provisional application Ser. No. 60/112,206, filed Dec. 15, 1998, and which is a continuation-in-part of abandoned U.S. application Ser. No. 09/586,673, filed Jun. 1, 2000, which is a continuation-in-part of abandoned U.S. provisional application Ser. No. 60/145,823, filed Jul. 27, 1999, and which is a continuation-in-part of abandoned U.S. application Ser. No. 09/586,672, filed Jun. 1, 2000, which is a continuation-in-part of abandoned U.S. provisional application Ser. No. 60/137,745, filed Jun. 3, 1999, and which is a continuation-in-part of abandoned U.S. application Ser. No. 09/414,905, filed Oct. 8, 1999, which is a continuation-in-part of abandoned U.S. provisional application Ser. No. 60/140,028, filed Jun. 16, 1999, all of which are incorporated herein by reference in their entireties. The invention relates to methods to make or use compounds, such as 16.alpha.-bromo-3.beta.-hydroxy-5.alpha.-androstane-17-one (16.alpha.bromoepiandrosterone or hereafter "BrEA") 3,7,16,17-tetrahydroxyandrost-5-ene, 3,7,16,17-tetrahydroxyandrostane, 3,17-dihydroxy-16-haloandrostane, methyl 2,3,4trihydroxy-1-O-(7,17-dioxoandrost-5-ene-3.beta.-yl)-.beta.-D-glucopyranosiduronate and related compounds. The invention relates to the use of compounds to treat a number of conditions, such as thrombocytopenia and neutropenia. Methods to prepare dehydroepiandrosterone ("DHEA") and other steroids and their biological properties have been described, see, e.g., U.S. Pat. Nos. 2,833,793, 2,911,418, 3,148,198, 3,471,480, 3,976,691, 4,268,441, 4,427,649, 4,542,129, 4,666,898, 4,956,355, 5,001,119, 5,043,165, 5,077,284, 5,028,631, 5,110,810, 5,157,031, 5,162,198, 5,175,154, 5,277,907, 5,292,730, 5,296,481, 5,372,996, 5,387,583, 5,407,684, 5,424,463, 5,461,042, 5,478,566, 5,506,223, 5,518,725, 5,527,788, 5,527,789, 5,532,230, 5,559,107, 5,562,910, 5,583,126, 5,585,371, 5,587,369, 5,591,736, 5,593,981, 5,610,150, 5,635,496, 5,641,766, 5,641,768, 5,656,621, 5,660,835, 5,686,438, 5,696,106, 5,700,793, 5,707,983, 5,709,878, 5,710,143, 5,714,481, 5,728,688, 5,736,537, 5,744,462, 5,753,237, 5,756,482, 5,776,921, 5,776,923, 5,780,460, 5,795,880, 5,798,347, 5,798,348, 5,804,576, 5,807,848, 5,807,849, 5,811,418, 5,824,313, 5,824,668, 5,824,671, 5,827,841, 5,837,269, 5,837,700, 5,843,932, 5,846,963, 5,859,000, 5,872,114 and 5,872,147; German patent numbers 2035738 and 2705917; PCT publication numbers WO 95/21617, WO 97/48367, WO 98/05338, WO 98/50040, WO 98/50041, WO 98/58650; European publication number 0020029; E. R. Glazier, J. Org. Chem. 1962 27:2937-2938, Ben-David, et al., Proc. Soc. Expt. Biol. Med. 1967 125:1136-1140, Coleman et al., Diabetes 1982 31:830, Oertel, et al., J. Steroid Biochem. 1972 3:493-496, Pashko, et al., Carcinogenesis 1981 2:717-721, Schwartz et al., Nutr. Cancer 1981 3:46-53; Dyner et al., J. Acquired Immune Deficiency Syndromes 1993 6:459-465; A. A. Afanasii and Y. A. Titov, Total Steroid Synthesis, Plenum Press, New York, 1970, see, e.g., p 1-304. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
Patents 149
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CpG-like nucleic acids and methods of use thereof Inventor(s): Schetter, Christian; (Hilden, DE), Vollmer, Jorg; (Duesseldorf, DE) Correspondence: Wolf Greenfield & Sacks, PC; Federal Reserve Plaza; 600 Atlantic Avenue; Boston; MA; 02210-2211; US Patent Application Number: 20030181406 Date filed: May 6, 2002 Abstract: Immunostimulatory compositions described as CpG-like nucleic acids are provided, including nucleic acids having immunostimulatory characteristics of CpG nucleic acid, despite certain substitutions of C, G, or C and G of the CpG dinucleotide. The substitutions can include, among others, exchange of methylated C for C, inosine for G, and ZpY for CpG, where Z is cytosine or dSpacer and Y is inosine, 2-aminopurine, nebularine, or dSpacer. Also provided are methods for inducing an immune response in a subject using the CpG-like nucleic acids. The methods are useful in the treatment of a subject that has or is at risk of developing an infectious disease, allergy, asthma, cancer, anemia, thrombocytopenia, or neutropenia. Excerpt(s): The application claims priority to U.S. provisional patent application No. 60/254,341 filed on Dec. 8, 2000. The present invention relates generally to immunostimulatory nucleic acids, compositions thereof, and methods of using the immunostimulatory nucleic acids. Bacterial DNA, but not vertebrate DNA, has strong immunostimulatory effects for a wide variety of human and murine immune cells. Krieg A M et al. (1995) Nature 374:546-9; Hartmann G et al. (1999) Proc Natl Acad Sci USA 96:9305-10; Hartmann G et al. (2000) J Immunol 164:1617-24; Bauer M et al. (1999) Immunology 97:699-705; Ballas Z K et al. (1996) J Immunol 157:1840-5. Unmethylated CpG dinucleotides are less frequent in eukaryotic DNA than in bacterial DNA. Krieg A M et al. (1995) Nature 374:546-9. It has been reported that unmethylated CpG dinucleotides within the context of specific flanking bases (referred to as CpG motifs) have a wide variety of effects on human immune cells such as B cells, natural killer (NK) cells, T cells, macrophages, monocytes and dendritic cells. Parronchi P et al. (1999) J Immunol 163:5946-53; Krieg A M (1999) Biochim Biophys Acta 1489:107-16; Krieg A M et al. (1995) Nature 374:546-9; Kranzer K et al. (2000) Immunology 99:170-8; Hartmann G et al. (1999) Proc Natl Acad Sci USA 96:9305-10. Methylated CpG dinucleotides, in contrast, have been reported to be nonstimulatory. Parronchi P et al. (1999) J Immunol 163:5946-53; Hartmann G et al. (1999) Proc Natl Acad Sci USA 96:9305-10; Hartmann G et al. (2000) J Immunol 164:944-53; Hartmann G et al. (2000) J Immunol 164:1617-24. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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DETECTION OF PATIENTS AT RISK FOR DEVELOPING ANTAGONIST/ AGONIST MEDIATED DISEASE STATES
INTEGRIN
Inventor(s): BILLHEIMER, JEFFREY T.; (WEST CHESTER, PA), BRETH, LEAH A.; (NEWARK, DE), BURN, TIMOTHY; (HOCKESSIN, DE), DICKER, IRA B.; (WILMINGTON, DE), GEORGE, HENRY J.; (NEWARK, DE), HOLLIS, GREGORY F.; (WILMINGTON, DE), HOLLIS, JEANNINE M.; (WILMINGTON, DE), KOCHIE, JENNIFER E.; (HOCKESSIN, DE), O'NEIL, KARYN T.; (KENNETT SQUARE, PA), SEIFFERT, DIETMAR A.; (BOOTHWYN, PA) Correspondence: The Dupont Pharmaceuticals CO; E I DU Pont DE Nemours And CO; Legal Patents; 1007 Market Street; Wilmington; DE; 19898 Patent Application Number: 20020081624 Date filed: January 26, 1999 Abstract: This invention relates to the detection of patients at risk for developing integrin antagonist/agonist mediated disease states. This invention relates to assays useful for the detection in a patient bodily fluid sample of drug-dependent antibodies which bind to integrins, or intergrin-associated proteins or complexes thereof in the presence of an integrin antagonist/agonist. This invention also relates to assays useful for the detection in a patient bodily fluid sample of drug-dependent antibodies (DDABS) that bind to integrins, including the platelet glycoprotein IIb/IIIa (GPIIb/IIIa), in the presence of a integrin agonist and/or antagonist. This invention also relates to procedures for identifying integrin antagonists/agonists that are less prone to elicit integrin antagonist/agonist mediated disease states.This invention also relates to procedures which increase the recovery of integrin-directed antibodies in body fluids, resulting in an increased sensitivity and specificity of DDAB detection assays. This invention also relates to procedures for treating blood samples, which dissociate antibodies to GPIIb/IIIa from the platelet surface, thereby increasing the recovery from the platelet supernatant. This invention also relates to the use of different GPIIb/IIIa preparations to identify patients at risk for early-onset thrombocytopenia upon treatment with GPIIb/IIIa antagonist/agonists, thereby increasing the specificity of antibody detection.This invention also relates to the use of DDABs as a positive control and calibration standard for DDAB assays.Such methods, procedures and assays are useful for identifying patients who may be at risk to develop disease states mediated by treatment with integrin antagonists/agonists. Excerpt(s): This invention also relates to procedures which increase the recovery of integrin-directed antibodies in body fluids, resulting in an increased sensitivity and specificity of DDAB detection assays. This invention also relates to procedures for treating blood samples, which dissociate antibodies to GPIIb/IIIa from the platelet surface, thereby increasing the recovery from the platelet supernatant. This invention also relates to the use of different GPIIb/IIIa preparations to identify patients at risk for early-onset thrombocytopenia upon treatment with GPIIb/IIIa antagonist/agonists, thereby increasing the specificity of antibody detection. This invention also relates to the use of DDABs as a positive control and calibration standard for DDAB assays. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
Patents 151
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Diagnostic assay for type 2 heparin-induced thrombocytopenia Inventor(s): Abdelouahed, Mustapha; (Worcester, MA), Lawler, John W.; (Swampscott, MA) Correspondence: Hamilton, Brook, Smith & Reynolds, P.C.; 530 Virginia Road; P.O. Box 9133; Concord; MA; 01742-9133; US Patent Application Number: 20020197697 Date filed: February 27, 2002 Abstract: Methods for detecting the presence of antibodies to PF4/heparin/TSP-1 complexes in a biological sample and for diagnosing Type 2 heparin-induced thrombocytopenia are described. Excerpt(s): This application is a continuation of International Application No. PCT/US00/23707, which designates the United States and was filed on Aug. 29, 2000, published in English, which claims the benefit of U.S. Provisional Application No. 60/151,314 filed Aug. 30, 1999. The entire teachings of each of these applications are incorporated herein by reference. Heparin is the injectable anticoagulant of choice for surgical patients requiring either vascular surgery or therapeutic intervention for cardiovascular disease, as well as for the post-surgical management of an immobile (e.g., orthopedic) patient. For example, it is administered to almost all patients during cardiac catheterization, angioplasty, cardiopulmonary bypass and the treatment of unstable angina and myocardial infarction (Bauer, T. L., et al., Circulation, 95: 1242-1246 (1997)). However, the therapeutic use of heparin is associated with some serious side effects including the development of heparin-induced thrombocytopenia (Chong, B. H., et al., Blut, 58:53-57 (1989)). Two types of heparin-induced thrombocytopenia with distinct etiologies are recognized. Type 1 is characterized by a relatively mild thrombocytopenia of early onset, that is, within the first few days of heparin therapy. It usually resolves without cessation of heparin (Jackson, M. R., et al., Surgery 121:419-424 (1997)). This type of thrombocytopenia is thought to be caused by an intrinsic proaggregatory effect of heparin (Chong, B. H., et al., Eur. J. Haematol., 43:245-251 (1989)). Clinical complications of type 1 thrombocytopenia are uncommon. Type 2 heparin-induced thrombocytopenia (referred to herein as HIT), is a drug-induced, immunoglobulinmediated thrombocytopenic disorder that is often associated with severe venous or arterial thrombosis attributed to the formation of platelet thrombi (Cines, D. B., et al., N. Engl J Med, 31:581 (1987); Celoria, G. M., et al., Angiology, 39:915 (1988)). HIT generally occurs 5-8 days following the first exposure to heparin. Platelet counts often drop to less than 100.times.10.sup.9/1 and in rare cases to 20.times.10.sup.9/1. The incidence of HIT is variable, with rates of occurrences as high as 24-30% reported in some of the earlier studies (Nelson, J. D., et al., Arch. Intern. Med., 138:548-552 (1978); Bell, W. R., et al., Ann. Intern. Med., 85:155-160 (1976)) and with lower values (5-10%) in the more recent studies (Almeida, J. I., et al., J. Vasc. Surg., 27:309-316 (1998); Griffiths, E., and Dzik, W. H., Trans. Med., 7:1-11 (1997); Aster, R. H., N. Eng. J. Med., 332:1374-1376 (1995)). Overall, about 5% of patients receiving heparin develop HIT and about 5-80% of those develop thrombosis, which can involve the arterial, the venous, or both systems (Gupta, A. K., et al., An. Pharmacol., 32:55-59 (1998); Warkentin, T. E., et al., Am. J. Med., 101:502-507 (1996); Chong, B. H., et a., Br. J. Haematol, 89:431-439 (1995)). Patients may develop cerebrovascular complications, myocardial infarction, limb ischemia, or deep venous thrombosis. The thrombotic complications are fatal in about 29% of patients, and an additional 21% have limb amputations (King, D. J., et al., Ann. Intern. Med., 100:535540 (1984)).
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Diketopiperazine derivatives to inhibit thrombin Inventor(s): Cheng, Yudu; (US), Manwell, Jeffrey; (Ohawa, CA) Correspondence: Ogilvy Renault; 1981 Mcgill College Avenue; Suite 1600; Montreal; QC; H3a2y3; CA Patent Application Number: 20030100562 Date filed: August 28, 2002 Abstract: The present invention relates to compounds to inhibit blood coagulation, and more particularly to novel diketopiperazine derivatives, pharmaceutically acceptable salts and compositions thereof, to specifically inhibit thrombin. The compound has the following general structure (I), wherein R.sup.1, R.sup.2 and R.sup.4 consist of a hydrogen, alkyl or aryl moiety, R.sup.3 consist of an alkyl or aryl moiety, wherein R.sup.5 consists of a hydrogen, alkyl, aryl, hydroaryl, heteroaryl, hydroheteroaryl, sulfonylalkyl, sulfonylaryl, sulfonylhydroaryl, sulfonylheteroaryl or sulfonylhydroheteroaryl moiety, and wherein R.sup.6 consists of a hydrogen, alkyl, aryl, hydroaryl, heteroaryl or hydroheteroaryl moiety. Also disclosed are methods of using the compound for treating coagulation disorders such as thrombosis and heparin associated thrombocytopenia. Excerpt(s): The present invention relates to compounds to inhibit blood coagulation, and more particularly to diketopiperazine derivatives, pharmaceutically acceptable salts and compositions thereof, to specifically inhibit thrombin. Thrombotic disorders are characterized by the formation of a thrombus obstructing the vascular blood flow, causing arterial or venous thrombosis or thromboembolism. Thrombi are composed of fibrin, platelets, white blood cells (WBCs) and red blood cells (RBCs). Thrombus formation involves several genetic and environmental factors. Genetically impaired anticoagulant mechanisms include factor V resistance to activated protein C, hyperhomocysteinemia, protein C deficiency, protein S deficiency, antithrombin deficiency and defective fibrinolysis, while thrombotic stimuli include surgery, pregnancy, oral contraceptive use and antiphospholipid antibodies. Chronic and acute thrombotic complications, including venous and arterial thrombosis, atrial fibrillation, stroke, myocardial infarction and pulmonary embolism are the leading cause of deaths worldwide. Antithrombotic therapy involves thrombolytic drug therapy, to remove thrombi, and the use of antiplatelet drugs and anticoagulants, to inhibit coagulation. Subsequent therapy varies depending on the venous or arterial circulatory system involved and the size and location of the vessels. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
Patents 153
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Immunostimulatory nucleic acids for the treatment of anemia, thrombocytopenia, and neutropenia Inventor(s): Bratzler, Robert L.; (Concord, MA), Petersen, Deanna M.; (Newton, MA), Schetter, Christian; (Hilden, DE) Correspondence: Wolf Greenfield & Sacks, PC; Federal Reserve Plaza; 600 Atlantic Avenue; Boston; MA; 02210-2211; US Patent Application Number: 20020165178 Date filed: June 28, 2001 Abstract: The invention involves administration of an immunostimulatory nucleic acid alone or in combination with an anemia, thrombocytopenia, or neutropenia medicament for the treatment or prevention of anemia, thrombocytopenia, and neutropenia in subjects. The agents in combination are administered in synergistic amounts or in various dosages or at various time schedules. The invention also relates to kits and compositions concerning the combination of immunostimulatory nucleic acids and anemia, thrombocytopenia, or neutropenia drugs. Excerpt(s): This application claims benefit of U.S. Provisional Application No. 60/214,368, filed Jun. 28, 2000. The present invention relates to immunostimulatory nucleic acids, compositions thereof and methods of using the immunostimulatory nucleic acids in the treatment of anemia, thrombocytopenia, and neutropenia. Hematopoiesis, the formation of blood cells, represents a complex physiologic phenomenon whereby blood cells of various lineages arise from common progenitor cells called hematopoietic stem cells. Hematopoietic development is regulated by colony-stimulating factors (CSFs), which promote colony formation and proliferation of cells of various lineages, and by potentiators, which potentiate maturation or differentiation. Many of the factors involved in hematopoiesis affect more than a single lineage. For example, erythropoietin (EPO) stimulates both erythrocyte and platelet production. Similarly, some factors can be classified both as CSF and as potentiator. For example, thrombopoietin (TPO) was reported to possess both megakaryocyte-CSF (Meg-CSF) and megakaryocyte potentiator (Meg-Pot) activity in the development of megakaryocytes in vivo. In addition, many factors are involved in the development of any given cell lineage. Thus Meg-CSFs reportedly include interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and stem cell factor, and Meg-Pots reportedly include IL-6, IL-7, IL-11, erythropoietin (EPO) and leukemia inhibitory factor (LIF). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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INHIBITION OF THROMBIN-INDUCED CREATINE KINASE INHIBITORS
PLATELET
AGGREGATION
BY
Inventor(s): Cunningham, Dennis D.; (Irvine, CA), Mahajan, Vinit; (Rancho Palos Verdes, CA), Pai, Sadashiva; (Irvine, CA) Correspondence: Christie, Parker & Hale, Llp; 350 West Colorado Boulevard; Suite 500; Pasadena; CA; 91105; US Patent Application Number: 20020111316 Date filed: September 21, 2001
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Abstract: Methods of using creatine compounds such as creatine kinase inhibitors, and more particularly, cyclocreatine and homocyclocreatine, to inhibit thrombin-induced cytoskeletal reorganization, platelet aggregation, inflammatory processes, endothelial cell contraction and related cardiovascular and CNS disorders are described.Pharmaceutically effective amounts of creatine compounds are administered to subjects in need thereof to thereby prevent and/or treat diseases and/or pathological conditions such as thrombosis, thrombocytopenia, atherosclerosis, coronary artery disease, unstable angina pectoris, myocardial infarction, stroke, coagulopathies, and transient ischemia attacks. Excerpt(s): This application claims the benefit of U.S. Provisional Application, Ser. No. 60/234,875, filed Sep. 21, 2000, the contents of which are hereby incorporated by reference in their entirety. The present invention relates to a new method of use for creatine compounds such as creatine kinase inhibitors and, more particularly, cyclocreatine, to block intracellular signals of the thrombin receptor Protease Activated Receptor-1, to thereby inhibit thrombin-induced cytoskeletal reorganization, platelet aggregation and endothelial cell contraction. Platelets are discoid cells found in large numbers in blood, which are important for blood coagulation and hemostasis. Upon activation by various stimuli like thrombin, thromboxane A.sub.2 and ADP, platelets change into a spheroid shape with filopodia, degranulate and aggregate. Platelet activation is important for hemostasis and underlies various pathological conditions such as unstable angina pectoris, myocardial infarction, stroke, and coagulopathies. One of the physiological agents that activate platelets is thrombin, a serine protease. Thrombin mediates its action through the activation of protease activated receptors (PARs). Cytoskeletal rearrangement and shape changes precede platelet aggregation following thrombin receptor activation. Thrombin mediates vascular permeability, morphological changes in neurons and astrocytes through activation of PAR-1. Two thrombin receptors, high affinity PAR-1 and low affinity PAR-4, have been identified on human platelets. Low concentrations (1 nM) of thrombin activates PAR-1 in human platelets, while complete activation of platelets require higher amounts (>10 nM) of thrombin and activation of PAR-4. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method and compositions for inhibiting thrombin-induced coagulation Inventor(s): Davis, Stacey; (College Station, TX), Hook, Magnus A.O.; (Houston, TX) Correspondence: Larson & Taylor, Plc; 1199 North Fairfax Street; Suite 900; Alexandria; VA; 22314; US Patent Application Number: 20030044418 Date filed: May 13, 2002 Abstract: A method of achieving safe and effective treatment or prevention of potentially harmful blood clots, or in inhibiting the coagulation of blood when so desired such as during a wide array of disease conditions including stroke, myocardial infarction, sickle-cell crisis and venous thrombosis, is provided by the administration of a fibrinogen-binding protein capable of binding at the N-terminal B.beta. chain of fibrinogen, such as SdrG or Fbe, or their respective binding regions such as the A domain. In addition, compositions comprising effective amounts of the fibrinogenbinding proteins are also provided. The present anti-coagulation compositions have been shown to inhibit thrombin-induced fibrin clot formation by interfering with the release of fibrinopeptide B and the resulting anti-coagulation effects can be achieved
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without potential for causing or exacerbating unwanted side effects such as thrombocytopenia associated with prior art anticoagulants such as heparin. Excerpt(s): This application claims the benefit of U.S. Provisional Patent Application No. 60/290,072, filed May 11, 2001. The present invention relates in general to SdrG, a fibrinogen-binding bacterial adhesin, and in particular to the use of SdrG or its binding region as an anti-coagulation agent by virtue of its ability to inhibit thrombin-induced fibrin clot formation by interfering with the release of fibrinopeptide B. In addition, the invention relates to methods and compositions utilizing SdrG or its binding region for treating or preventing thrombin-induced coagulation and conditions associated therewith. Coagulase-negative staphylococci (CNS) are important opportunistic pathogens that are particularly associated with foreign body infections in humans. Staphylococcus epidermidis is the most common pathogenic species of CNS and accounts for 74-92% of the infections caused by this group of staphylococci (1). The molecular pathogenesis of most infections is complex and involves multiple microbial factors and host components, but is generally initiated by the adherence of the microbe to host tissues. Bacterial adherence involves specific surface components called adhesins, and bacterial pathogens, such as staphylococci that live in the extracellular space of the host, target extracellular matrix (ECM) components, including fibrinogen (Fg) and fibronectin, for adherence and colonization. This process is mediated by a subfamily of adhesins that have been termed MSCRAMM.RTM.s (microbial surface components recognizing adhesive matrix molecules) (2). Staphylococcus aureus expresses multiple MSCRAMM.RTM.s of which several have been characterized in some detail (For a recent review see Ref. 3), and various MSCRAMM.RTM.s have been the subject of U.S. Patents, including fibronectin binding proteins such as disclosed in U.S. Pat. Nos. 5,175,096; 5,320,951; 5,416,021; 5,440,014; 5,571,514; 5,652,217; 5,707,702; 5,789,549; 5,840,846; 5,980,908; and 6,086,895; fibrinogen binding proteins such as disclosed in U.S. Pat. Nos. 6,008,341 and 6,177,084; and collagen binding proteins as disclosed in 5,851,794 and 6,288,214; all of these patents incorporated herein by reference. In addition, other information concerning SdrG and other MSCRAMM.RTM.s can be found in U.S. Ser. No. 09/810,428, filed Mar. 19, 2001, incorporated herein by reference; and U.S. Ser. No. 09/386,962, filed Aug. 31, 1999, incorporated herein by reference. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method of treating heparin-induced thrombocytopenia Inventor(s): Fisher, Charles Jack; (Carmel, IN), Yan, Sau-Chi Betty; (Indianapolis, IN) Correspondence: Brian P. Barrett; Eli Lilly And Company; Lilly Corporate Center; Patent Division Dc: 1104; Indianapolis; IN; 46285; US Patent Application Number: 20010018050 Date filed: May 11, 2001 Abstract: The present invention provides a method of treatment of heparin-induced thrombocytopenia (HIT) with protein C. The claimed invention provides a needed therapy for a potentially serious and debilitating disorder while avoiding complications such as bleeding tendency, toxicity and general side effects of currently available anticoagulant agents. Excerpt(s): This application claims priority of Provisional Application Ser. No. 60/108,432 filed Nov. 13, 1998. This invention relates to medical science particularly the
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treatment of heparin-induced thrombocytopenia with protein C. Protein C is a vitamin K dependent serine protease and naturally occurring anticoagulant that plays a role in the regulation of hemostasis by inactivating Factors Va and VIIIa in the coagulation cascade. Human protein C circulates as a 2-chain zymogen, but functions at the endothelial and platelet surface following conversion to activated protein C (aPC) by limited proteolysis with thrombin in complex with the cell surface membrane protein, thrombomodulin. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Oligonucleotide compositions and their use to induce differentiation of cells Inventor(s): Filion, Mario C.; (Laval, CA), Phillips, Nigel C.; (Pointe-Clarie, CA) Correspondence: John S. Pratt, Esq; Kilpatrick Stockton, Llp; 1100 Peachtree Street; Suite 2800; Atlanta; GA; 30309; US Patent Application Number: 20030045493 Date filed: April 22, 2002 Abstract: The present invention provides compositions comprising a 3'-OH, 5'-OH, chemically unmodified, synthetic phosphodiester nucleotide sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, and a pharmaceutically acceptable carrier, wherein the compositions are useful to induce differentiation of cells or to stimulate differentiation or production of pluripotent cells. The present invention provides methods of using these compositions to induce differentiation of pluripotent cells, including bone marrow derived cells, and to treat disease associated with insufficient differentiation of cells in animals and humans, including but not limited to leukemia, lymphoma, non-malignant blood disorders such as hemoglobinopathies, sickle cell disease, myelodysplastic syndrome, pancytopenia, anemia, thrombocytopenia and leukopenia. Excerpt(s): The present application claims priority to U.S. provisional patent application serial No. 60/286,158 filed Apr. 24, 2001. The present invention provides compositions comprising specific oligonucleotides combined with a pharmaceutically acceptable carrier, wherein the compositions are useful to induce differentiation of cells, including pluripotent cells, leukemic cells, lymphoma cells and bone marrow-derived cells, and to treat diseases such as leukemia, lymphoma and disorders associated with insufficient differentiation of cells. Numerous diseases and conditions in animals and humans are associated with insufficient differentiation of cells or with an insufficiency of cells. Many of these cells are derived from bone marrow. Such diseases and conditions include but are not limited to leukemia, lymphoma, and non-malignant blood disorders such as hemoglobinopathies, sickle cell disease, myelodysplastic syndrome and insufficient production of bone marrow derived cells following therapies such as radiation and chemotherapy. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Peptides and compounds that bind to a receptor Inventor(s): Barrett, Ronald W.; (Saratoga, CA), Cwirla, Steven E.; (Menlo Park, CA), Dower, William J.; (Menlo Park, CA), Duffin, David J.; (East Palo Alto, CA), Gates, Christian M.; (Santa Cruz, CA), Haselden, Sherril S.; (Santa Cruz, CA), Mattheakis, Larry C.; (Cupertino, CA), Schatz, Peter J.; (Mountain View, CA), Wagstrom, Christopher R.; (Los Altos, CA), Wrighton, Nicholas C.; (Palo Alto, CA) Correspondence: David J Levy, Corporate Intellectual Property; Glaxosmithkline; Five Moore DR.; PO Box 13398; Durham; NC; 27709-3398; US Patent Application Number: 20030158116 Date filed: February 27, 2002 Abstract: Described are peptides and peptide mimetics that bind to and activate the thrombopoietin receptor. Such peptides and peptide mimetics are useful in methods for treating hematological disorders and particularly, thrombocytopenia resulting from chemotherapy, radiation therapy, or bone marrow transfusions as well as in diagnostic methods employing labeled peptides and peptide mimetics. Excerpt(s): This application is a continuation of U.S. patent application Ser. No. 09/549,090, filed Apr. 13, 2000, which is a continuation of U.S. application Ser. No. 08/973,225, now U.S. Pat. No. 6,083,913, filed Dec. 4, 1997 pursuant to 35 U.S.C. 371 as a United States National Phase Application of International Application No. PCT/US96/09623, filed Jun. 7, 1996, which claims priority from U.S. patent application Ser. No. 08/485,301, filed Jun. 7, 1995, and U.S. patent application Ser. No. 08/478,128, filed Jun. 7, 1995. The present invention provides peptides and compounds that bind to and activate the thrombopoietin receptor (c-mpl or TPO-R) or otherwise act as a TPO agonist. The invention has application in the fields of biochemistry and medicinal chemistry and particularly provides TPO agonists for use in the treatment of human disease. Megakaryocytes are bone marrow-derived cells, which are responsible for producing circulating blood platelets. Although comprising <0.25% of the bone marrow cells in most species, they have >10 times the volume of typical marrow cells. See Kuter et. al. Proc. Natl. Acad. Sci. USA 91:11104-11108 (1994). Megakaryocytes undergo a process known as endomitosis whereby they replicate their nuclei but fail to undergo cell division and thereby give rise to polyploid cells. In response to a decreased platelet count, the endomitotic rate increases, higher ploidy megakaryocytes are formed, and the number of megakaryocytes may increase up to 3-fold. See Harker J. Clin. Invest. 47:458465 (1968). In contrast, in response to an elevated platelet count, the endomitotic rate decreases, lower ploidy megakaryocytes are formed, and the number of megakaryocytes may decrease by 50%. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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PROPYLENE GLYCOL AS AN AGENT TO STIMUATE THROMBOPOIESIS Inventor(s): Asch , Adam; ( Mount Kisco, New York), Schiff , Nicholas; ( New York, New York) Correspondence: Darby & Darby; P.C.; 805 Third Avenue; New York; New York; 10022; US Patent Application Number: 20030036567 Date filed: July 31, 2002
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Abstract: Propylene glycol can be administered therapeutically to effectively reverse thrombocytopenia and increase platelet cell counts, particularly in patients suffering from medical conditions such as HIV/AIDS or undergoing chemotherapy. Excerpt(s): This application claims priority under 35 U.S.C.sctn.119(e) of provisional application Serial No. 60/309,701, filed August 2, 2001, which is incorporated herein by reference in its entirety. This invention relates to therapies employing propylene glycol, and especially those which include the treatment of thrombocytopenia in immunodeficient and chemotherapy patients. Platelet Disorders. Hematopoietic differentiation into the myeloid pathway follows three branches, erythroid, megakaryocytic and phagocytic. Platelets, which play a critical role in blood coagulation, wound healing and the storage and release of cytokines, are produced by megakaryocytosis. A portion of the platelets are sequestered in the spleen; the remaining platelets circulate in the bloodstream, and under normal conditions are replenished as needed by the megakaryocyte, a process regulated by thrombopoietin (TPO). TPO binds to platelets; when platelet numbers are reduced, the increased level of free TPO signals megakaryocyte and platelet production. Thrombocytopenia, depletion of the circulating level of platelets to less than 100,00/mL, is caused by one of three mechanisms: decreased bone marrow production, increased splenic sequestration, and accelerated platelet destruction. Radiation therapy, cytotoxic chemotherapeutic agents, surgery, accidental blood loss, and other specific disease conditions depress megakaryocyte production and may cause thrombocytopenia. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
PTTG knockout rodent as a model to study mechanisms for various physiological phenomena, including diabetes Inventor(s): Melmed, Shlomo; (Los Angeles, CA), Wang, Zhiyong; (Los Angeles, CA) Correspondence: Edward G. Poplawski, ESQ.; Sidley Austin Brown & Wood; 555 West Fifth Street; Los Angeles; CA; 90013-1010; US Patent Application Number: 20030106080 Date filed: October 15, 2001 Abstract: Disclosed is a null mutant (or knockout) rodent comprising in its germ cells an artificially induced PTTG null mutation. In some embodiments, the null mutant rodent can be generated by way of homologous recombination in an embryonic stem cell or germ cell. The inventive null mutant rodent can be used to study mammalian physiology at the cellular, tissue, and/or organismal level with respect to various phenotypes, including hyperglycemia, hypoinsulinaemia, hypoleptinemia, diabetes, chromosomal aneuploidy, premature centromere division, chromosomal damage, aberrant mitotic cellular division, thrombocytopenia, thymic hyperplasia, splenic hypoplasia, testicular hypoplasia, and female subfertility. Also disclosed is an animal model for diabetes. Also disclosed is a somatic or germ cell obtained from the null mutant rodent. Also disclosed is a cell line derived from a cell obtained from the null mutant rodent. Excerpt(s): Throughout the application, various publications are referenced in parentheses. The disclosures of these publications in their entireties are hereby incorporated by reference in the application in order to more fully describe the state of the art to which this invention pertains. The present invention is related to the biomedical arts, in particular to genetics. The particular gene that is the subject of the
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present invention is PTTG, which is believed to have a role in proper cell cycle progression. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Thrombopoietin mimetics Inventor(s): Duffy, Kevin J; (Norristown, PA), Luengo, Juan I; (Audubon, PA), Price, Alan T; (Phoenixville, PA), Zhang, Lihua; (Collegeville, PA) Correspondence: Smithkline Beecham Corporation; Corporate Intellectual Property-us, Uw2220; P. O. Box 1539; King OF Prussia; PA; 19406-0939; US Patent Application Number: 20030083361 Date filed: September 12, 2002 Abstract: Invented are non-peptide TPO mimetics. Also invented is a method of treating thrombocytopenia, in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a selected substituted naphthimidazole derivative. Excerpt(s): This invention relates to thrombopoietin (TPO) mimetics and their use as promoters of thrombopoiesis and megakaryocytopoiesis. Megakaryocytes are bone marrow-derived cells, which are responsible for producing circulating blood platelets. Although comprising <0.25% of the bone marrow cells in most species, they have >10 times the volume of typical marrow cells. See Kuter et al. Proc. Natl. Acad. Aci. USA 91: 11104-11108 (1994). Megakaryocytes undergo a process known as endomitosis whereby they replicate their nuclei but fail to undergo cell division and thereby give rise to polypoid cells. In response to a decreased platelet count, the endomitotic rate increases, higher ploidy megakaryocytes are formed, and the number of megakaryocytes may increase up to 3-fold. See Harker J. Clin. Invest. 47: 458-465 (1968). In contrast, in response to an elevated platelet count, the endomitotic rate decreases, lower ploidy megakaryocytes are formed, and the number of megakaryocytes may decrease by 50%. The exact physiological feedback mechanism by which the mass of circulating platelets regulates the endomitotic rate and number of bone marrow megakaryocytes is not known. The circulating thrombopoietic factor involved in mediating this feedback loop is now thought to be thrombopoietin (TPO). More specifically, TPO has been shown to be the main humoral. regulator in situations involving thrombocytopenia. See, e.g., Metcalf Nature 369:519-520 (1994). TPO has been shown in several studies to increase platelet counts, increase platelet size, and increase isotope incorporation into platelets of recipient animals. Specifically, TPO is thought to affect megakaryocytopoiesis in several ways: (1) it produces increases in megakaryocyte size and number; (2) it produces an increase in DNA content, in the form of polyploidy, in megakaryocytes; (3) it increases megakaryocyte endomitosis; (4) it produces increased maturation of megakaryocytes; and (5) it produces an increase in the percentage of precursor cells, in the form of small acetylcholinesterase-positive cells, in the bone marrow. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Thrombopoietin receptor modulating peptide Inventor(s): Naranda, Tatjana; (Mountain View, CA), Olsson, Lennart; (Mountain View, CA) Correspondence: S Peter Ludwig; Darby & Darby; Post Office Box 5257; New York; NY; 10150-5257; US Patent Application Number: 20030181659 Date filed: March 3, 2003 Abstract: The present invention relates to novel diagnostic and pharmaceutical compositions enabling the treatment of thrombocytopenia. Excerpt(s): The present invention relates to an oligopeptide with the biological activity of a thrombopoietin (TPO) receptor modulating compound, nucleotide sequences encoding the oligopeptide, vectors comprising the nucleotide sequences, host cells comprising the vectors, antibodies reactive with the oligopeptides, pharmaceutical and diagnostic compositions comprising the oligopeptides, nucleotide sequences, antibodies and/or host cells as well as to methods for genetically modifying a cell, methods for modulating the activity of a TPO receptor (TPO-R) and methods to screen for further TPO receptor modulating compounds. Thrombocytopenia is a widespread, serious and life-threatening disease, occurring both as a primary hematological and as an induced disorder. Patients suffering from severe thrombocytopenia are at a serious risk of spontaneous haemorrhage. Induced thrombocytopenia may be caused by e.g. bone marrow transfusions, cancer chemotherapy, irradiation or allergic reactions. About 50 percent of all new cancer patients diagnosed undergo some form of chemotherapy and receive platelet transfusions. Thrombocytopenia affects at least 25 percent of all patients undergoing chemotherapy. Because repeated cycles of dose-intensive chemotherapy deplete blood platelets which prevent bleeding and aid in the repair of damaged blood vessels, cancer treatments very often must be interrupted to allow platelet counts to recover. The failure of the platelet count to recover causes delay and/or limits use of subsequent cycles of chemotherapy, diminishing the chances of successful treatment. Treatment of thrombocytopenia is primarily carried out by transfusion of fresh platelet preparations, which are very expensive and not as readily available as a drug, that by injection or oral administration, could increase the number of platelets to the normal level. Each year in the US alone approximately 8 million units of platelets are transfused into patients to reduce the risk of severe bleeding. At least 30 percent of the transfusions result in complications, usually febrile reactions, but occasionally bacteremia, graftversus-host disease, or acute pulmonary injury. In 15 to 25 percent of patients who require repeated platelet transfusions, incremental platelet responses are inadequate as a result of HLA alloimmunization. In addition, platelet transfusions are expensive. In particular, chemotherapy-induced thrombocytopenia is currently managed by platelet transfusion and/or reducing or delaying chemotherapy until the platelet count increases. Transfusions, however, may place patients at a risk for blood-borne infections such as hepatitis B and hepatitis C, HIV infections and human T-lymphotropic virus, or for immune reactions such as fever. Reducing chemotherapy doses and delaying or stopping treatment can theoretically allow cancerous cells to grow or spread. Thus, there is an urgent need for designing effective drugs for the treatment of thrombocytopenia, which, however, requires detailed understanding of its molecular and biochemical causes. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Keeping Current In order to stay informed about patents and patent applications dealing with thrombocytopenia, 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 “thrombocytopenia” (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 thrombocytopenia. You can also use this procedure to view pending patent applications concerning thrombocytopenia. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.
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CHAPTER 7. BOOKS ON THROMBOCYTOPENIA Overview This chapter provides bibliographic book references relating to thrombocytopenia. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on thrombocytopenia 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 “thrombocytopenia” (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 thrombocytopenia: •
Oral Manifestations of AIDS Source: Torrance, CA: Homestead Schools, Inc. 2000. [37 p.]. Contact: Available from Homestead Schools, Inc. 23844 Hawthorne Boulevard, Suite 200, Torrance, CA 90505. (310) 791-9975. Fax (310) 791-0135. E-mail:
[email protected]. Website: www.homesteadschools.com. PRICE: $36.00 plus shipping and handling. Course No. 6215. Summary: Knowledge of HIV infection has become a critically important requirement for professionals responsible for oral health care delivery. This continuing education program for dentists focuses on the oral manifestations of AIDS. Topics covered include the nature of HIV infection, including demographics, pathogenesis, transmission, progression, survival and treatment strategies; the oral manifestations of HIV infection, including the role of clinicians and dental professionals, transmission risks, saliva, other
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transmissible diseases, differential diagnosis, and patient approach; fungal infections, including candidiasis, histoplasmosis, and other oral fungal infections; viral infections, including herpes family viruses, Epstein-Barr virus (EBV) and oral hairy leukoplakia, varicella virus reactivation, cytomegalovirus (CMV), human papillomavirus (HPV) and condyloma acuminatum, molluscum contagiosum (MC), and hepatitis viruses; bacterial infections, including necrotizing ulcerative gingivitis and periodontitis, non-oral-flora opportunists, and tuberculosis (TB); HIV associated malignancies, including Kaposi's sarcoma (KS), non-Hodgkin's lymphoma, and squamous carcinoma; and other HIVassociated lesions, including recurrent aphthous-like stomatitis, hypersensitivity and lichenoid reaction, sialadenitis (inflamed salivary glands) and xerostomia (dry mouth), thrombocytopenia, and ulcerative stomatitis and unclassified lesions. The program includes a posttest with which readers can qualify for continuing education credit. •
Atlas of Diseases of the Oral Cavity in HIV Infection Source: Copenhagen, Denmark: Munksgaard. 1995. 152 p. Contact: Available from Munksgaard. 35 Norre Sogade, P.O. Box 2148, DK-1016, Copenhagen K, Denmark. Telephone +45 33 12 70 30; Fax +45 33 12 93 87; E-mail:
[email protected]; http://www.munksgaard.dk/publishers/. PRICE: DKK 400,000 plus postage; contact directly for current price in US dollars. ISBN: 8716115090. Summary: This atlas of oral diseases in HIV infection depicts and describes the oral manifestations of HIV in three sections. The authors stress that oral manifestations are often the key to an initial clinical diagnosis of HIV infection. The introductory material discusses epidemiology, the global aspects of HIV seropositivity, predictions for the future, and the classification of oral lesions associated with HIV infection. The first section covers lesions strongly associated with HIV infection including candidiasis, hyperplasia, angular cheilitis, hairy leukoplakia, periodontal diseases, linear gingival erythema, necrotizing gingivitis, stomatitis and periodontitis, Kaposi's sarcoma, and non-Hodgkin's lymphoma. The second section covers lesions less commonly associated with HIV infection including tuberculosis, hyperpigmentation, pigmentation of the nails, enlargement of major salivary glands, lymphoepithelial lesion, thrombocytopenia, atypical ulceration, herpes labialis, herpetic stomatitis, herpes zoster, varicella, condyloma acuminatum, focal epithelial hyperplasis, and verruca vulgaris. The third section outlines lesions seen in HIV infection, notably Klebsiella pneumonia infection, bacillar epithelioid angiomatosis, toxic epidermal necrolysis, drug-induced ulcerations, cryptococcoses, mucormycosis, penicilliosis, facial nerve paralysis, aphthous ulceration, cytomegalovirus-induced oral ulceration, and molluscum contagiosum. A final section describes other lesions, including exfoliative cheilitis, impetigo contagiosa, secondary syphilis, lichenoid lesions of buccal mucosa, and oral cancer. The atlas depicts each manifestation with a full-color photograph and provides brief descriptions. The book concludes with a list of references, coding according to the international classification of diseases, and a subject index. 111 figures. 193 references.
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Cancers and Blood Disorders of AIDS Source: AIDS: Facts and Issues. Contact: Rutgers University Press, 109 Church St, New Brunswick, NJ, 08901, (908) 9327365. Summary: This chapter points out that the attack of the AIDS virus on the immune system lowers the barriers not only to many opportunistic infections, but also to various
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rare and aggressive cancers and to several blood disorders. Many of these are listed, including Kaposis sarcoma, lymphomas, solid tumors, pancytopenia, and immune thrombocytopenia purpura.
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 “thrombocytopenia” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “thrombocytopenia” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “thrombocytopenia” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
Heparin Induced Thrombocytopenia by Theodore E. Werkentin, Andreas Greinacher (2003); ISBN: 0824756258; http://www.amazon.com/exec/obidos/ASIN/0824756258/icongroupinterna
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Heparin-Induced Thrombocytopenia by Theodore E. Warkentin (Editor), Andreas Greinacher (Editor); ISBN: 0824706587; http://www.amazon.com/exec/obidos/ASIN/0824706587/icongroupinterna
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Protein A columns for immune thrombocytopenia (SuDoc HE 20.6512/7:990/7) by Harry Handelsman; ISBN: B00010C51G; http://www.amazon.com/exec/obidos/ASIN/B00010C51G/icongroupinterna
The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select “Search LOCATORplus.” Once you are in the search area, simply type “thrombocytopenia” (or synonyms) into the search box, and select “books only.” From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine:11 •
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Alloimmune disorders of pregnancy: anaemia, thrombocytopenia, and neutropenia in the fetus and newborn Author: Hadley, Andrew G. (Andrew Gordon),; Year: 1976; Cambridge; New York: Cambridge University Press, 2002; ISBN: 0521781205 http://www.amazon.com/exec/obidos/ASIN/0521781205/icongroupinterna
In addition to LOCATORPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a "Books" button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.
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Clinical and immunological studies in thrombocytopenia Author: Veenhoven, Willem Adriaan.; Year: 1993; Groningen: Drukkerij D. Niemeyer, 1979
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Heparin-induced thrombocytopenia Author: Warkentin, Theodore E.,; Year: 1979; New York: Dekker, c2000; ISBN: 0824702719 http://www.amazon.com/exec/obidos/ASIN/0824702719/icongroupinterna
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Platelet kinetics in normal subjects and in haematological disorders; with special reference to thrombocytopenia and to the role of the spleen. Author: Kotilainen, Martti.; Year: 2000; Copenhagen, Munksgaard, 1969
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Platelet metabolism and membrane function: biochemical studies on hereditary thrombopathic thrombocytopenia. Author: Baadenhuijsen, Hendrik.; Year: 1999; Meppel: Krips Repro NV, 1971
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Technology report: anticoagulant options in heparin-induced thrombocytopenia. Author: Adarmes, Carolyn.; Year: 1974; Oak Brook, Ill.: UHC, c1998
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Thrombocytopenia following local radiotherapy. Author: Mossberg, Harry,; Year: 1998; Stockholm, 1947
Chapters on Thrombocytopenia In order to find chapters that specifically relate to thrombocytopenia, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and thrombocytopenia 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 “thrombocytopenia” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on thrombocytopenia: •
Bleeding Disorders Source: in Little, J.W., et al. Dental Management of the Medically Compromised Patient. 5th ed. St. Louis, MO: Mosby, Inc. 1997. p. 466-494. Contact: Available from Harcourt Health Sciences. 11830 Westline Industrial Drive, St. Louis, MO 63146. (800) 325-4177. Fax (800) 874-6418. Website: www.harcourthealth.com. PRICE: $48.00 plus shipping and handling. ISBN: 0815156340. Summary: A working knowledge of the multitude of compromised health states is essential for dental professionals, as the majority of medically compromised patients need or want oral health care. This chapter on bleeding disorders is from a text that provides the dental practitioner with an up to date reference work describing the dental management of patients with selected medical problems. In this chapter, the authors provide dentists with an understanding of the mechanisms involved in the normal control of bleeding, describe the common causes of bleeding problems, present an approach for indentifying patients with possible bleeding disorders, and describe in general terms the management of these patients once they have been identified. The authors discuss incidence and prevalence, etiology, pathophysiology and complications, classification, signs and symptoms (clinical presentation and laboratory findings), the medical management of patients with various bleeding diseases, and the dental management of this population. Topics covered in the last section include aspirin therapy, Coumarin therapy, possible liver disease, chronic leukemia, malabsorption
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syndrome, long term antibiotic therapy, end stage renal disease (ESRD), hemodialysis, vascular wall alteration, and management of the patient with a serious bleeding disorder (e.g., hemophilia or thrombocytopenia). 9 figures. 23 tables. 50 references. •
Escherichia Coli O157:H7 Gastroenteritis and the Hemolytic Uremic Syndrome: An Emerging Infectious Disease Source: in Coggins, C.H., ed. Annual Review of Medicine: Selected Topics in the Clinical Sciences, Volume 50. Palo Alto, CA: Annual Reviews. 1999. p. 355-367. Contact: Available from Annual Reviews. 4139 El Camino Way, P.O. Box 10139, Palo Alto, CA 94303-0139. (650) 493-4400. E-mail:
[email protected]. Website: www.AnnualReviews.org. PRICE: $60.00 plus shipping and handling. ISBN: 0824305507. Summary: Escherichia coli O157:H7 is an increasingly common cause of a variety of illnesses, including blood diarrhea and the hemolytic uremic syndrome (HUS). This emerging infectious agent was first identified in 1982 and has been isolated with increasing frequency since then. This article reviews the epidemiology, clinical spectrum, diagnosis, treatment, and prevention of infections with E. coli O157:H7. Infection with E. coli O157:H7 can be entirely asymptomatic or can present with a wide variety of clinical findings, including watery diarrhea, bloody diarrhea, HUS, thrombotic thrombocytopenic purpura (TTP), and death. The illness usually resolves after 1 week with no obvious sequelae; however, 5 to 10 percent of children with E. coli O157:H7 infection will develop HUS. HUS consists of the triad of microangiopathic hemolytic anemia, thrombocytopenia, and oliguric renal failure. Antimicrobial agents have no proven value in the treatment of E. coli O157:H7 infections. Antimotility agents should not be given to patients with bloody diarrhea or suspected E. coli O157:H7 infection, as these drugs may increase the risk of HUS in these patients. Treatment of HUS is supportive, with particular attention to the management of fluids and electrolytes. With meticulous care, the mortality rate for HUS is approximately 4 percent. 1 figure. 62 references. (AA-M).
•
Immunologically Mediated Disease Source: in Scully, C. and Cawson, R.A. Medical Problems in Dentistry. 4th ed. Woburn, MA: Butterworth-Heinemann. 1998. p. 438-453. Contact: Available from Butterworth-Heinemann. 225 Wildwood Avenue, Woburn, MA 01801-2041. (800) 366-2665 or (781) 904-2500. Fax (800) 446-6520 or (781) 933-6333. E-mail:
[email protected]. Website: www.bh.com. PRICE: $110.00. ISBN: 0723610568. Summary: Immunologically mediated diseases may be allergic, autoimmune, immune complex-mediated or due to a type IV hypersensitivity or other reaction. This chapter on immunologically mediated disease is from a text that covers the general medical and surgical conditions relevant to the oral health care sciences. Topics include atopic disease, food intolerance, acute allergic angioedema, oral allergy syndrome, non-allergic immunologically mediated disease, hereditary angioedema, autoimmune disease, connective tissue diseases, Raynaud's disease, systemic lupus erythematosus (SLE), discoid lupus erythematosus, antiphospholipid syndrome, systemic sclerosis (scleroderma), autoimmune thrombocytopenia, Behcet's syndrome, Sweet's syndrome, polyarteritis nodosa, midline granuloma syndrome, and Wegener's granulomatosis. For each condition, the authors discuss general aspects, diagnosis and management issues, dental aspects, and patient care strategies. The chapter includes a summary of the points covered. 3 figures. 10 tables. 29 references.
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Haematology Source: in Maddison, P.J.; et al., Eds. Oxford Textbook of Rheumatology. Volume 1. New York, NY: Oxford University Press, Inc. 1993. p. 367-375. Contact: Available from Oxford University Press, Inc., New York, NY. Summary: This chapter for health professionals focuses on the interpretation of hematological data as it relates to rheumatic disease. Problems with techniques of examining blood cells are examined. Anemias in rheumatoid arthritis and other autoimmune diseases are described. Thrombocytosis and thrombocytopenia in rheumatoid arthritis and platelet abnormalities in systemic lupus are discussed. White blood cell abnormalities in rheumatic disease are identified, including Flety's syndrome, leucopenia, and leucocytosis. Coagulation abnormalities in systemic lupus are described, including lupus anticoagulant. The impact of acute phase reactants on the erythrocyte sedimentation rate (ESR) is examined. Causes of a high ESR are identified. Primary blood disorders are discussed, including coagulation disorders, hematological malignancies, hemoglobinopathies, hemochromatosis, and disorders presenting as gout. 22 references, 1 figure, and 7 tables.
•
Oral Manifestations: Classification Source: in Greenspan, D., et al. AIDS and the Mouth. Copenhagen, Denmark: Munksgaard. 1992. p. 85-90. Contact: Available from Munksgaard. 35 Norre Sogade, P.O. Box 2148, DK-1016, Copenhagen K, Denmark. Telephone +45 33 12 70 30; Fax +45 33 12 93 87; E-mail:
[email protected]; http://www.munksgaard.dk/publishers/. PRICE: DKK 516 plus postage; contact directly for current price in US dollars. ISBN: 8716103211. Summary: This chapter on the classification of oral manifestations of HIV infection is from a medical textbook on the diagnosis and management of oral lesions related to AIDS. The authors define and classify fungal infections including candidiasis, histoplasmosis, cryptococcoses, and geotrichosis; bacterial infections including necrotizing gingivitis and progressive periodontitis, mycobacterium avium intracellular, actinomycosis, cat-scratch disease, Klebsiella pneumoniae infection, Enterobacter cloacae, Escherichia coli, exacerbation of apical periodontitis, sinusitis, and submandibular cellulitis; viral infections including herpetic stomatitis, cytomegalovirus, Epstein-Barr virus, varicella zoster virus, and papillomavirus lesions; neoplasms including Kaposi's sarcoma, non-Hodgkin's lymphoma, and squamous cell carcinoma; neurologic disturbances including trigeminal neuropathy and facial palsy; and oral manifestations of unknown cause, including recurrent aphthous ulceration (RAU), progressive necrotizing ulceration, toxic epidermolysis (Lyell's syndrome), delayed wound healing, idiopathic thrombocytopenia, salivary gland enlargement, xerostomia, and oral mucosal hyperpigmentation. The authors note that this classification system is designed to be used in epidemiologic studies. 2 tables. 6 references.
•
Oral Manifestations of Systemic Diseases Source: in Eisen, D. and Lynch, D.P. Mouth: Diagnosis and Treatment. St. Louis, MO: Mosby, Inc. 1998. p. 212-236. Contact: Available from Harcourt Health Sciences. Book Order Fulfillment Department, 11830 Westline Industrial Drive, St. Louis, MO 63146-9988. Website: www.mosby.com. PRICE: $79.95 plus shipping and handling. ISBN: 0815131054.
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Summary: This chapter on the oral manifestations of systemic diseases is from a textbook on the mouth that offers information to primary care physicians and to many specialists in medicine and dentistry. The chapter covers six areas: gastrointestinal diseases, cutaneous diseases, hematologic (blood) diseases, nutritional disorders, connective tissue disorders, and multisystem diseases. Specific conditions discussed include Crohn's disease, ulcerative colitis and pyostomatitis vegetans, hepatitis and other liver disease, psoriasis, pityriasis rosea, acanthosis nigricans, iron deficiency anemia, pernicious anemia, thalassemias, hemolytic disease of the newborn, polycythemia vera, thrombocytopenia, neutropenia, leukemia, multiple myeloma, Langerhans cell histiocytosis, riboflavin (vitamin B12) deficiency, niacin deficiency, folic acid deficiency, pyridoxine deficiency, vitamin C deficiency, vitamin K deficiency, zinc deficiency, Sjogren's syndrome, Melkersson Rosenthal syndrome, Wegener's granulomatosis, lethal midline granuloma, and amyloidosis. For each condition, the authors describe symptoms, identification, complications, and treatment. The chapter is illustrated with numerous full color photographs of the conditions under discussion. 29 figures. 2 tables. 84 references. •
Oral Manifestations of Unknown Etiology Source: in Greenspan, D., et al. AIDS and the Mouth. Copenhagen, Denmark: Munksgaard. 1992. p. 148-155. Contact: Available from Munksgaard. 35 Norre Sogade, P.O. Box 2148, DK-1016, Copenhagen K, Denmark. Telephone +45 33 12 70 30; Fax +45 33 12 93 87; E-mail:
[email protected]; http://www.munksgaard.dk/publishers/. PRICE: DKK 516 plus postage; contact directly for current price in US dollars. ISBN: 8716103211. Summary: This chapter, from a medical textbook on the diagnosis and management of oral lesions related to AIDS, discusses oral manifestations of unknown etiology that are associated with AIDS. Oral manifestations discussed include recurrent aphthous ulceration (RAU), progressive necrotizing ulceration, toxic epidermolysis (Lyell's syndrome), delayed wound healing, idiopathic thrombocytopenia, salivary gland enlargement, xerostomia, and oral mucosal hyperpigmentation. Full-color photographs illustrate most of the manifestations described. 9 figures. 19 references.
•
Oral Mucosal Hemorrhage Source: in Bork, K., et al. Diseases of the Oral Mucosa and the Lips. Orlando, FL: W.B. Saunders Company. 1993. p. 84-87. Contact: Available from W.B. Saunders Company. Order Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887-4430. (800) 545-2522 (individuals) or (800) 782-4479 (schools); Fax (800) 874-6418 or (407) 352-3445; http://www.wbsaunders.com. PRICE: $99.00 plus shipping and handling. ISBN: 0721640397. Summary: This chapter, from a textbook on diseases of the oral mucosa and the lips, discusses oral mucosal hemorrhage. There are many causes of mucosal hemorrhage, including drug eruptions, bullous diseases, viral exanthems, hemopoietic disorders, and trauma. The most common site of oral bleeding is the gingiva. The chapter covers the clinical features; histopathology; and diagnosis of post-traumatic hematoma, thrombocytopenia, clotting abnormalities, hemorrhage due to vessel damage, and purpura with gammopathies. Full-color photographs illustrate the chapter; each section provides references. 6 figures. 11 references. (AA-M).
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Disorders of the Blood Source: in Grundy, M.C.; Shaw, L.; and Hamilton, D.V. Illustrated Guide to Dental Care for the Medically Compromised Patient. St. Louis, MO: Mosby-Year Book, Inc. 1993. p. 27-36. Contact: Available from Mosby-Year Book, Inc. 11830 Westline Industrial Drive, St. Louis, MO 63146-9934. (800) 426-4545 or (314) 872-8370; Fax (800) 535-9935 or (314) 4321380; E-mail:
[email protected]; http://www.mosby.com. PRICE: $24.95 plus shipping and handling. ISBN: 0815140223. Summary: This chapter, from an illustrated guide to dental care for medically compromised patients, discusses disorders of the blood. Topics covered include hemophilia; Christmas disease (hemophilia B); Von Willebrand's disease (vascular hemophilia); thrombocytopenia; anemia, including sickle cell anemia and thalassemia; and leukemia. For each condition, the authors provide a brief description, the components of medical management, and suggestions for dental care. Illustrations, including photographs, are included. 7 figures.
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CHAPTER 8. MULTIMEDIA ON THROMBOCYTOPENIA Overview In this chapter, we show you how to keep current on multimedia sources of information on thrombocytopenia. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine.
Bibliography: Multimedia on Thrombocytopenia The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the multimedia database, go to the following Web site: http://locatorplus.gov/. Select “Search LOCATORplus.” Once in the search area, simply type in thrombocytopenia (or synonyms). Then, in the option box provided below the search box, select “Audiovisuals and Computer Files.” From there, you can choose to sort results by publication date, author, or relevance. The following multimedia has been indexed on thrombocytopenia: •
Heparin associated thrombocytopenia [videorecording] Source: [presented by] Marshfield Clinic and St. Joseph's Hospital; Year: 1982; Format: Videorecording; Marshfield, WI: Marshfield Regional Video Network, 1982
•
Management of neonatal immune thrombocytopenia [videorecording] Source: [presented by] the Medical University of South Carolina, Departments of Pathology and Laboratory Medicine and Pediatrics; produced by the Health Communications Network, Division of Televis; Year: 1994; Format: Videorecording; Charleston, S.C.: The University, c1994
•
Thrombocytopenia in pregnancy [videorecording] Source: [presented by] the Emory Medical Television Network, Emory University, School of Medicine of the Robert Woodruff Health Sciences Center; Year: 1992; Format: Videorecording; Atlanta, Ga.: The University, c1992
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CHAPTER 9. PERIODICALS THROMBOCYTOPENIA
AND
NEWS
ON
Overview In this chapter, we suggest a number of news sources and present various periodicals that cover thrombocytopenia.
News Services and Press Releases One of the simplest ways of tracking press releases on thrombocytopenia 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 “thrombocytopenia” (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 thrombocytopenia. 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 “thrombocytopenia” (or synonyms). The following was recently listed in this archive for thrombocytopenia: •
Argatroban curbs heparin-induced thrombocytopenia Source: Reuters Industry Breifing Date: August 28, 2003
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•
Delayed-onset heparin-induced thrombocytopenia increasingly common Source: Reuters Medical News Date: February 06, 2002
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Delayed-onset thrombocytopenia described with heparin use Source: Reuters Industry Breifing Date: October 08, 2001
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Heparin-induced thrombocytopenia can occur rapidly after prior heparin use Source: Reuters Medical News Date: April 26, 2001
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Receptron begins phase I trial of thrombocytopenia treatment Source: Reuters Industry Breifing Date: April 02, 2001
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H. pylori eradication may improve platelet count in thrombocytopenia Source: Reuters Medical News Date: February 08, 2001
•
Thrombocytopenia common in psychiatric patients taking valproate Source: Reuters Industry Breifing Date: January 23, 2001 The NIH
Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “thrombocytopenia” (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.
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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 “thrombocytopenia” (or synonyms). If you know the name of a company that is relevant to thrombocytopenia, 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 “thrombocytopenia” (or synonyms).
Newsletter Articles Use the Combined Health Information Database, and limit your search criteria to “newsletter articles.” Again, you will need to use the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter Article.” Type “thrombocytopenia” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months. The following is a typical result when searching for newsletter articles on thrombocytopenia: •
How Systemic Lupus Erythematosus Affects the Blood Source: Lupus Letter. 1(2):3; 1996. Contact: Available from Lupus Foundation of america, National Office, 4 Research Place, Suite 180, Rockville, MD 20850-3226. (301) 670-9292. (800) 558-0121. Summary: This newsletter article for lupus patients uses a question and answer format to explain how systemic lupus erythematosus (SLE) affects the blood. Types of blood cells and their functions are identified. Common blood cell conditions that occur in individuals with SLE are highlighted, including anemia, thrombocytopenia, and leukopenia. In addition, the causes of these conditions are presented.
Academic Periodicals covering Thrombocytopenia Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to thrombocytopenia. In addition to these sources, you can search for articles covering thrombocytopenia 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 10. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.
U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for thrombocytopenia. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a non-profit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI Advice for the Patient can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP).
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Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.
Mosby’s Drug Consult Mosby’s Drug Consult database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/.
PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee.
Researching Orphan Drugs Although the list of orphan drugs is revised on a daily basis, you can quickly research orphan drugs that might be applicable to thrombocytopenia 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 “thrombocytopenia” (or synonyms) into the search box, and click “Submit Query.” When you receive your results, note that not all of the drugs may be relevant, as some may have been withdrawn from orphan status. Write down or print out the name of each drug and the relevant contact information. From there, visit the Pharmacopeia Web site and type the name of each orphan drug into the search box at http://www.nlm.nih.gov/medlineplus/druginformation.html. You may need to contact the sponsor or NORD for further information. NORD conducts “early access programs for investigational new drugs (IND) under the Food and Drug Administration’s (FDA’s) approval ‘Treatment INDs’ programs which allow for a limited number of individuals to receive investigational drugs before FDA marketing approval.” If the orphan product about which you are seeking information is approved for
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marketing, information on side effects can be found on the product’s label. If the product is not approved, you may need to contact the sponsor. The following is a list of orphan drugs currently listed in the NORD Orphan Drug Designation Database for thrombocytopenia: •
Ancrod (trade name: Arvin) http://www.rarediseases.org/nord/search/nodd_full?code=559
•
Recombinant human interleukin-11 (trade name: Neumega rhIL-11 Growth Factor) http://www.rarediseases.org/nord/search/nodd_full?code=829
•
Lepirudin (trade name: Refludan) http://www.rarediseases.org/nord/search/nodd_full?code=818
•
Purified Extract of Pseudomonas Aeruginosa (trade name: ImmuDyn) http://www.rarediseases.org/nord/search/nodd_full?code=847
•
Pegylated Recombinant Human Megakarocyte Growth & (trade name: MEGAGEN) http://www.rarediseases.org/nord/search/nodd_full?code=853
•
Oprelvekin (trade name: Neumega) http://www.rarediseases.org/nord/search/nodd_full?code=889
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 Institute12: •
Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm
•
National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/
•
National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
•
National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25
•
National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm
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National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
•
National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
•
National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/
12
These publications are typically written by one or more of the various NIH Institutes.
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•
National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm
•
National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/
•
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm
•
National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm
•
National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/
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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
•
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
•
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.13 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:14 •
Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html
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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
13 Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 14 See http://www.nlm.nih.gov/databases/databases.html.
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•
Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html
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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 Gateway15 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.16 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “thrombocytopenia” (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 35327 78 990 332 0 36727
HSTAT17 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.18 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.19 Simply search by “thrombocytopenia” (or synonyms) at the following Web site: http://text.nlm.nih.gov.
15
Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.
16
The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 17 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 18 19
The HSTAT URL is http://hstat.nlm.nih.gov/.
Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.
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Coffee Break: Tutorials for Biologists20 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.21 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.22 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.
Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •
CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.
•
Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
The Genome Project and Thrombocytopenia In the following section, we will discuss databases and references which relate to the Genome Project and thrombocytopenia. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).23 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. 20 Adapted 21
from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.
The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 22 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process. 23 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.
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To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “thrombocytopenia” (or synonyms) into the search box, and click “Submit Search.” If too many results appear, you can narrow the search by adding the word “clinical.” Each report will have additional links to related research and databases. In particular, the option “Database Links” will search across technical databases that offer an abundance of information. The following is an example of the results you can obtain from the OMIM for thrombocytopenia: •
Amegakaryocytic Thrombocytopenia, Congenital Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?604498
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Dyserythropoietic Anemia with Thrombocytopenia Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?300367
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Giant Platelet Syndrome with Thrombocytopenia Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?137560
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Hemangioma-thrombocytopenia Syndrome Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?141000
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Osteochondrodysplasia, Rhizomelic, with Callosal Agenesis, Thrombocytopenia, Hydrocephalus, and Hypertension Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?166990
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Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?605432
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Thrombasthenia-thrombocytopenia, Hereditary Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?187900
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Thrombocytopenia 1 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?313900
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Thrombocytopenia 2 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?188000
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Thrombocytopenia with Elevated Serum Iga and Renal Disease Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?314000
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Thrombocytopenia, Autosomal Recessive Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?273900
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Thrombocytopenia, Congenital Dysmegakaryopoietic, Paris-trousseau Type Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600588
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Thrombocytopenia, Cyclic Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?188020
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Thrombocytopenia, Paris-trousseau Type Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?188025
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Thrombocytopenia, Platelet Dysfunction, Hemolysis, and Imbalanced Globin Synthesis Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?314050
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Thrombocytopenia--absent Radius Syndrome Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?274000
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Genes and Disease (NCBI - Map) The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. This Web site categorizes each disorder by system of the body. Go to http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to revisit it from time to time. The following systems and associated disorders are addressed: •
Cancer: Uncontrolled cell division. Examples: Breast and ovarian cancer, Burkitt lymphoma, chronic myeloid leukemia, colon cancer, lung cancer, malignant melanoma, multiple endocrine neoplasia, neurofibromatosis, p53 tumor suppressor, pancreatic cancer, prostate cancer, Ras oncogene, RB: retinoblastoma, von Hippel-Lindau syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Cancer.html
•
Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn’s disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html
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Metabolism: Food and energy. Examples: Adreno-leukodystrophy, atherosclerosis, Best disease, Gaucher disease, glucose galactose malabsorption, gyrate atrophy, juvenile-onset diabetes, obesity, paroxysmal nocturnal hemoglobinuria, phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html
•
Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan syndrome, myotonic dystrophy, spinal muscular atrophy. Web site: http://www.ncbi.nlm.nih.gov/disease/Muscle.html
•
Nervous System: Mind and body. Examples: Alzheimer disease, amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, fragile X syndrome, Friedreich’s ataxia, Huntington disease, Niemann-Pick disease, Parkinson disease, Prader-Willi syndrome, Rett syndrome, spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html
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Signals: Cellular messages. Examples: Ataxia telangiectasia, Cockayne syndrome, glaucoma, male-patterned baldness, SRY: sex determination, tuberous sclerosis, Waardenburg syndrome, Werner syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Signals.html
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Transporters: Pumps and channels. Examples: Cystic fibrosis, deafness, diastrophic dysplasia, Hemophilia A, long-QT syndrome, Menkes syndrome, Pendred syndrome, polycystic kidney disease, sickle cell anemia, Wilson’s disease, Zellweger syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Transporters.html
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Entrez Entrez is a search and retrieval system that integrates several linked databases at the National Center for Biotechnology Information (NCBI). These databases include nucleotide sequences, protein sequences, macromolecular structures, whole genomes, and MEDLINE through PubMed. Entrez provides access to the following databases: •
3D Domains: Domains from Entrez Structure, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo
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Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books
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Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome
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NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/
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Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide
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OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
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PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset
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ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo
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Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein
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PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed
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Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure
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Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy
To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=genome, and then select the database that you would like to search. The databases available are listed in the drop box next to “Search.” Enter “thrombocytopenia” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database24 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually 24 Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html.
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limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html. The Genome Database25 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “thrombocytopenia” (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms).
25
Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.
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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on thrombocytopenia can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internetbased 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 thrombocytopenia. 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 thrombocytopenia. 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 “thrombocytopenia”:
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•
Other guides Anemia http://www.nlm.nih.gov/medlineplus/anemia.html Bleeding Disorders http://www.nlm.nih.gov/medlineplus/bleedingdisorders.html Head and Brain Injuries http://www.nlm.nih.gov/medlineplus/headandbraininjuries.html Hemophilia http://www.nlm.nih.gov/medlineplus/hemophilia.html
Within the health topic page dedicated to thrombocytopenia, the following was listed: •
General/Overviews What Is a Bleeding Disorder? Source: National Hemophilia Foundation http://www.hemophilia.org/bdi/bdi_general.htm
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Diagnosis/Symptoms Platelet Count Source: American Association for Clinical Chemistry http://www.labtestsonline.org/understanding/analytes/platelet/test.html Understanding Your Complete Blood Count Source: National Institutes of Health, Clinical Center http://www.cc.nih.gov/ccc/patient_education/pepubs/cbc97.pdf
•
Coping Information for Teachers and Childcare Providers Source: National Hemophilia Foundation http://www.hemophilia.org/bdi/bdi_providers.htm Tips for Travellers Source: World Federation of Hemophilia http://www.wfh.org/ShowDoc.asp?Rubrique=26&Document=53&IndLangue=2
•
Specific Conditions/Aspects Bleeding Disorders: Financial and Insurance Issues Source: National Hemophilia Foundation http://www.hemophilia.org/bdi/bdi_issues.htm Factor V Leiden http://circ.ahajournals.org/cgi/reprint/107/15/e94.pdf Hereditary Bleeding Disorders Source: National Center for Infectious Diseases http://www.cdc.gov/ncidod/dastlr/hematology/hemophilia.htm
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Hypercoagulation: Excessive Blood Clotting Source: American Academy of Family Physicians http://familydoctor.org/244.xml Immune Thrombocytopenic Purpura Source: National Institute of Diabetes and Digestive and Kidney Diseases http://www.niddk.nih.gov/health/hematol/pubs/itp/itp.htm Platelets and Cardiovascular Disease http://circ.ahajournals.org/cgi/reprint/108/13/e88.pdf von Willebrand Disease Source: National Hemophilia Foundation http://www.hemophilia.org/bdi/bdi_types3.htm •
Children Blood Source: Nemours Foundation http://kidshealth.org/parent/general/body_basics/blood.html
•
From the National Institutes of Health What Is Idiopathic Thrombocytopenic Purpura? Source: National Heart, Lung, and Blood Institute http://dci.nhlbi.nih.gov/Diseases/Itp/ITP_WhatIs.html What Is von Willebrand Disease? Source: National Heart, Lung, and Blood Institute http://dci.nhlbi.nih.gov/Diseases/vWD/vWD_WhatIs.html
•
Men Bleeding and Clotting Disorders in Women Source: National Center for Infectious Diseases http://www.cdc.gov/ncidod/dastlr/hematology/women.htm Bleeding Disorders Source: National Women's Health Information Center http://www.4woman.gov/faq/bleed.htm Bleeding Disorders in Women: Questions and Answers for Newly Diagnosed Women Source: National Center for Infectious Diseases http://www.cdc.gov/ncidod/dastlr/Hematology/women_facts.htm
•
Organizations Hematologic Diseases Branch Source: Centers for Disease Control and Prevention http://www.cdc.gov/ncidod/dastlr/Hematology/ National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/
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•
Research Major Initiative to Boost Research on Protein Technologies: NHLBI Launches Innovative Proteomics Centers Source: National Heart, Lung, and Blood Institute http://www.nih.gov/news/pr/oct2002/nhlbi-09.htm New Way to Reverse Excessive Blood Thinning from Warfarin Source: American College of Physicians http://www.annals.org/cgi/content/full/137/11/I-41 Treatment of Refractory Thrombotic Thrombocytopenic Purpura Source: American College of Physicians http://www.annals.org/cgi/content/full/138/2/I-38 Vitamin K Reverses Overanticoagulation with Warfarin More Quickly When Given by Mouth Than by Injection Source: American College of Physicians http://www.annals.org/cgi/content/full/137/4/I-39
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Women Bleeding and Clotting Disorders in Women Source: National Center for Infectious Diseases http://www.cdc.gov/ncidod/dastlr/hematology/women.htm Bleeding Disorders Source: National Women's Health Information Center http://www.4woman.gov/faq/bleed.htm Bleeding Disorders in Women: Questions and Answers for Newly Diagnosed Women Source: National Center for Infectious Diseases http://www.cdc.gov/ncidod/dastlr/Hematology/women_facts.htm
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 thrombocytopenia. 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:
Patient Resources
•
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Guidelines for Women With HIV/AIDS Contact: Project Inform, HIV Treatment Hotline, 205 13th St Ste 2001, San Francisco, CA, 94103, (415) 558-8669, http://www.projectinform.org. Summary: This fact sheet addresses social, psychological, sexual, and physical issues concerning HIV that are specific to women. One section outlines ways of handling relationships and discussing HIV status with family, friends, partners/lovers, and children. Psychological topics covered include support groups and stress management. Methods of safer sex discussed include latex condoms, female condoms, and dental dams. Information is provided on the following opportunistic infections and HIVrelated problems that particularly affect women: idiopathic thrombocytopenia (ITP), menstrual abnormalities, cervical cancer, pelvic inflammatory disease, and vaginal infections. The sheet also examines recent perinatal transmission research, making difficult decisions in pregnancy, and what to do if a child is HIV positive. It includes a list of hotlines, newsletters, organizations, and special programs.
•
Blood Disorders in SLE Source: Rockville, MD: Lupus Foundation of America, Inc. 1997. 6 p. Contact: Available from Lupus Foundation of America, Inc. 1300 Piccard Drive, Suite 200, Rockville, MD 20850-4303. (800) 558-0121 or (301) 670-9292. Website: www.lupus.org/lupus. PRICE: Available as part of a package of 21 different lupusrelated brochures for $3.95 plus shipping and handling. Summary: This pamphlet for people with lupus describes the major hematological abnormalities of systemic lupus erythematosus (SLE). The most common hematological abnormality in SLE is anemia, which is a reduction in the number of red blood cells. Anemia in a person with SLE may be caused by chronic inflammation, prolonged uremia, iron deficiency, or hemolytic anemia. Another hematologic abnormality is thrombocytopenia, which is a deficiency of platelets leading to excessive bruising of the skin or bleeding from the gums, nose, or intestines. The most common cause of thrombocytopenia in a person with lupus is immune thrombocytopenia. Other hematologic problems include clotting disturbances, granulocytopenia, and lymphocytopenia. The pamphlet also discusses blood transfusions in terms of testing donor blood for antibodies against the virus that causes acquired immune deficiency syndrome, storing one's blood for later transfusion, and designating a specific blood donor. It also provides information on the Lupus Foundation of America.
•
Escherichia Coli O157:H7 Infection Source: American Family Physician. 56(3): 859-861. September 1, 1997. Contact: Available from American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237. Website: www.aafp.org. Summary: This three page fact sheet reviews basic information about Escherichia coli O157:H7 infection and how to prevent it. E. coli is the name of a strain of bacteria that causes severe gastroenteritis (cramps and diarrhea). E. coli is one of the leading causes of bloody diarrhea. The symptoms are worse in children and older people, and especially in people who have another illness. Written in a question and answer format, the fact sheet covers how E. coli infection is transmitted, the symptoms of E. coli infection, complications arising from E. coli infection, diagnostic strategies for establishing E. coli infection, treatment options, and ways to prevent infection with E. coli. The most common way to get this infection is by eating rare (undercooked)
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hamburgers. The germ can also be passed from person to person in day care centers and nursing homes. The most common complication of E. coli infection is hemolytic uremic syndrome (HUS), which consists of hemolytic anemia (low red blood cell count), thrombocytopenia (low platelet count), and renal (kidney) failure. A stool culture is required to confirm E. coli infection. There is no special treatment for E. coli infection, except hydration (drinking a lot of water) and watching for complications. The fact sheet lists rules to follow to prevent contracting foodborne infections such as E. coli. These rules cover handwashing techniques, cooking meat thoroughly, defrosting meats safely, and handling leftovers properly. The fact sheet is also available online. The National Guideline Clearinghouse™ The National Guideline Clearinghouse™ offers hundreds of evidence-based clinical practice guidelines published in the United States and other countries. You can search this site located at http://www.guideline.gov/ by using the keyword “thrombocytopenia” (or synonyms). The following was recently posted: •
Thrombocytopenia Source: Finnish Medical Society Duodecim - Professional Association; 2001 April 30; Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=3393&nbr=2619&a mp;string=thrombocytopenia 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 thrombocytopenia. 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
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Family Village: http://www.familyvillage.wisc.edu/specific.htm
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Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
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Med Help International: http://www.medhelp.org/HealthTopics/A.html
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Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
Patient Resources
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Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/
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WebMDHealth: http://my.webmd.com/health_topics
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Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to thrombocytopenia. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with thrombocytopenia. 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 thrombocytopenia. 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 “thrombocytopenia” (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 “thrombocytopenia”. 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 “thrombocytopenia” (or synonyms) into the
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“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 “thrombocytopenia” (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.26
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
26
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)27: •
Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/
•
Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)
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Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm
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California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html
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California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html
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California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html
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California: Gateway Health Library (Sutter Gould Medical Foundation)
•
California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/
•
California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp
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California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html
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California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/
•
California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/
•
California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/
•
California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html
•
California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/
•
Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/
•
Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/
•
Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/
27
Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.
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•
Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml
•
Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm
•
Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html
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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/
•
Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm
•
Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html
•
Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/
•
Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm
•
Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/
•
Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/
•
Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/
•
Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm
•
Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html
•
Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm
•
Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/
•
Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/
•
Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10
•
Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/
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•
Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html
•
Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp
•
Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp
•
Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/
•
Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html
•
Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm
•
Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp
•
Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/
•
Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html
•
Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/
•
Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm
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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
•
Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330
•
Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)
•
National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html
•
National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/
•
National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/
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•
Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm
•
New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/
•
New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm
•
New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm
•
New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/
•
New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html
•
New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/
•
New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html
•
New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/
•
Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm
•
Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp
•
Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/
•
Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/
•
Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml
•
Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html
•
Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html
•
Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml
•
Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp
•
Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm
•
Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/
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•
South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp
•
Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/
•
Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/
•
Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72
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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •
ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html
•
MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp
•
Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/
•
Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html
•
On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/
•
Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp
•
Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm
Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on thrombocytopenia: •
Basic Guidelines for Thrombocytopenia ITP Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000535.htm Thrombocytopenia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000586.htm
•
Signs & Symptoms for Thrombocytopenia Bleeding disorders Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001304.htm Blood in the stools Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003130.htm Bruising Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003235.htm
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GI bleeding Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003133.htm Nosebleeds Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003106.htm Pinpoint red spots Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003235.htm Rash Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003220.htm Vomiting blood Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003118.htm •
Diagnostics and Tests for Thrombocytopenia Biopsy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003416.htm Bone marrow aspiration Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003658.htm CBC Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003642.htm Platelet aggregation test Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003669.htm Platelet associated antibodies Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003552.htm Platelet count Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003647.htm Platelets Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003647.htm PT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003652.htm PTT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003653.htm
•
Background Topics for Thrombocytopenia Bleeding Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000045.htm
Online Glossaries 209
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
211
THROMBOCYTOPENIA DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 2-Aminopurine: A purine that is an isomer of adenine (6-aminopurine). [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Abscess: A localized, circumscribed collection of pus. [NIH] Acanthosis Nigricans: A circumscribed melanosis consisting of a brown-pigmented, velvety verrucosity or fine papillomatosis appearing in the axillae and other body folds. It occurs in association with endocrine disorders, underlying malignancy, administration of certain drugs, or as in inherited disorder. [NIH] Accelerated phase: Refers to chronic myelogenous leukemia that is progressing. The number of immature, abnormal white blood cells in the bone marrow and blood is higher than in the chronic phase, but not as high as in the blast phase. [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] Acetylcholinesterase: An enzyme that catalyzes the hydrolysis of acetylcholine to choline and acetate. In the CNS, this enzyme plays a role in the function of peripheral neuromuscular junctions. EC 3.1.1.7. [NIH] Actin: Essential component of the cell skeleton. [NIH] Actinomycosis: Infections with bacteria of the genus Actinomyces. [NIH] Acute leukemia: A rapidly progressing cancer of the blood-forming tissue (bone marrow). [NIH]
Acute myelogenous leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute nonlymphocytic leukemia. [NIH] Acute myeloid leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myelogenous leukemia or acute nonlymphocytic leukemia. [NIH] Acute nonlymphocytic leukemia: A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute myelogenous leukemia. [NIH] Acute renal: A condition in which the kidneys suddenly stop working. In most cases,
212 Thrombocytopenia
kidneys can recover from almost complete loss of function. [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] 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 Deaminase: An enzyme that catalyzes the hydrolysis of adenosine to inosine with the elimination of ammonia. Since there are wide tissue and species variations in the enzyme, it has been used as a tool in the study of human and animal genetics and in medical diagnosis. EC 3.5.4.4. [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] 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] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [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] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]
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
Dictionary 213
tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]
Agarose: A polysaccharide complex, free of nitrogen and prepared from agar-agar which is produced by certain seaweeds (red algae). It dissolves in warm water to form a viscid solution. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] 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] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allo: A female hormone. [NIH] Allogeneic: Taken from different individuals of the same species. [NIH] Allograft: An organ or tissue transplant between two humans. [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alternative medicine: Practices not generally recognized by the medical community as
214 Thrombocytopenia
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] Amber: A yellowish fossil resin, the gum of several species of coniferous trees, found in the alluvial deposits of northeastern Germany. It is used in molecular biology in the analysis of organic matter fossilized in amber. [NIH] Ameliorated: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amenorrhea: Absence of menstruation. [NIH] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Amygdala: Almond-shaped group of basal nuclei anterior to the inferior horn of the lateral ventricle of the brain, within the temporal lobe. The amygdala is part of the limbic system. [NIH]
Amyloidosis: A group of diseases in which protein is deposited in specific organs (localized amyloidosis) or throughout the body (systemic amyloidosis). Amyloidosis may be either primary (with no known cause) or secondary (caused by another disease, including some types of cancer). Generally, primary amyloidosis affects the nerves, skin, tongue, joints, heart, and liver; secondary amyloidosis often affects the spleen, kidneys, liver, and adrenal glands. [NIH] Anaemia: A reduction below normal in the number of erythrocytes per cu. mm., in the quantity of haemoglobin, or in the volume of packed red cells per 100 ml. of blood which occurs when the equilibrium between blood loss (through bleeding or destruction) and blood production is disturbed. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] 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
Dictionary 215
cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anaplasia: Loss of structural differentiation and useful function of neoplastic cells. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] 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] Aneuploidy: The chromosomal constitution of cells which deviate from the normal by the addition or subtraction of chromosomes or chromosome pairs. In a normally diploid cell the loss of a chromosome pair is termed nullisomy (symbol: 2N-2), the loss of a single chromosome is monosomy (symbol: 2N-1), the addition of a chromosome pair is tetrasomy (symbol: 2N+2), the addition of a single chromosome is trisomy (symbol: 2N+1). [NIH] Angina: Chest pain that originates in the heart. [NIH] Angina Pectoris: The symptom of paroxysmal pain consequent to myocardial ischemia usually of distinctive character, location and radiation, and provoked by a transient stressful situation during which the oxygen requirements of the myocardium exceed the capacity of the coronary circulation to supply it. [NIH] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Angioplasty: Endovascular reconstruction of an artery, which may include the removal of atheromatous plaque and/or the endothelial lining as well as simple dilatation. These are procedures performed by catheterization. When reconstruction of an artery is performed surgically, it is called endarterectomy. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] 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] Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] 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] Anthracycline: A member of a family of anticancer drugs that are also antibiotics. [NIH]
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Antiallergic: Counteracting allergy or allergic conditions. [EU] 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] Antibodies, Antiphospholipid: Autoantibodies directed against phospholipids. These antibodies are characteristically found in patients with systemic lupus erythematosus, antiphospholipid syndrome, related autoimmune diseases, some non-autoimmune diseases, and also in healthy individuals. [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] Antibody therapy: Treatment with an antibody, a substance that can directly kill specific tumor cells or stimulate the immune system to kill tumor cells. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Anticonvulsant: An agent that prevents or relieves convulsions. [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-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]
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Antineoplastic Agents: Substances that inhibit or prevent the proliferation of neoplasms. [NIH]
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] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [EU] 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] 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] Aplastic anemia: A condition in which the bone marrow is unable to produce blood cells. [NIH]
Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Aqueous: Having to do with water. [NIH] 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] Arenavirus: The only genus in the family Arenaviridae. It contains two groups LCM-Lassa complex viruses and Tacaribe complex viruses, which are distinguished by antigenic relationships and geographic distribution. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH]
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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] 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] Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Arteriovenous Fistula: An abnormal communication between an artery and a vein. [NIH] Arthrosis: A disease of a joint. [EU] Aspirate: Fluid withdrawn from a lump, often a cyst, or a nipple. [NIH] Aspiration: The act of inhaling. [NIH] Aspirin: A drug that reduces pain, fever, inflammation, and blood clotting. Aspirin belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied in cancer prevention. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atherogenic: Causing the formation of plaque in the lining of the arteries. [NIH] Atopic: Pertaining to an atopen or to atopy; allergic. [EU] 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] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH]
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Attenuated: Strain with weakened or reduced virulence. [NIH] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Audiology: The study of hearing and hearing impairment. [NIH] Autoantibodies: Antibodies that react with self-antigens (autoantigens) of the organism that produced them. [NIH] Autoantigens: Endogenous tissue constituents that have the ability to interact with autoantibodies and cause an immune response. [NIH] Autodigestion: Autolysis; a condition found in disease of the stomach: the stomach wall is digested by the gastric juice. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Avian: A plasmodial infection in birds. [NIH] Babesiosis: A group of tick-borne diseases of mammals including zoonoses in humans. They are caused by protozoans of the genus babesia, which parasitize erythrocytes, producing hemolysis. In the U.S., the organism's natural host is mice and transmission is by the deer tick ixodes scapularis. [NIH] Bacillus: A genus of Bacillaceae that are spore-forming, rod-shaped cells. Most species are saprophytic soil forms with only a few species being pathogenic. [NIH] Bacteremia: The presence of viable bacteria circulating in the blood. Fever, chills, tachycardia, and tachypnea are common acute manifestations of bacteremia. The majority of cases are seen in already hospitalized patients, most of whom have underlying diseases or procedures which render their bloodstreams susceptible to invasion. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Infections: Infections by bacteria, general or unspecified. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] 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] Bacteriuria: The presence of bacteria in the urine with or without consequent urinary tract infection. Since bacteriuria is a clinical entity, the term does not preclude the use of urine/microbiology for technical discussions on the isolation and segregation of bacteria in the urine. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus
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pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]
Bernard-Soulier Syndrome: A familial coagulation disorder characterized by a prolonged bleeding time, unusually large platelets, and impaired prothrombin consumption. [NIH] Beta-Thalassemia: A disorder characterized by reduced synthesis of the beta chains of hemoglobin. There is retardation of hemoglobin A synthesis in the heterozygous form (thalassemia minor), which is asymptomatic, while in the homozygous form (thalassemia major, Cooley's anemia, Mediterranean anemia, erythroblastic anemia), which can result in severe complications and even death, hemoglobin A synthesis is absent. [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 Ducts: Tubes that carry bile from the liver to the gallbladder for storage and to the small intestine for use in digestion. [NIH] Bile Pigments: Pigments that give a characteristic color to bile including: bilirubin, biliverdine, and bilicyanin. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biliary Tract: The gallbladder and its ducts. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biogenesis: The origin of life. It includes studies of the potential basis for life in organic compounds but excludes studies of the development of altered forms of life through mutation and natural selection, which is evolution. [NIH] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response
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modifier (BRM) therapy. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Bioterrorism: The use of biological agents in terrorism. This includes the malevolent use of bacteria, viruses, or toxins against people, animals, or plants. [NIH] Bladder: The organ that stores urine. [NIH] Blast phase: The phase of chronic myelogenous leukemia in which the number of immature, abnormal white blood cells in the bone marrow and blood is extremely high. Also called blast crisis. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Blasts: Immature blood cells. [NIH] Bleeding Time: Duration of blood flow after skin puncture. This test is used as a measure of capillary and platelet function. [NIH] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [NIH] Blood Cell Count: A count of the number of leukocytes and erythrocytes per unit volume in a sample of venous blood. A complete blood count (CBC) also includes measurement of the hemoglobin, hematocrit, and erythrocyte indices. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Coagulation Factors: Endogenous substances, usually proteins, that are involved in the blood coagulation process. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood 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 Volume: Volume of circulating blood. It is the sum of the plasma volume and erythrocyte volume. [NIH] Blood-Brain Barrier: Specialized non-fenestrated tightly-joined endothelial cells (tight junctions) that form a transport barrier for certain substances between the cerebral
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capillaries and the brain tissue. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]
Body Fluids: Liquid components of living organisms. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone marrow aspiration: The removal of a small sample of bone marrow (usually from the hip) through a needle for examination under a microscope. [NIH] Bone Marrow Cells: Cells contained in the bone marrow including fat cells, stromal cells, megakaryocytes, and the immediate precursors of most blood cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [NIH] Bone 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] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]
Breakdown: A physical, metal, or nervous collapse. [NIH] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [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] Bullous: Pertaining to or characterized by bullae. [EU] 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] 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
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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] Calculi: An abnormal concretion occurring mostly in the urinary and biliary tracts, usually composed of mineral salts. Also called stones. [NIH] Calpain: Cysteine proteinase found in many tissues. Hydrolyzes a variety of endogenous proteins including neuropeptides, cytoskeletal proteins, proteins from smooth muscle, cardiac muscle, liver, platelets and erythrocytes. Two subclasses having high and low calcium sensitivity are known. Removes Z-discs and M-lines from myofibrils. Activates phosphorylase kinase and cyclic nucleotide-independent protein kinase. [NIH] Camptothecin: An alkaloid isolated from the stem wood of the Chinese tree, Camptotheca acuminata. This compound selectively inhibits the nuclear enzyme DNA topoisomerase. Several semisynthetic analogs of camptothecin have demonstrated antitumor activity. [NIH] Candidiasis: Infection with a fungus of the genus Candida. It is usually a superficial infection of the moist cutaneous areas of the body, and is generally caused by C. albicans; it most commonly involves the skin (dermatocandidiasis), oral mucous membranes (thrush, def. 1), respiratory tract (bronchocandidiasis), and vagina (vaginitis). Rarely there is a systemic infection or endocarditis. Called also moniliasis, candidosis, oidiomycosis, and formerly blastodendriosis. [EU] Candidosis: An infection caused by an opportunistic yeasts that tends to proliferate and become pathologic when the environment is favorable and the host resistance is weakened. [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] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbamazepine: An anticonvulsant used to control grand mal and psychomotor or focal seizures. Its mode of action is not fully understood, but some of its actions resemble those of phenytoin; although there is little chemical resemblance between the two compounds, their three-dimensional structure is similar. [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] Carboplatin: An organoplatinum compound that possesses antineoplastic activity. [NIH] Carboxy: Cannabinoid. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinogens: Substances that increase the risk of neoplasms in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. [NIH] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]
Carcinostatic: Pertaining to slowing or stopping the growth of cancer. [NIH]
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Cardiac: Having to do with the heart. [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] Cardiology: The study of the heart, its physiology, and its functions. [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] 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 State: The condition of harboring an infective organism without manifesting symptoms of infection. The organism must be readily transmissable to another susceptible host. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ, or body cavity for injecting or withdrawing fluids for diagnostic or therapeutic purposes. It differs from intubation in that the tube here is used to restore or maintain patency in obstructions. [NIH] Catheters: A small, flexible tube that may be inserted into various parts of the body to inject or remove liquids. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Cat-Scratch Disease: A self-limiting bacterial infection of the regional lymph nodes caused by Afipia felis, a gram-negative bacterium recently identified by the Centers for Disease Control and Prevention and by Bartonella henselae. It usually arises one or more weeks following a feline scratch, with raised inflammatory nodules at the site of the scratch being the primary symptom. [NIH] Causal: Pertaining to a cause; directed against a cause. [EU]
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Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Caveolae: Endocytic/exocytic cell membrane structures rich in glycosphingolipids, cholesterol, and lipid-anchored membrane proteins that function in endocytosis (potocytosis), transcytosis, and signal transduction. Caveolae assume various shapes from open pits to closed vesicles. Caveolar coats are composed of caveolins. [NIH] Caveolins: The main structural proteins of caveolae. Several distinct genes for caveolins have been identified. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Count: A count of the number of cells of a specific kind, usually measured per unit volume of sample. [NIH] Cell 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 Lineage: The developmental history of cells as traced from the first division of the original cell or cells in the embryo. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell Membrane Structures: Structures which are part of the cell membrane or have cell membrane as a major part of their structure. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [NIH] Cellulitis: An acute, diffuse, and suppurative inflammation of loose connective tissue, particularly the deep subcutaneous tissues, and sometimes muscle, which is most commonly seen as a result of infection of a wound, ulcer, or other skin lesions. [NIH] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw
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material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Centromere: The clear constricted portion of the chromosome at which the chromatids are joined and by which the chromosome is attached to the spindle during cell division. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] 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] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] 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] Cheilitis: Inflammation of the lips. It is of various etiologies and degrees of pathology. [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] Chemotherapeutics: Noun plural but singular or plural in constructions : chemotherapy. [EU]
Chemotherapy: Treatment with anticancer drugs. [NIH] Chenodeoxycholic Acid: A bile acid, usually conjugated with either glycine or taurine. It acts as a detergent to solubilize fats for intestinal absorption and is reabsorbed by the small intestine. It is used as cholagogue, a choleretic laxative, and to prevent or dissolve gallstones. [NIH] Chimeras: Organism that contains a mixture of genetically different cells. [NIH] Chimeric Proteins: Proteins in individuals that are derived from genetically different zygotes. [NIH] Choleretic: A choleretic agent. [EU] Cholestanol: A cholesterol derivative found in human feces, gallstones, eggs, and other
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biological matter. [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] Cholic Acid: A major primary bile acid produced in the liver and usually conjugated with glycine or taurine. It facilitates fat absorption and cholesterol excretion. [NIH] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic granulocytic leukemia: A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myelogenous leukemia or chronic myeloid leukemia. [NIH] Chronic leukemia: A slowly progressing cancer of the blood-forming tissues. [NIH] Chronic lymphocytic leukemia: A slowly progressing disease in which too many white blood cells (called lymphocytes) are found in the body. [NIH] Chronic myelogenous leukemia: CML. A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myeloid leukemia or chronic granulocytic leukemia. [NIH] Chronic phase: Refers to the early stages of chronic myelogenous leukemia or chronic lymphocytic leukemia. The number of mature and immature abnormal white blood cells in the bone marrow and blood is higher than normal, but lower than in the accelerated or blast phase. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Cinchona: A genus of rubiaceous South American trees that yields the toxic cinchona alkaloids from their bark; quinine, quinidine, chinconine, cinchonidine and others are used to treat malaria and cardiac arrhythmias. [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]
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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] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]
Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]
Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Clot Retraction: Retraction of a clot resulting from contraction of platelet pseudopods attached to fibrin strands that is dependent on the contractile protein thrombosthenin. Used as a measure of platelet function. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] 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] Cognitive restructuring: A method of identifying and replacing fear-promoting, irrational beliefs with more realistic and functional ones. [NIH] Cohort Studies: Studies in which subsets of a defined population are identified. These groups may or may not be exposed to factors hypothesized to influence the probability of the occurrence of a particular disease or other outcome. Cohorts are defined populations which, as a whole, are followed in an attempt to determine distinguishing subgroup characteristics. [NIH] 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] Coliphages: Viruses whose host is Escherichia coli. [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
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consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Colloidal: Of the nature of a colloid. [EU] Colony-Stimulating Factors: Glycoproteins found in a subfraction of normal mammalian plasma and urine. They stimulate the proliferation of bone marrow cells in agar cultures and the formation of colonies of granulocytes and/or macrophages. The factors include interleukin-3 (IL-3), granulocyte colony-stimulating factor (G-CSF), macrophage colonystimulating factor (M-CSF), and granulocyte-macrophage colony-stimulating factor (GMCSF). [NIH] Combination chemotherapy: Treatment using more than one anticancer drug. [NIH] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable compounds at once. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] 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,
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megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementation: The production of a wild-type phenotype when two different mutations are combined in a diploid or a heterokaryon and tested in trans-configuration. [NIH] Complete remission: The disappearance of all signs of cancer. Also called a complete response. [NIH] Complete response: The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Condoms: A sheath that is worn over the penis during sexual behavior in order to prevent pregnancy or spread of sexually transmitted disease. [NIH] Condyloma: C. acuminatum; a papilloma with a central core of connective tissue in a treelike structure covered with epithelium, usually occurring on the mucous membrane or skin of the external genitals or in the perianal region. [EU] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Congenita: Displacement, subluxation, or malposition of the crystalline lens. [NIH] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH]
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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] Constriction: The act of constricting. [NIH] Consumption: Pulmonary tuberculosis. [NIH] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Contraceptive: An agent that diminishes the likelihood of or prevents conception. [EU] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Artery Bypass: Surgical therapy of ischemic coronary artery disease achieved by grafting a section of saphenous vein, internal mammary artery, or other substitute between the aorta and the obstructed coronary artery distal to the obstructive lesion. [NIH] Coronary Circulation: The circulation of blood through the coronary vessels of the heart. [NIH]
Coronary 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] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Corticosteroid: Any of the steroids elaborated by the adrenal cortex (excluding the sex hormones of adrenal origin) in response to the release of corticotrophin (adrenocorticotropic hormone) by the pituitary gland, to any of the synthetic equivalents of these steroids, or to angiotensin II. They are divided, according to their predominant biological activity, into three major groups: glucocorticoids, chiefly influencing carbohydrate, fat, and protein metabolism; mineralocorticoids, affecting the regulation of electrolyte and water balance;
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and C19 androgens. Some corticosteroids exhibit both types of activity in varying degrees, and others exert only one type of effect. The corticosteroids are used clinically for hormonal replacement therapy, for suppression of ACTH secretion by the anterior pituitary, as antineoplastic, antiallergic, and anti-inflammatory agents, and to suppress the immune response. Called also adrenocortical hormone and corticoid. [EU] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Cost Savings: Reductions in all or any portion of the costs of providing goods or services. Savings may be incurred by the provider or the consumer. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Creatine: An amino acid that occurs in vertebrate tissues and in urine. In muscle tissue, creatine generally occurs as phosphocreatine. Creatine is excreted as creatinine in the urine. [NIH]
Creatine Kinase: A transferase that catalyzes formation of phosphocreatine from ATP + creatine. The reaction stores ATP energy as phosphocreatine. Three cytoplasmic isoenzymes have been identified in human tissues: MM from skeletal muscle, MB from myocardial tissue, and BB from nervous tissue as well as a mitochondrial isoenzyme. Macro-creatine kinase refers to creatine kinase complexed with other serum proteins. EC 2.7.3.2. [NIH] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] 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] Cross-Sectional Studies: Studies in which the presence or absence of disease or other health-related variables are determined in each member of the study population or in a representative sample at one particular time. This contrasts with longitudinal studies which are followed over a period of time. [NIH] Cryoglobulinemia: A condition characterized by the presence of abnormal or abnormal quantities of cryoglobulins in the blood. They are precipitated into the microvasculature on exposure to cold and cause restricted blood flow in exposed areas. [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] Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH]
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Cyst: A sac or capsule filled with fluid. [NIH] Cystathionine beta-Synthase: A multifunctional pyridoxal phosphate enzyme. In the second stage of cysteine biosynthesis it catalyzes the reaction of homocysteine with serine to form cystathionine with the elimination of water. Deficiency of this enzyme leads to hyperhomocysteinemia and homocystinuria. EC 4.2.1.22. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cytarabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]
Cytogenetics: A branch of genetics which deals with the cytological and molecular behavior of genes and chromosomes during cell division. [NIH] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] 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] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytoskeletal Proteins: Major constituent of the cytoskeleton found in the cytoplasm of eukaryotic cells. They form a flexible framework for the cell, provide attachment points for organelles and formed bodies, and make communication between parts of the cell possible. [NIH]
Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Daclizumab: A monoclonal antibody that is being studied for treatment of adult T-cell leukemia. Also called dacliximab. Monoclonal antibodies are laboratory-produced substances that can locate and bind to cancer cells. [NIH] Dactinomycin: An anticancer drug that belongs to the family of drugs called antitumor antibiotics. [NIH] Dalteparin: A drug that helps prevent the formation of blood clots; it belongs to the family of drugs called anticoagulants. [NIH] Databases, Bibliographic: Extensive collections, reputedly complete, of references and citations to books, articles, publications, etc., generally on a single subject or specialized subject area. Databases can operate through automated files, libraries, or computer disks. The concept should be differentiated from factual databases which is used for collections of data and facts apart from bibliographic references to them. [NIH] Daunorubicin: Very toxic anthracycline aminoglycoside antibiotic isolated from Streptomyces peucetius and others, used in treatment of leukemias and other neoplasms. [NIH]
Day Care: Institutional health care of patients during the day. The patients return home at night. [NIH]
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De novo: In cancer, the first occurrence of cancer in the body. [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] Defense Mechanisms: Unconscious process used by an individual or a group of individuals in order to cope with impulses, feelings or ideas which are not acceptable at their conscious level; various types include reaction formation, projection and self reversal. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Dehydroepiandrosterone: DHEA. A substance that is being studied as a cancer prevention drug. It belongs to the family of drugs called steroids. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dendritic cell: A special type of antigen-presenting cell (APC) that activates T lymphocytes. [NIH]
Dengue Virus: A species of the genus Flavivirus which causes an acute febrile and sometimes hemorrhagic disease in man. Dengue is mosquito-borne and four serotypes are known. [NIH] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dental Care: The total of dental diagnostic, preventive, and restorative services provided to meet the needs of a patient (from Illustrated Dictionary of Dentistry, 1982). [NIH] Dentate Gyrus: Gray matter situated above the gyrus hippocampi. It is composed of three layers. The molecular layer is continuous with the hippocampus in the hippocampal fissure. The granular layer consists of closely arranged spherical or oval neurons, called granule cells, whose axons pass through the polymorphic layer ending on the dendrites of pyramidal cells in the hippocampus. [NIH] Dentists: Individuals licensed to practice dentistry. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Dermatitis: Any inflammation of the skin. [NIH] Dermatology: A medical specialty concerned with the skin, its structure, functions, diseases, and treatment. [NIH] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Developed Countries: Countries that have reached a level of economic achievement through an increase of production, per capita income and consumption, and utilization of natural and human resources. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The
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dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diarrhoea: Abnormal frequency and liquidity of faecal discharges. [EU] Diastolic: Of or pertaining to the diastole. [EU] Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Dihydroxy: AMPA/Kainate antagonist. [NIH] Dilatation: The act of dilating. [NIH] Dilution: A diluted or attenuated medicine; in homeopathy, the diffusion of a given quantity of a medicinal agent in ten or one hundred times the same quantity of water. [NIH] Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discoid: Shaped like a disk. [EU] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disease-Free Survival: Period after successful treatment in which there is no appearance of the symptoms or effects of the disease. [NIH] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Docetaxel: An anticancer drug that belongs to the family of drugs called mitotic inhibitors. [NIH]
Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and homozygotes. [EU]
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Dopa: The racemic or DL form of DOPA, an amino acid found in various legumes. The dextro form has little physiologic activity but the levo form (levodopa) is a very important physiologic mediator and precursor and pharmacological agent. [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] 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] Dosimetry: All the methods either of measuring directly, or of measuring indirectly and computing, absorbed dose, absorbed dose rate, exposure, exposure rate, dose equivalent, and the science associated with these methods. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Eruptions: Adverse cutaneous reactions caused by ingestion, parenteral use, or local application of a drug. These may assume various morphologic patterns and produce various types of lesions. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenal Ulcer: An ulcer in the lining of the first part of the small intestine (duodenum). [NIH]
Duodenum: The first part of the small intestine. [NIH] Dura mater: The outermost, toughest, and most fibrous of the three membranes (meninges) covering the brain and spinal cord; called also pachymeninx. [EU] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dyskeratosis Congenita: A disturbance in normal keratinization, resulting, in the eye, in hornification of the epithelial layer of the cornea or conjunctiva. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Eclampsia: Onset of convulsions or coma in a previously diagnosed pre-eclamptic patient. [NIH]
Eczema: A pruritic papulovesicular dermatitis occurring as a reaction to many endogenous and exogenous agents (Dorland, 27th ed). [NIH] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service
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produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Ehrlichiosis: A tick-borne disease characterized by fever, headache, myalgias, anorexia, and occasionally rash. In humans the disease is caused by Ehrlichia chaffeensis, in dogs it is caused by E. canis, and in horses, E. equi. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] 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]
Embolectomy: Surgical removal of an obstructing clot or foreign material which has been transported from a distant vessel by the bloodstream. Removal of a clot at its original site is called thrombectomy. [NIH] Emboli: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embolism: Blocking of a blood vessel by a blood clot or foreign matter that has been transported from a distant site by the blood stream. [NIH] Embolization: The blocking of an artery by a clot or foreign material. Embolization can be done as treatment to block the flow of blood to a tumor. [NIH] Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] 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 embryoge). [NIH] Emesis: Vomiting; an act of vomiting. Also used as a word termination, as in haematemesis. [EU]
Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]
Encephalitis: Inflammation of the brain due to infection, autoimmune processes, toxins, and other conditions. Viral infections (see encephalitis, viral) are a relatively frequent cause of this condition. [NIH]
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Encephalomyelitis: A general term indicating inflammation of the brain and spinal cord, often used to indicate an infectious process, but also applicable to a variety of autoimmune and toxic-metabolic conditions. There is significant overlap regarding the usage of this term and encephalitis in the literature. [NIH] Endarterectomy: Surgical excision, performed under general anesthesia, of the atheromatous tunica intima of an artery. When reconstruction of an artery is performed as an endovascular procedure through a catheter, it is called atherectomy. [NIH] Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocarditis: Exudative and proliferative inflammatory alterations of the endocardium, characterized by the presence of vegetations on the surface of the endocardium or in the endocardium itself, and most commonly involving a heart valve, but sometimes affecting the inner lining of the cardiac chambers or the endocardium elsewhere. It may occur as a primary disorder or as a complication of or in association with another disease. [EU] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endocrinology: A subspecialty of internal medicine concerned with the metabolism, physiology, and disorders of the endocrine system. [NIH] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endoderm: The inner of the three germ layers of the embryo. [NIH] Endometrium: The layer of tissue that lines the uterus. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have 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] Endotoxins: Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Entorhinal Cortex: Cortex where the signals are combined with those from other sensory systems. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or
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biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]
Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Eosinophil: A polymorphonuclear leucocyte with large eosinophilic granules in its cytoplasm, which plays a role in hypersensitivity reactions. [NIH] Epidemiologic Studies: Studies designed to examine associations, commonly, hypothesized causal relations. They are usually concerned with identifying or measuring the effects of risk factors or exposures. The common types of analytic study are case-control studies, cohort studies, and cross-sectional studies. [NIH] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epidermoid carcinoma: A type of cancer in which the cells are flat and look like fish scales. Also called squamous cell carcinoma. [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] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]
Epoprostenol: A prostaglandin that is biosynthesized enzymatically from prostaglandin endoperoxides in human vascular tissue. It is a potent inhibitor of platelet aggregation. The sodium salt has been also used to treat primary pulmonary hypertension. [NIH] Equine Infectious Anemia: Viral disease of horses caused by the equine infectious anemia virus (EIAV). It is characterized by intermittent fever, weakness, and anemia. Chronic infection consists of acute episodes with remissions. [NIH] Erythema: Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of causes. [NIH] Erythrocyte Indices: Quantification of size and cell hemoglobin content or concentration of the erythrocyte, usually derived from erythrocyte count, blood hemoglobin concentration, and hematocrit. Includes the mean cell volume (MCV), mean cell hemoglobin (MCH), and mean cell hemoglobin concentration (MCHC). Use also for cell diameter and thickness. [NIH] Erythrocyte Volume: Volume of circulating erythrocytes. It is usually measured by
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radioisotope dilution technique. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythropoiesis: The production of erythrocytes. [EU] Erythropoietin: Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. [NIH] Escalation: Progressive use of more harmful drugs. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]
Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [NIH] Estrogen: One of the two female sex hormones. [NIH] Etoposide: A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excitability: Property of a cardiac cell whereby, when the cell is depolarized to a critical level (called threshold), the membrane becomes permeable and a regenerative inward current causes an action potential. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Exfoliation: A falling off in scales or layers. [EU] Exhaustion: The feeling of weariness of mind and body. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [NIH]
External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH]
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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] Extravasation: A discharge or escape, as of blood, from a vessel into the tissues. [EU] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] 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] Facial: Of or pertaining to the face. [EU] Facial Nerve: The 7th cranial nerve. The facial nerve has two parts, the larger motor root which may be called the facial nerve proper, and the smaller intermediate or sensory root. Together they provide efferent innervation to the muscles of facial expression and to the lacrimal and salivary glands, and convey afferent information for taste from the anterior two-thirds of the tongue and for touch from the external ear. [NIH] Factor V: Heat- and storage-labile plasma glycoprotein which accelerates the conversion of prothrombin to thrombin in blood coagulation. Factor V accomplishes this by forming a complex with factor Xa, phospholipid, and calcium (prothrombinase complex). Deficiency of factor V leads to Owren's disease. [NIH] Factor VII: Heat- and storage-stable plasma protein that is activated by tissue thromboplastin to form factor VIIa in the extrinsic pathway of blood coagulation. The activated form then catalyzes the activation of factor X to factor Xa. [NIH] Factor VIIa: Activated form of factor VII. Factor VIIa activates factor X in the extrinsic pathway of blood coagulation. [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] Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Fatty Liver: The buildup of fat in liver cells. The most common cause is alcoholism. Other causes include obesity, diabetes, and pregnancy. Also called steatosis. [NIH] Febrile: Pertaining to or characterized by fever. [EU] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Femoral: Pertaining to the femur, or to the thigh. [EU] Femoral Artery: The main artery of the thigh, a continuation of the external iliac artery. [NIH] Fetal Death: Death of the young developing in utero. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three 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]
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Fibrinolysis: The natural enzymatic dissolution of fibrin. [NIH] Fibrinolytic: Pertaining to, characterized by, or causing the dissolution of fibrin by enzymatic action [EU] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibronectin: An adhesive glycoprotein. One form circulates in plasma, acting as an opsonin; another is a cell-surface protein which mediates cellular adhesive interactions. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Filovirus: A genus of the family Filoviridae containing two species: Ebola virus and Marburg virus. Both were originally associated with African monkeys but are capable of causing severe hemorrhagic disease in humans. The natural host of either virus is unknown. Transmission is by close personal contact. [NIH] Flatus: Gas passed through the rectum. [NIH] Flow Cytometry: Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. [NIH] Fludarabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]
Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorescent Dyes: Dyes that emit light when exposed to light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags. They are used as markers in biochemistry and immunology. [NIH] Fluorouracil: A pyrimidine analog that acts as an antineoplastic antimetabolite and also has immunosuppressant. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. [NIH] Foam Cells: Lipid-laden macrophages originating from monocytes or from smooth muscle cells. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Forearm: The part between the elbow and the wrist. [NIH]
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Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [NIH] Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gallstones: The solid masses or stones made of cholesterol or bilirubin that form in the gallbladder or bile ducts. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [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 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] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gas exchange: Primary function of the lungs; transfer of oxygen from inhaled air into the blood and of carbon dioxide from the blood into the lungs. [NIH] Gastric: Having to do with the stomach. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]
Gastroenteritis: An acute inflammation of the lining of the stomach and intestines, characterized by anorexia, nausea, diarrhoea, abdominal pain, and weakness, which has various causes, including food poisoning due to infection with such organisms as Escherichia coli, Staphylococcus aureus, and Salmonella species; consumption of irritating food or drink; or psychological factors such as anger, stress, and fear. Called also enterogastritis. [EU] Gastroenterology: A subspecialty of internal medicine concerned with the study of the physiology and diseases of the digestive system and related structures (esophagus, liver, gallbladder, and pancreas). [NIH] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH]
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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 Targeting: The integration of exogenous DNA into the genome of an organism at sites where its expression can be suitably controlled. This integration occurs as a result of homologous recombination. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Counseling: Advising families of the risks involved pertaining to birth defects, in order that they may make an informed decision on current or future pregnancies. [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Techniques: Chromosomal, biochemical, intracellular, and other methods used in the study of genetics. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genitourinary: Pertaining to the genital and urinary organs; urogenital; urinosexual. [EU] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Geotrichosis: Infection due to the fungus Geotrichum. [NIH] Geriatric: Pertaining to the treatment of the aged. [EU] 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] Giant Cells: Multinucleated masses produced by the fusion of many cells; often associated with viral infections. In AIDS, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium leads to cell death and thus may account for the cytopathic effect of the virus. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]
Glomerular Filtration Rate: The volume of water filtered out of plasma through glomerular capillary walls into Bowman's capsules per unit of time. It is considered to be equivalent to inulin clearance. [NIH] Glomeruli: Plural of glomerulus. [NIH]
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Glomerulonephritis: Glomerular disease characterized by an inflammatory reaction, with leukocyte infiltration and cellular proliferation of the glomeruli, or that appears to be the result of immune glomerular injury. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [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 Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucuronic Acid: Derivatives of uronic acid found throughout the plant and animal kingdoms. They detoxify drugs and toxins by conjugating with them to form glucuronides in the liver which are more water-soluble metabolites that can be easily eliminated from the body. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]
Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]
Glycerophospholipids: Derivatives of phosphatidic acid in which the hydrophobic regions are composed of two fatty acids and a polar alcohol is joined to the C-3 position of glycerol through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. [NIH] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [NIH] Glycogen Storage Disease: A group of inherited metabolic disorders involving the enzymes responsible for the synthesis and degradation of glycogen. In some patients, prominent liver involvement is presented. In others, more generalized storage of glycogen occurs, sometimes with prominent cardiac involvement. [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] 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]
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Gout: Hereditary metabolic disorder characterized by recurrent acute arthritis, hyperuricemia and deposition of sodium urate in and around the joints, sometimes with formation of uric acid calculi. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]
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 Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Graft-versus-host disease: GVHD. A reaction of donated bone marrow or peripheral stem cells against a person's tissue. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Gram-positive: Retaining the stain or resisting decolorization by alcohol in Gram's method of staining, a primary characteristic of bacteria whose cell wall is composed of a thick layer of peptidologlycan with attached teichoic acids. [EU] Granule: A small pill made from sucrose. [EU] Granulocyte Colony-Stimulating Factor: A glycoprotein of MW 25 kDa containing internal disulfide bonds. It induces the survival, proliferation, and differentiation of neutrophilic granulocyte precursor cells and functionally activates mature blood neutrophils. Among the family of colony-stimulating factors, G-CSF is the most potent inducer of terminal differentiation to granulocytes and macrophages of leukemic myeloid cell lines. [NIH] Granulocyte-Macrophage Colony-Stimulating Factor: An acidic glycoprotein of MW 23 kDa with internal disulfide bonds. The protein is produced in response to a number of inflammatory mediators by mesenchymal cells present in the hemopoietic environment and at peripheral sites of inflammation. GM-CSF is able to stimulate the production of neutrophilic granulocytes, macrophages, and mixed granulocyte-macrophage colonies from bone marrow cells and can stimulate the formation of eosinophil colonies from fetal liver progenitor cells. GM-CSF can also stimulate some functional activities in mature granulocytes and macrophages. [NIH] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Granulocytopenia: A deficiency in the number of granulocytes, a type of white blood cell. [NIH]
Granuloma: A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents. [NIH] Grasses: A large family, Gramineae, of narrow-leaved herbaceous monocots. Many grasses produce highly allergenic pollens and are hosts to cattle parasites and toxic fungi. [NIH]
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Gravis: Eruption of watery blisters on the skin among those handling animals and animal products. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Gynecology: A medical-surgical specialty concerned with the physiology and disorders primarily of the female genital tract, as well as female endocrinology and reproductive physiology. [NIH] Habitat: An area considered in terms of its environment, particularly as this determines the type and quality of the vegetation the area can carry. [NIH] Haematemesis: The vomiting of blood. [EU] Haematological: Relating to haematology, that is that branch of medical science which treats of the morphology of the blood and blood-forming tissues. [EU] Haematology: The science of the blood, its nature, functions, and diseases. [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] Haemolysis: Disruption of the integrity of the red cell membrane causing release of haemoglobin. Haemolysis may be caused by bacterial haemolysins, by antibodies that cause complement-dependent lysis, by placing red cells in a hyptonic solution, or by defects in the red cell membrane. [EU] Haemopoietic: Haematopoietic; pertaining to or effecting the formation of blood cells. [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] Hair follicles: Shafts or openings on the surface of the skin through which hair grows. [NIH] Hairy cell leukemia: A type of chronic leukemia in which the abnormal white blood cells appear to be covered with tiny hairs when viewed under a microscope. [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] Handwashing: The act of cleansing the hands with water or other liquid, with or without the inclusion of soap or other detergent, for the purpose of removing soil or microorganisms. [NIH] Hantavirus: A genus of the family Bunyaviridae causing Hantavirus infections, first identified during the Korean war. Infection is found primarily in rodents and humans. Transmission does not appear to involve arthropods. The genus has one recognized group (Hantaan group) consisting of several species including Dobrava-Belgrade virus, Seoul virus, Prospect Hill virus, Puumala virus, Thottapalayam virus, and Hantaan virus, the type species. [NIH]
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Hantavirus Pulmonary Syndrome: Acute respiratory illness in humans caused by the Muerto Canyon virus whose primary rodent reservoir is the deer mouse Peromyscus maniculatus. First identified in the southwestern United States, this syndrome is characterized most commonly by fever, myalgias, headache, cough, and rapid respiratory failure. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Hematocrit: Measurement of the volume of packed red cells in a blood specimen by centrifugation. The procedure is performed using a tube with graduated markings or with automated blood cell counters. It is used as an indicator of erythrocyte status in disease. For example, anemia shows a low hematocrit, polycythemia, high values. [NIH] Hematologic malignancies: Cancers of the blood or bone marrow, including leukemia and lymphoma. Also called hematologic cancers. [NIH] Hematology: A subspecialty of internal medicine concerned with morphology, physiology, and pathology of the blood and blood-forming tissues. [NIH] Hematoma: An extravasation of blood localized in an organ, space, or tissue. [NIH] Hematopoiesis: The development and formation of various types of blood cells. [NIH] Hematopoietic Stem Cells: Progenitor cells from which all blood cells derive. [NIH] Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [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] 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
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lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobin M: A group of abnormal hemoglobins in which amino acid substitutions take place in either the alpha or beta chains but near the heme iron. This results in facilitated oxidation of the hemoglobin to yield excess methemoglobin which leads to cyanosis. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemolysis: The destruction of erythrocytes by many different causal agents such as antibodies, bacteria, chemicals, temperature, and changes in tonicity. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemorrhagic Fever with Renal Syndrome: An acute febrile disease occurring predominately in Asia. It is characterized by fever, prostration, vomiting, hemorrhagic phenonema, shock, and renal failure. It is caused by any one of several closely related species of the genus Hantavirus. The most severe form is caused by Hantaan virus whose natural host is the rodent Apodemus agrarius. A milder form is caused by Seoul virus and related species and transmitted by the rodents Rattus rattus and R. norvegicus. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]
Heparin: Heparinic acid. A highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. [NIH] Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatitis A: Hepatitis caused by hepatovirus. It can be transmitted through fecal contamination of food or water. [NIH] Hepatitis Viruses: Any of the viruses that cause inflammation of the liver. They include both DNA and RNA viruses as well viruses from humans and animals. [NIH] Hepatocytes: The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. [NIH] Hepatomegaly: Enlargement of the liver. [NIH] Hepatovirus: A genus of Picornaviridae causing infectious hepatitis naturally in humans and experimentally in other primates. It is transmitted through fecal contamination of food or water. [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.
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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 Zoster: Acute vesicular inflammation. [NIH] Heterodimers: Zippered pair of nonidentical proteins. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]
Heterozygotes: Having unlike alleles at one or more corresponding loci on homologous chromosomes. [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] Histiocytosis: General term for the abnormal appearance of histiocytes in the blood. Based on the pathological features of the cells involved rather than on clinical findings, the histiocytic diseases are subdivided into three groups: Langerhans cell histiocytosis, nonLangerhans cell histiocytosis, and malignant histiocytic disorders. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homozygotes: An individual having a homozygous gene pair. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Human papillomavirus: HPV. A virus that causes abnormal tissue growth (warts) and is often associated with some types of cancer. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU]
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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] Hydration: Combining with water. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hydroxyurea: An antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase. [NIH] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hyperglycemia: Abnormally high blood sugar. [NIH] Hyperhomocysteinemia: An inborn error of methionone metabolism which produces an excess of homocysteine in the blood. It is often caused by a deficiency of cystathionine betasynthase and is a risk factor for coronary vascular disease. [NIH] Hyperlipoproteinemia: Metabolic disease characterized by elevated plasma cholesterol and/or triglyceride levels. The inherited form is attributed to a single gene mechanism. [NIH] Hyperpigmentation: Excessive pigmentation of the skin, usually as a result of increased melanization of the epidermis rather than as a result of an increased number of melanocytes. Etiology is varied and the condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] 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]
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Hyperuricemia: A buildup of uric acid (a byproduct of metabolism) in the blood; a side effect of some anticancer drugs. [NIH] Hypoplasia: Incomplete development or underdevelopment of an organ or tissue. [EU] Hypotension: Abnormally low blood pressure. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Idiotype: The unique antigenic determinant in the variable region. [NIH] Iduronic Acid: Component of dermatan sulfate. Differs in configuration from glucuronic acid only at the C-5 position. [NIH] Iloprost: An eicosanoid, derived from the cyclooxygenase pathway of arachidonic acid metabolism. It is a stable and synthetic analog of epoprostenol, but with a longer half-life than the parent compound. Its actions are similar to prostacyclin. Iloprost produces vasodilation and inhibits platelet aggregation. [NIH] Immune Complex Diseases: Group of diseases mediated by the deposition of large soluble complexes of antigen and antibody with resultant damage to tissue. Besides serum sickness and the arthus reaction, evidence supports a pathogenic role for immune complexes in many other systemic immunologic diseases including glomerulonephritis, systemic lupus erythematosus and polyarteritis nodosa. [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] Immune Tolerance: The specific failure of a normally responsive individual to make an immune response to a known antigen. It results from previous contact with the antigen by an immunologically immature individual (fetus or neonate) or by an adult exposed to extreme high-dose or low-dose antigen, or by exposure to radiation, antimetabolites, antilymphocytic serum, etc. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]
effects
of
foreign
Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU]
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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] Immunologic Diseases: Disorders caused by abnormal or absent immunologic mechanisms, whether humoral, cell-mediated or both. [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] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Immunotoxins: Semisynthetic conjugates of various toxic molecules, including radioactive isotopes and bacterial or plant toxins, with specific immune substances such as immunoglobulins, monoclonal antibodies, and antigens. The antitumor or antiviral immune substance carries the toxin to the tumor or infected cell where the toxin exerts its poisonous effect. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Impetigo: A common superficial bacterial infection caused by staphylococcus aureus or group A beta-hemolytic streptococci. Characteristics include pustular lesions that rupture and discharge a thin, amber-colored fluid that dries and forms a crust. This condition is commonly located on the face, especially about the mouth and nose. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incubated: Grown in the laboratory under controlled conditions. (For instance, white blood cells can be grown in special conditions so that they attack specific cancer cells when returned to the body.) [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate
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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]
Infectious Mononucleosis: A common, acute infection usually caused by the Epstein-Barr virus (Human herpesvirus 4). There is an increase in mononuclear white blood cells and other atypical lymphocytes, generalized lymphadenopathy, splenomegaly, and occasionally hepatomegaly with hepatitis. [NIH] Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Influenza: An acute viral infection involving the respiratory tract. It is marked by inflammation of the nasal mucosa, the pharynx, and conjunctiva, and by headache and severe, often generalized, myalgia. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inlay: In dentistry, a filling first made to correspond with the form of a dental cavity and then cemented into the cavity. [NIH] 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] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune,
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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] Intensive Care: Advanced and highly specialized care provided to medical or surgical patients whose conditions are life-threatening and require comprehensive care and constant monitoring. It is usually administered in specially equipped units of a health care facility. [NIH]
Intercellular Junctions: Strictly, and so far as it can be distinguished, the amorphous isotropic layer between adjacent primary walls of cells. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-11: Lymphohematopoietic cytokine that has the ability to modulate antigenspecific antibody responses, potentiate megakaryocytes, and regulate bone marrow adipogenesis. [NIH] Interleukin-15: Cytokine that stimulates the proliferation of T-lymphocytes and shares biological activities with IL-2. IL-15 also can induce B-lymphocyte proliferation and differentiation. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Interleukin-3: A multilineage cell growth factor secreted by lymphocytes, epithelial cells, and astrocytes which stimulates clonal proliferation and differentiation of various types of blood and tissue cells. Also called multi-CSF, it is considered one of the hematopoietic colony stimulating factors. [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] Interleukins: Soluble factors which stimulate growth-related activities of leukocytes as well as other cell types. They enhance cell proliferation and differentiation, DNA synthesis,
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secretion of other biologically active molecules and responses to immune and inflammatory stimuli. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] Interphase: The interval between two successive cell divisions during which the chromosomes are not individually distinguishable and DNA replication occurs. [NIH] Interspecific: Occurring among members of different species. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestines: The section of the alimentary canal from the stomach to the anus. It includes the large intestine and small intestine. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intraocular: Within the eye. [EU] Intravascular: Within a vessel or vessels. [EU] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Inulin: A starch found in the tubers and roots of many plants. Since it is hydrolyzable to fructose, it is classified as a fructosan. It has been used in physiologic investigation for determination of the rate of glomerular function. [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] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Irinotecan: An anticancer drug that belongs to a family of anticancer drugs called topoisomerase inhibitors. It is a camptothecin analogue. Also called CPT 11. [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] Islet: Cell producing insulin in pancreas. [NIH] Isoenzyme: Different forms of an enzyme, usually occurring in different tissues. The isoenzymes of a particular enzyme catalyze the same reaction but they differ in some of their properties. [NIH] Ixodes: A large, widely distributed genus of ticks consisting of approximately 245 species. Many infest man and other mammals and several are vectors of diseases such as Lyme disease, tick-borne encephalitis (encephalitis, tick-borne), and Kyasanur forest disease. [NIH] Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH]
Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Kanamycin: Antibiotic complex produced by Streptomyces kanamyceticus from Japanese soil. Comprises 3 components: kanamycin A, the major component, and kanamycins B and C, the minor components. [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] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Killer Cells: Lymphocyte-like effector cells which mediate antibody-dependent cell cytotoxicity. They kill antibody-coated target cells which they bind with their Fc receptors. [NIH]
Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Lacrimal: Pertaining to the tears. [EU] Lactation: The period of the secretion of milk. [EU] 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] Laxative: An agent that acts to promote evacuation of the bowel; a cathartic or purgative. [EU]
Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Lentivirus: A genus of the family Retroviridae consisting of non-oncogenic retroviruses that
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produce multi-organ diseases characterized by long incubation periods and persistent infection. Lentiviruses are unique in that they contain open reading frames (ORFs) between the pol and env genes and in the 3' env region. Five serogroups are recognized, reflecting the mammalian hosts with which they are associated. HIV-1 is the type species. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH] 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]
Leukaemia: An acute or chronic disease of unknown cause in man and other warm-blooded animals that involves the blood-forming organs, is characterized by an abnormal increase in the number of leucocytes in the tissues of the body with or without a corresponding increase of those in the circulating blood, and is classified according of the type leucocyte most prominently involved. [EU] Leukapheresis: The preparation of leukocyte concentrates with the return of red cells and leukocyte-poor plasma to the donor. [NIH] Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Leukocytosis: A transient increase in the number of leukocytes in a body fluid. [NIH] Leukopenia: A condition in which the number of leukocytes (white blood cells) in the blood is reduced. [NIH] Leukoplakia: A white patch that may develop on mucous membranes such as the cheek, gums, or tongue and may become cancerous. [NIH] Levodopa: The naturally occurring form of dopa and the immediate precursor of dopamine. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. It is used for the treatment of parkinsonism and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]
Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Limbic: Pertaining to a limbus, or margin; forming a border around. [EU] Limbic System: A set of forebrain structures common to all mammals that is defined functionally and anatomically. It is implicated in the higher integration of visceral, olfactory, and somatic information as well as homeostatic responses including fundamental survival behaviors (feeding, mating, emotion). For most authors, it includes the amygdala, epithalamus, gyrus cinguli, hippocampal formation (see hippocampus), hypothalamus, parahippocampal gyrus, septal nuclei, anterior nuclear group of thalamus, and portions of the basal ganglia. (Parent, Carpenter's Human Neuroanatomy, 9th ed, p744; NeuroNames, http://rprcsgi.rprc.washington.edu/neuronames/index.html (September 2, 1998)). [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together
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from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipid Peroxides: Peroxides produced in the presence of a free radical by the oxidation of unsaturated fatty acids in the cell in the presence of molecular oxygen. The formation of lipid peroxides results in the destruction of the original lipid leading to the loss of integrity of the membranes. They therefore cause a variety of toxic effects in vivo and their formation is considered a pathological process in biological systems. Their formation can be inhibited by antioxidants, such as vitamin E, structural separation or low oxygen tension. [NIH] 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] Liposomal: A drug preparation that contains the active drug in very tiny fat particles. This fat-encapsulated drug is absorbed better, and its distribution to the tumor site is improved. [NIH]
Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver scan: An image of the liver created on a computer screen or on film. A radioactive substance is injected into a blood vessel and travels through the bloodstream. It collects in the liver, especially in abnormal areas, and can be detected by the scanner. [NIH] 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] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Long-Term Care: Care over an extended period, usually for a chronic condition or disability, requiring periodic, intermittent, or continuous care. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically
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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]
Lymphadenopathy: Disease or swelling of the lymph nodes. [NIH] Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphoblastic: One of the most aggressive types of non-Hodgkin lymphoma. [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] Lymphocytic: Referring to lymphocytes, a type of white blood cell. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphokine: A soluble protein produced by some types of white blood cell that stimulates other white blood cells to kill foreign invaders. [NIH] Lymphokine-activated killer cells: White blood cells that are stimulated in a laboratory to kill tumor cells. Also called LAK cells. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lymphopenia: Reduction in the number of lymphocytes. [NIH] Lymphoproliferative: Disorders characterized by proliferation of lymphoid tissue, general or unspecified. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Macrophage Colony-Stimulating Factor: A mononuclear phagocyte colony-stimulating factor synthesized by mesenchymal cells. The compound stimulates the survival, proliferation, and differentiation of hematopoietic cells of the monocyte-macrophage series. M-CSF is a disulfide-bonded glycoprotein dimer with a MW of 70 kDa. It binds to a specific high affinity receptor (receptor, macrophage colony-stimulating factor). [NIH] Macrophage Inflammatory Proteins: Heparin-binding proteins that exhibit a number of inflammatory and immunoregulatory activities. Originally identified as secretory products of macrophages, these chemokines are produced by a variety of cell types including neutrophils, fibroblasts, and epithelial cells. They likely play a significant role in respiratory tract defenses. [NIH] Maculopapular: Both macular and papular, as an eruption consisting of both macules and papules; sometimes erroneously used to designate a papule that is only slightly elevated. [EU]
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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] Maintenance therapy: Treatment that is given to help a primary (original) treatment keep working. Maintenance therapy is often given to help keep cancer in remission. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malabsorption syndrome: A group of symptoms such as gas, bloating, abdominal pain, and diarrhea resulting from the body's inability to properly absorb nutrients. [NIH] Malaria: A protozoan disease caused in humans by four species of the genus Plasmodium (P. falciparum (malaria, falciparum), P. vivax (malaria, vivax), P. ovale, and P. malariae) and transmitted by the bite of an infected female mosquito of the genus Anopheles. Malaria is endemic in parts of Asia, Africa, Central and South America, Oceania, and certain Caribbean islands. It is characterized by extreme exhaustion associated with paroxysms of high fever, sweating, shaking chills, and anemia. Malaria in animals is caused by other species of plasmodia. [NIH] Malaria, Falciparum: Malaria caused by Plasmodium falciparum. This is the severest form of malaria and is associated with the highest levels of parasites in the blood. This disease is characterized by irregularly recurring febrile paroxysms that in extreme cases occur with acute cerebral, renal, or gastrointestinal manifestations. [NIH] Malaria, Vivax: Malaria caused by Plasmodium vivax. This form of malaria is less severe than malaria, falciparum, but there is a higher probability for relapses to occur. Febrile paroxysms often occur every other day. [NIH] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]
Mammary: Pertaining to the mamma, or breast. [EU] Mastication: The act and process of chewing and grinding food in the mouth. [NIH] McMaster: Index used to measure painful syndromes linked to arthrosis. [NIH] Meat: The edible portions of any animal used for food including domestic mammals (the major ones being cattle, swine, and sheep) along with poultry, fish, shellfish, and game. [NIH]
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] Medical Records: Recording of pertinent information concerning patient's illness or illnesses. [NIH] Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical
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Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Megakaryocytes: Very large bone marrow cells which release mature blood platelets. [NIH] Megaloblastic: A large abnormal red blood cell appearing in the blood in pernicious anaemia. [EU] 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] Melanophores: Chromatophores (large pigment cells of fish, amphibia, reptiles and many invertebrates) which contain melanin. Short term color changes are brought about by an active redistribution of the melanophores pigment containing organelles (melanosomes). Mammals do not have melanophores; however they have retained smaller pigment cells known as melanocytes. [NIH] Melanosis: Disorders of increased melanin pigmentation that develop without preceding inflammatory disease. [NIH] Melanosomes: Melanin-containing organelles found in melanocytes and melanophores. [NIH]
Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Meningitis: Inflammation of the meninges. When it affects the dura mater, the disease is termed pachymeningitis; when the arachnoid and pia mater are involved, it is called leptomeningitis, or meningitis proper. [EU] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [NIH]
Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning.
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Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesoderm: The middle germ layer of the embryo. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [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] Methoxsalen: A naturally occurring furocoumarin compound found in several species of plants, including Psoralea corylifolia. It is a photoactive substance that forms DNA adducts in the presence of ultraviolet A irradiation. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Mice Minute Virus: The type species of parvovirus prevalent in mouse colonies and found as a contaminant of many transplanted tumors or leukemias. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Microvilli: Minute projections of cell membranes which greatly increase the surface area of the cell. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Mineralocorticoids: A group of corticosteroids primarily associated with the regulation of water and electrolyte balance. This is accomplished through the effect on ion transport in renal tubules, resulting in retention of sodium and loss of potassium. Mineralocorticoid secretion is itself regulated by plasma volume, serum potassium, and angiotensin II. [NIH] Minority Groups: A subgroup having special characteristics within a larger group, often bound together by special ties which distinguish it from the larger group. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH]
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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] Mitotic inhibitors: Drugs that kill cancer cells by interfering with cell division (mitostis). [NIH]
Mixed Connective Tissue Disease: A syndrome with overlapping clinical features of systemic lupus erythematosus, scleroderma, polymyositis, and Raynaud's phenomenon. The disease is differentially characterized by high serum titers of antibodies to ribonucleasesensitive extractable (saline soluble) nuclear antigen and a "speckled" epidermal nuclear staining pattern on direct immunofluorescence. [NIH] Mobility: Capability of movement, of being moved, or of flowing freely. [EU] Mobilization: The process of making a fixed part or stored substance mobile, as by separating a part from surrounding structures to make it accessible for an operative procedure or by causing release into the circulation for body use of a substance stored in the body. [EU] 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] 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] Monocytes: Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. [NIH] Monogenic: A human disease caused by a mutation in a single gene. [NIH] Mononuclear: A cell with one nucleus. [NIH] Monosomy: The condition in which one chromosome of a pair is missing. In a normally diploid cell it is represented symbolically as 2N-1. [NIH] Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH]
Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Mucins: A secretion containing mucopolysaccharides and protein that is the chief
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constituent of mucus. [NIH] Mucociliary: Pertaining to or affecting the mucus membrane and hairs (including eyelashes, nose hair, .): mucociliary clearing: the clearance of mucus by ciliary movement ( particularly in the respiratory system). [EU] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] Multiple Myeloma: A malignant tumor of plasma cells usually arising in the bone marrow; characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria, and anemia. [NIH] Multiple Organ Failure: A progressive condition usually characterized by combined failure of several organs such as the lungs, liver, kidney, along with some clotting mechanisms, usually postinjury or postoperative. [NIH] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Myalgia: Pain in a muscle or muscles. [EU] Mycobacterium: A genus of gram-positive, aerobic bacteria. Most species are free-living in soil and water, but the major habitat for some is the diseased tissue of warm-blooded hosts. [NIH]
Mycobacterium avium: A bacterium causing tuberculosis in domestic fowl and other birds. In pigs, it may cause localized and sometimes disseminated disease. The organism occurs occasionally in sheep and cattle. It should be distinguished from the M. avium complex, which infects primarily humans. [NIH] Mycobacterium bovis: The bovine variety of the tubercle bacillus. It is called also Mycobacterium bovis. [NIH] Myelin: The fatty substance that covers and protects nerves. [NIH] Myelodysplasia: Abnormal bone marrow cells that may lead to myelogenous leukemia. [NIH]
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Myelodysplastic syndrome: Disease in which the bone marrow does not function normally. Also called preleukemia or smoldering leukemia. [NIH] Myelofibrosis: A disorder in which the bone marrow is replaced by fibrous tissue. [NIH] Myelogenous: Produced by, or originating in, the bone marrow. [NIH] Myeloid Cells: Cells which include the monocytes and the granulocytes. [NIH] Myeloproliferative Disorders: Disorders in which one or more stimuli cause proliferation of hemopoietically active tissue or of tissue which has embryonic hemopoietic potential. [NIH] Myelosuppression: A condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. Myelosuppression is a side effect of some cancer treatments. [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] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myofibrils: Highly organized bundles of actin, myosin, and other proteins in the cytoplasm of skeletal and cardiac muscle cells that contract by a sliding filament mechanism. [NIH] Myositis: Inflammation of a voluntary muscle. [EU] Myotonia: Prolonged failure of muscle relaxation after contraction. This may occur after voluntary contractions, muscle percussion, or electrical stimulation of the muscle. Myotonia is a characteristic feature of myotonic disorders. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Nasal Mucosa: The mucous membrane lining the nasal cavity. [NIH] Natural selection: A part of the evolutionary process resulting in the survival and reproduction of the best adapted individuals. [NIH] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Necrolysis: Separation or exfoliation of tissue due to necrosis. [EU] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH]
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Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephritis: Inflammation of the kidney; a focal or diffuse proliferative or destructive process which may involve the glomerulus, tubule, or interstitial renal tissue. [EU] Nephrology: A subspecialty of internal medicine concerned with the anatomy, physiology, and pathology of the kidney. [NIH] Nephropathy: Disease of the kidneys. [EU] Nephrosis: Descriptive histopathologic term for renal disease without an inflammatory component. [NIH] Nephrotic: Pertaining to, resembling, or caused by nephrosis. [EU] Nephrotic Syndrome: Clinical association of heavy proteinuria, hypoalbuminemia, and generalized edema. [NIH] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of the nervous system. [NIH] 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] Neuropeptides: Peptides released by neurons as intercellular messengers. Many neuropeptides are also hormones released by non-neuronal cells. [NIH] 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
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nuclei during their decay. [NIH] Neutropenia: An abnormal decrease in the number of neutrophils, a type of white blood cell. [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] Nickel: A trace element with the atomic symbol Ni, atomic number 28, and atomic weight 58.69. It is a cofactor of the enzyme urease. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]
Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] 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 Medicine: A specialty field of radiology concerned with diagnostic, therapeutic, and investigative use of radioactive compounds in a pharmaceutical form. [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] Nucleoli: A small dense body (sub organelle) within the nucleus of eukaryotic cells, visible by phase contrast and interference microscopy in live cells throughout interphase. Contains RNA and protein and is the site of synthesis of ribosomal RNA. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Obstetrics: A medical-surgical specialty concerned with management and care of women during pregnancy, parturition, and the puerperium. [NIH] Oligopeptides: Peptides composed of between two and twelve amino acids. [NIH] Oligosaccharides: Carbohydrates consisting of between two and ten monosaccharides connected by either an alpha- or beta-glycosidic link. They are found throughout nature in both the free and bound form. [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]
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Opacity: Degree of density (area most dense taken for reading). [NIH] Open Reading Frames: Reading frames where successive nucleotide triplets can be read as codons specifying amino acids and where the sequence of these triplets is not interrupted by stop codons. [NIH] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] 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] Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [NIH] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Oral Health: The optimal state of the mouth and normal functioning of the organs of the mouth without evidence of disease. [NIH] Oral Manifestations: Disorders of the mouth attendant upon non-oral disease or injury. [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] 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] 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] Otorhinolaryngology: That branch of medicine concerned with medical and surgical treatment of the head and neck, including the ears, nose and throat. [EU] 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] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Ovum Implantation: Endometrial implantation of the blastocyst. [NIH] Oxaliplatin: An anticancer drug that belongs to the family of drugs called platinum compounds. [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
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molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]
Oxygenator: An apparatus by which oxygen is introduced into the blood during circulation outside the body, as during open heart surgery. [NIH] Pachymeningitis: Inflammation of the dura mater of the brain, the spinal cord or the optic nerve. [NIH] Paclitaxel: Antineoplastic agent isolated from the bark of the Pacific yew tree, Taxus brevifolia. Paclitaxel stabilizes microtubules in their polymerized form and thus mimics the action of the proto-oncogene proteins c-mos. [NIH] Palate: The structure that forms the roof of the mouth. It consists of the anterior hard palate and the posterior soft palate. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Palsy: Disease of the peripheral nervous system occurring usually after many years of increased lead absorption. [NIH] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Pancreatitis: Acute or chronic inflammation of the pancreas, which may be asymptomatic or symptomatic, and which is due to autodigestion of a pancreatic tissue by its own enzymes. It is caused most often by alcoholism or biliary tract disease; less commonly it may be associated with hyperlipaemia, hyperparathyroidism, abdominal trauma (accidental or operative injury), vasculitis, or uraemia. [EU] Pancytopenia: Deficiency of all three cell elements of the blood, erythrocytes, leukocytes and platelets. [NIH] Papilloma: A benign epithelial neoplasm which may arise from the skin, mucous membranes or glandular ducts. [NIH] Papillomavirus: A genus of Papovaviridae causing proliferation of the epithelium, which may lead to malignancy. A wide range of animals are infected including humans, chimpanzees, cattle, rabbits, dogs, and horses. [NIH] Paralysis: Loss of ability to move all or part of the body. [NIH] Paranasal Sinuses: Air-filled extensions of the respiratory part of the nasal cavity into the frontal, ethmoid, sphenoid, and maxillary cranial bones. They vary in size and form in different individuals and are lined by the ciliated mucous membranes of the nasal cavity. [NIH]
Parathyroid: 1. Situated beside the thyroid gland. 2. One of the parathyroid glands. 3. A sterile preparation of the water-soluble principle(s) of the parathyroid glands, ad-ministered parenterally as an antihypocalcaemic, especially in the treatment of acute hypoparathyroidism with tetany. [EU] Parathyroid Glands: Two small paired endocrine glands in the region of the thyroid gland. They secrete parathyroid hormone and are concerned with the metabolism of calcium and phosphorus. [NIH] Parathyroid hormone: A substance made by the parathyroid gland that helps the body store and use calcium. Also called parathormone, parathyrin, or PTH. [NIH]
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Parenchyma: The essential elements of an organ; used in anatomical nomenclature as a general term to designate the functional elements of an organ, as distinguished from its framework, or stroma. [EU] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. [EU] Parotid: The space that contains the parotid gland, the facial nerve, the external carotid artery, and the retromandibular vein. [NIH] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [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] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]
Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [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] Pelvic inflammatory disease: A bacteriological disease sometimes associated with intrauterine device (IUD) usage. [NIH] Penicillin: An antibiotic drug used to treat infection. [NIH] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] Pentostatin: A potent inhibitor of adenosine deaminase. The drug is effective in the treatment of many lymphoproliferative malignancies, particularly hairy-cell leukemia. It is also synergistic with some other antineoplastic agents and has immunosuppressive activity.
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[NIH]
Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Perianal: Located around the anus. [EU] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]
Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Periodontitis: Inflammation of the periodontal membrane; also called periodontitis simplex. [NIH]
Perioperative: Around the time of surgery; usually lasts from the time of going into the hospital or doctor's office for surgery until the time the patient goes home. [NIH] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peripheral stem cells: Immature cells found circulating in the bloodstream. New blood cells develop from peripheral stem cells. [NIH] Pernicious: Tending to a fatal issue. [EU] Pernicious anemia: A type of anemia (low red blood cell count) caused by the body's inability to absorb vitamin B12. [NIH] Petechiae: Pinpoint, unraised, round red spots under the skin caused by bleeding. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] Pharmacodynamic: Is concerned with the response of living tissues to chemical stimuli, that is, the action of drugs on the living organism in the absence of disease. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH]
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Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylase: An enzyme of the transferase class that catalyzes the phosphorylysis of a terminal alpha-1,4-glycosidic bond at the non-reducing end of a glycogen molecule, releasing a glucose 1-phosphate residue. Phosphorylase should be qualified by the natural substance acted upon. EC 2.4.1.1. [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photochemotherapy: Therapy using oral or topical photosensitizing agents with subsequent exposure to light. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Photopheresis: A process in which peripheral blood is exposed in an extracorporeal flow system to photoactivated 8-methoxypsoralen (methoxsalen) and ultraviolet light - a procedure known as PUVA therapy. Photopheresis is at present a standard therapy for advanced cutaneous T-cell lymphoma; it shows promise in the treatment of autoimmune diseases. [NIH] Photosensitizing Agents: Drugs that are pharmacologically inactive but when exposed to ultraviolet radiation or sunlight are converted to their active metabolite to produce a beneficial reaction affecting the diseased tissue. These compounds can be administered topically or systemically and have been used therapeutically to treat psoriasis and various types of neoplasms. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]
Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH]
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Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pigmentation: Coloration or discoloration of a part by a pigment. [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] Pityriasis: A name originally applied to a group of skin diseases characterized by the formation of fine, branny scales, but now used only with a modifier. [EU] Pityriasis Rosea: A mild exanthematous inflammation of unknown etiology. It is characterized by the presence of salmon-colored maculopapular lesions. The most striking feature is the arrangement of the lesions such that the long axis is parallel to the lines of cleavage. The eruptions are usually generalized, affecting chiefly the trunk, and the course is often self-limiting. [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] Plant sterols: Plant-based compounds that can compete with dietary cholesterol to be absorbed by the intestines. This results in lower blood cholesterol levels. They may have some effect in cancer prevention. Also known as phytosterols. [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 Exchange: Removal of plasma and replacement with various fluids, e.g., fresh frozen plasma, plasma protein fractions (PPF), albumin preparations, dextran solutions, saline. Used in treatment of autoimmune diseases, immune complex diseases, diseases of excess plasma factors, and other conditions. [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] Plasma Volume: Volume of plasma in the circulation. It is usually measured by indicator dilution techniques. [NIH] Plasmacytoma: Any discrete, presumably solitary, mass of neoplastic plasma cells either in bone marrow or various extramedullary sites. [NIH] 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]
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Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [NIH] Platelet 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]
Platelet Storage Pool Deficiency: Disorder characterized by a decrease or lack of platelet dense bodies in which the releasable pool of adenine nucleotides and 5HT are normally stored. [NIH] Platelet Transfusion: The transfer of blood platelets from a donor to a recipient or reinfusion to the donor. [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]
Platinum Compounds: Inorganic compounds which contain platinum as the central atom. [NIH]
Ploidy: The number of sets of chromosomes in a cell or an organism. For example, haploid means one set and diploid means two sets. [NIH] Podophyllotoxin: The main active constituent of the resin from the roots of may apple or mandrake (Podophyllum peltatum and P. emodi). It is a potent spindle poison, toxic if taken internally, and has been used as a cathartic. It is very irritating to skin and mucous membranes, has keratolytic actions, has been used to treat warts and keratoses, and may have antineoplastic properties, as do some of its congeners and derivatives. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [NIH]
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Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polyarteritis Nodosa: A form of necrotizing vasculitis involving small- and medium-sized arteries. The signs and symptoms result from infarction and scarring of the affected organ system. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polycythemia Vera: A myeloproliferative disorder of unknown etiology, characterized by abnormal proliferation of all hematopoietic bone marrow elements and an absolute increase in red cell mass and total blood volume, associated frequently with splenomegaly, leukocytosis, and thrombocythemia. Hematopoiesis is also reactive in extramedullary sites (liver and spleen). In time myelofibrosis occurs. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polyploid: An organism with more than two chromosome sets in its vegetative cells. [NIH] Polyploidy: The chromosomal constitution of a cell containing multiples of the normal number of chromosomes; includes triploidy (symbol: 3N), tetraploidy (symbol: 4N), etc. [NIH]
Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polytherapy: A therapy which uses more than one drug. [EU] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postoperative: After surgery. [NIH] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-traumatic: Occurring as a result of or after injury. [EU] 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]
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Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] 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] Prednisolone: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. [NIH] Prednisone: A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. [NIH] Preeclampsia: A toxaemia of late pregnancy characterized by hypertension, edema, and proteinuria, when convulsions and coma are associated, it is called eclampsia. [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] Pre-eclamptic: A syndrome characterized by hypertension, albuminuria, and generalized oedema, occurring only in pregnancy. [NIH] Preleukemia: Conditions in which the abnormalities in the peripheral blood or bone marrow represent the early manifestations of acute leukemia, but in which the changes are not of sufficient magnitude or specificity to permit a diagnosis of acute leukemia by the usual clinical criteria. [NIH] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Primary central nervous system lymphoma: Cancer that arises in the lymphoid tissue found in the central nervous system (CNS). The CNS includes the brain and spinal cord. [NIH]
Primary endpoint: The main result that is measured at the end of a study to see if a given treatment worked (e.g., the number of deaths or the difference in survival between the treatment group and the control group). What the primary endpoint will be is decided before the study begins. [NIH] 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] Prognostic factor: A situation or condition, or a characteristic of a patient, that can be used to estimate the chance of recovery from a disease, or the chance of the disease recurring (coming back). [NIH]
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Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] 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] Prone: Having the front portion of the body downwards. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Propylene Glycol: A clear, colorless, viscous organic solvent and diluent used in pharmaceutical preparations. [NIH] Prospective Studies: Observation of a population for a sufficient number of persons over a sufficient number of years to generate incidence or mortality rates subsequent to the selection of the study group. [NIH] 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] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein 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,
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phospholipid, and calcium ions. Deficiency of prothrombin leads to hypoprothrombinemia. [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] Proto-Oncogene Proteins: Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity. [NIH] Proto-Oncogene Proteins c-mos: Cellular proteins encoded by the c-mos genes. They function in the cell cycle to maintain maturation promoting factor in the active state and have protein-serine/threonine kinase activity. Oncogenic transformation can take place when c-mos proteins are expressed at the wrong time. [NIH] Pruritic: Pertaining to or characterized by pruritus. [EU] Pseudopodia: A dynamic actin-rich extension of the surface of an animal cell used for locomotion or prehension of food. [NIH] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychomotor: Pertaining to motor effects of cerebral or psychic activity. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]
Puerperium: Period from delivery of the placenta until return of the reproductive organs to their normal nonpregnant morphologic state. In humans, the puerperium generally lasts for six to eight weeks. [NIH] Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Embolism: Embolism in the pulmonary artery or one of its branches. [NIH] 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
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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] Pustular: Pertaining to or of the nature of a pustule; consisting of pustules (= a visible collection of pus within or beneath the epidermis). [EU] Putrefaction: The process of decomposition of animal and vegetable matter by living organisms. [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] Quiescent: Marked by a state of inactivity or repose. [EU] Quinidine: An optical isomer of quinine, extracted from the bark of the Cinchona tree and similar plant species. This alkaloid dampens the excitability of cardiac and skeletal muscles by blocking sodium and potassium currents across cellular membranes. It prolongs cellular action potential, and decreases automaticity. Quinidine also blocks muscarinic and alphaadrenergic neurotransmission. [NIH] Quinine: An alkaloid derived from the bark of the cinchona tree. It is used as an antimalarial drug, and is the active ingredient in extracts of the cinchona that have been used for that purpose since before 1633. Quinine is also a mild antipyretic and analgesic and has been used in common cold preparations for that purpose. It was used commonly and as a bitter and flavoring agent, and is still useful for the treatment of babesiosis. Quinine is also useful in some muscular disorders, especially nocturnal leg cramps and myotonia congenita, because of its direct effects on muscle membrane and sodium channels. The mechanisms of its antimalarial effects are not well understood. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] 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] Radioimmunotherapy: Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (immunotoxins) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (radiotherapy). [NIH] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH]
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Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Radiopharmaceutical: Any medicinal product which, when ready for use, contains one or more radionuclides (radioactive isotopes) included for a medicinal purpose. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Radius: The lateral bone of the forearm. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Reactivation: The restoration of activity to something that has been inactivated. [EU] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombinant Proteins: Proteins prepared by recombinant DNA technology. [NIH] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Reconstitution: 1. A type of regeneration in which a new organ forms by the rearrangement of tissues rather than from new formation at an injured surface. 2. The restoration to original form of a substance previously altered for preservation and storage, as the restoration to a liquid state of blood serum or plasma that has been dried and stored. [EU] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH]
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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] Regional lymph node: In oncology, a lymph node that drains lymph from the region around a tumor. [NIH] Relapse: The return of signs and symptoms of cancer after a period of improvement. [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] Remission Induction: Therapeutic act or process that initiates a response to a complete or partial remission level. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Repressor: Any of the specific allosteric protein molecules, products of regulator genes, which bind to the operator of operons and prevent RNA polymerase from proceeding into the operon to transcribe messenger RNA. [NIH] Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [NIH] Resolving: The ability of the eye or of a lens to make small objects that are close together, separately visible; thus revealing the structure of an object. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respiratory failure: Inability of the lungs to conduct gas exchange. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Reticular: Coarse-fibered, netlike dermis layer. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It
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occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retinopathy: 1. Retinitis (= inflammation of the retina). 2. Retinosis (= degenerative, noninflammatory condition of the retina). [EU] Retreatment: The therapy of the same disease in a patient, with the same agent or procedure repeated after initial treatment, or with an additional or alternate measure or follow-up. It does not include therapy which requires more than one administration of a therapeutic agent or regimen. Retreatment is often used with reference to a different modality when the original one was inadequate, harmful, or unsuccessful. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Rheumatic Diseases: Disorders of connective tissue, especially the joints and related structures, characterized by inflammation, degeneration, or metabolic derangement. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Riboflavin: Nutritional factor found in milk, eggs, malted barley, liver, kidney, heart, and leafy vegetables. The richest natural source is yeast. It occurs in the free form only in the retina of the eye, in whey, and in urine; its principal forms in tissues and cells are as FMN and FAD. [NIH] Ribonuclease: RNA-digesting enzyme. [NIH] Ribonucleoside Diphosphate Reductase: An enzyme of the oxidoreductase class that catalyzes the formation of 2'-deoxyribonucleotides from the corresponding ribonucleotides using NADPH as the ultimate electron donor. The deoxyribonucleoside diphosphates are used in DNA synthesis. (From Dorland, 27th ed) EC 1.17.4.1. [NIH] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rituximab: A type of monoclonal antibody used in cancer detection or therapy. Monoclonal antibodies are laboratory-produced substances that can locate and bind to cancer cells. [NIH] Rod: A reception for vision, located in the retina. [NIH] Saline: A solution of salt and water. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Saphenous: Applied to certain structures in the leg, e. g. nerve vein. [NIH] Saphenous Vein: The vein which drains the foot and leg. [NIH] Sarcoidosis: An idiopathic systemic inflammatory granulomatous disorder comprised of epithelioid and multinucleated giant cells with little necrosis. It usually invades the lungs with fibrosis and may also involve lymph nodes, skin, liver, spleen, eyes, phalangeal bones,
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and parotid glands. [NIH] Sarcoma: A connective tissue neoplasm formed by proliferation of mesodermal cells; it is usually highly malignant. [NIH] Scans: Pictures of structures inside the body. Scans often used in diagnosing, staging, and monitoring disease include liver scans, bone scans, and computed tomography (CT) or computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) scans. In liver scanning and bone scanning, radioactive substances that are injected into the bloodstream collect in these organs. A scanner that detects the radiation is used to create pictures. In CT scanning, an x-ray machine linked to a computer is used to produce detailed pictures of organs inside the body. MRI scans use a large magnet connected to a computer to create pictures of areas inside the body. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Scleroderma: A chronic disorder marked by hardening and thickening of the skin. Scleroderma can be localized or it can affect the entire body (systemic). [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Sebaceous: Gland that secretes sebum. [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] Sediment: A precipitate, especially one that is formed spontaneously. [EU] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] 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] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Senescence: The bodily and mental state associated with advancing age. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sepsis: The presence of bacteria in the bloodstream. [NIH]
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Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU] Sequencer: Device that reads off the order of nucleotides in a cloned gene. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [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] Serositis: Inflammation of a serous membrane. [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 in atrophic rhinitis of pigs. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]
Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Sinusitis: An inflammatory process of the mucous membranes of the paranasal sinuses that occurs in three stages: acute, subacute, and chronic. Sinusitis results from any condition causing ostial obstruction or from pathophysiologic changes in the mucociliary transport mechanism. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH]
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Small cell lung cancer: A type of lung cancer in which the cells appear small and round when viewed under the microscope. Also called oat cell lung cancer. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smoldering leukemia: Disease in which the bone marrow does not function normally. Also called preleukemia or myelodysplastic syndrome. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [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 Support: Support systems that provide assistance and encouragement to individuals with physical or emotional disabilities in order that they may better cope. Informal social support is usually provided by friends, relatives, or peers, while formal assistance is provided by churches, groups, etc. [NIH] 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] 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] Sodium Channels: Cell membrane glycoproteins selective for sodium ions. Fast sodium current is associated with the action potential in neural membranes. [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] Somatic cells: All the body cells except the reproductive (germ) cells. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by
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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] Spirochete: Lyme disease. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Splenectomy: An operation to remove the spleen. [NIH] Splenomegaly: Enlargement of the spleen. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Squamous: Scaly, or platelike. [EU] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cells: Flat cells that look like fish scales under a microscope. These cells cover internal and external surfaces of the body. [NIH] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]
Standard therapy: A currently accepted and widely used treatment for a certain type of cancer, based on the results of past research. [NIH] Staphylococcus: A genus of gram-positive, facultatively anaerobic, coccoid bacteria. Its organisms occur singly, in pairs, and in tetrads and characteristically divide in more than one plane to form irregular clusters. Natural populations of Staphylococcus are membranes of warm-blooded animals. Some species are opportunistic pathogens of humans and animals. [NIH] Staphylococcus aureus: Potentially pathogenic bacteria found in nasal membranes, skin, hair follicles, and perineum of warm-blooded animals. They may cause a wide range of infections and intoxications. [NIH] Steatosis: Fatty degeneration. [EU] 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 cell transplantation: A method of replacing immature blood-forming cells that were destroyed by cancer treatment. The stem cells are given to the person after treatment to help the bone marrow recover and continue producing healthy blood cells. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the
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ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stent: A device placed in a body structure (such as a blood vessel or the gastrointestinal tract) to provide support and keep the structure open. [NIH] Sterile: Unable to produce children. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroids: Drugs used to relieve swelling and inflammation. [NIH] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]
Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stomatitis: Inflammation of the oral mucosa, due to local or systemic factors which may involve the buccal and labial mucosa, palate, tongue, floor of the mouth, and the gingivae. [EU]
Stool: The waste matter discharged in a bowel movement; feces. [NIH] Streptococci: A genus of spherical Gram-positive bacteria occurring in chains or pairs. They are widely distributed in nature, being important pathogens but often found as normal commensals in the mouth, skin, and intestine of humans and other animals. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stress management: A set of techniques used to help an individual cope more effectively with difficult situations in order to feel better emotionally, improve behavioral skills, and often to enhance feelings of control. Stress management may include relaxation exercises, assertiveness training, cognitive restructuring, time management, and social support. It can be delivered either on a one-to-one basis or in a group format. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stroma: The middle, thickest layer of tissue in the cornea. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [NIH] 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] Subiculum: A region of the hippocampus that projects to other areas of the brain. [NIH] Submandibular: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH]
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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]
Supplementation: Adding nutrients to the diet. [NIH] Support group: A group of people with similar disease who meet to discuss how better to cope with their cancer and treatment. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suppurative: Consisting of, containing, associated with, or identified by the formation of pus. [NIH] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Synostosis: The joining of contiguous and separate bones by osseous tissue. [NIH] Syphilis: A contagious venereal disease caused by the spirochete Treponema pallidum. [NIH]
Systemic: Affecting the entire body. [NIH] Systemic disease: Disease that affects the whole body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tachycardia: Excessive rapidity in the action of the heart, usually with a heart rate above 100 beats per minute. [NIH] Tachypnea: Rapid breathing. [NIH] Taurine: 2-Aminoethanesulfonic acid. A conditionally essential nutrient, important during mammalian development. It is present in milk but is isolated mostly from ox bile and strongly conjugates bile acids. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] 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] Temporal Lobe: Lower lateral part of the cerebral hemisphere. [NIH] Testicular: Pertaining to a testis. [EU]
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Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Tetany: 1. Hyperexcitability of nerves and muscles due to decrease in concentration of extracellular ionized calcium, which may be associated with such conditions as parathyroid hypofunction, vitamin D deficiency, and alkalosis or result from ingestion of alkaline salts; it is characterized by carpopedal spasm, muscular twitching and cramps, laryngospasm with inspiratory stridor, hyperreflexia and choreiform movements. 2. Tetanus. [EU] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Thalassemia: A group of hereditary hemolytic anemias in which there is decreased synthesis of one or more hemoglobin polypeptide chains. There are several genetic types with clinical pictures ranging from barely detectable hematologic abnormality to severe and fatal anemia. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [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] Thrombasthenia: A congenital bleeding disorder with prolonged bleeding time, absence of aggregation of platelets in response to most agents, especially ADP, and impaired or absent clot retraction. Platelet membranes are deficient in or have a defect in the glycoprotein IIbIIIa complex (platelet glycoprotein GPIIB-IIIA complex). [NIH] Thrombectomy: Surgical removal of an obstructing clot or foreign material from a blood vessel at the point of its formation. Removal of a clot arising from a distant site is called embolectomy. [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] Thrombocytosis: Increased numbers of platelets in the peripheral blood. [EU] Thromboembolism: Obstruction of a vessel by a blood clot that has been transported from a distant site by the blood stream. [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
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thrombosis. [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] Thrombopoietin: A humoral factor that controls blood platelet production through stimulation of megakaryocyte populations. Bone marrow megakaryocytes increase in both size and number in response to exposure to thrombopoietin. [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] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tic: An involuntary compulsive, repetitive, stereotyped movement, resembling a purposeful movement because it is coordinated and involves muscles in their normal synergistic relationships; tics usually involve the face and shoulders. [EU] Tick-Borne Diseases: Bacterial, viral, or parasitic diseases transmitted to humans and animals by the bite of infected ticks. The families Ixodidae and Argasidae contain many bloodsucking species that are important pests of man and domestic birds and mammals and probably exceed all other arthropods in the number and variety of disease agents they transmit. Many of the tick-borne diseases are zoonotic. [NIH] Ticlopidine: Ticlopidine is an effective inhibitor of platelet aggregation. The drug has been found to significantly reduce infarction size in acute myocardial infarcts and is an effective antithrombotic agent in arteriovenous fistulas, aorto-coronary bypass grafts, ischemic heart disease, venous thrombosis, and arteriosclerosis. [NIH] Time Management: Planning and control of time to improve efficiency and effectiveness. [NIH]
Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Titre: The quantity of a substance required to produce a reaction with a given volume of another substance, or the amount of one substance required to correspond with a given amount of another substance. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tonic: 1. Producing and restoring the normal tone. 2. Characterized by continuous tension. 3. A term formerly used for a class of medicinal preparations believed to have the power of restoring normal tone to tissue. [EU]
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Tonicity: The normal state of muscular tension. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Topoisomerase inhibitors: A family of anticancer drugs. The topoisomerase enzymes are responsible for the arrangement and rearrangement of DNA in the cell and for cell growth and replication. Inhibiting these enzymes may kill cancer cells or stop their growth. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Toxaemia: 1. The condition resulting from the spread of bacterial products (toxins) by the bloodstream. 2. A condition resulting from metabolic disturbances, e.g. toxaemia of pregnancy. [EU] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] 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] Transgenes: Genes that are introduced into an organism using gene transfer techniques. [NIH]
Translating: Conversion from one language to another language. [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]
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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] Trauma Centers: Specialized hospital facilities which provide diagnostic and therapeutic services for trauma patients. [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] Triad: Trivalent. [NIH] Trigeminal: Cranial nerve V. It is sensory for the eyeball, the conjunctiva, the eyebrow, the skin of face and scalp, the teeth, the mucous membranes in the mouth and nose, and is motor to the muscles of mastication. [NIH] Trisomy: The possession of a third chromosome of any one type in an otherwise diploid cell. [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] Trypsin: A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tubercle: A rounded elevation on a bone or other structure. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] 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] Typhoid fever: The most important member of the enteric group of fevers which also includes the paratyphoids. [NIH] Typhoid fever: The most important member of the enteric group of fevers which also includes the paratyphoids. [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] Ulceration: 1. The formation or development of an ulcer. 2. An ulcer. [EU] Ulcerative colitis: Chronic inflammation of the colon that produces ulcers in its lining. This condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and
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mucus from the bowel. [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] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Unnecessary Procedures: Diagnostic, therapeutic, and investigative procedures prescribed and performed by health professionals, the results of which do not justify the benefits or hazards and costs to the patient. [NIH] Uraemia: 1. An excess in the blood of urea, creatinine, and other nitrogenous end products of protein and amino acids metabolism; more correctly referred to as azotemia. 2. In current usage the entire constellation of signs and symptoms of chronic renal failure, including nausea, vomiting anorexia, a metallic taste in the mouth, a uraemic odour of the breath, pruritus, uraemic frost on the skin, neuromuscular disorders, pain and twitching in the muscles, hypertension, edema, mental confusion, and acid-base and electrolyte imbalances. [EU]
Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] 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] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]
Uric: A kidney stone that may result from a diet high in animal protein. When the body breaks down this protein, uric acid levels rise and can form stones. [NIH] Urinalysis: Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urogenital: Pertaining to the urinary and genital apparatus; genitourinary. [EU] Urology: A surgical specialty concerned with the study, diagnosis, and treatment of diseases of the urinary tract in both sexes and the genital tract in the male. It includes the specialty of andrology which addresses both male genital diseases and male infertility. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage,
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secretion, or excretion. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vaginal: Of or having to do with the vagina, the birth canal. [NIH] Vaginitis: Inflammation of the vagina characterized by pain and a purulent discharge. [NIH] Valproic Acid: A fatty acid with anticonvulsant properties used in the treatment of epilepsy. The mechanisms of its therapeutic actions are not well understood. It may act by increasing GABA levels in the brain or by altering the properties of voltage dependent sodium channels. [NIH] Varicella: Chicken pox. [EU] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasculitis: Inflammation of a blood vessel. [NIH] Vasoactive: Exerting an effect upon the calibre of blood vessels. [EU] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilators: Any nerve or agent which induces dilatation of the blood vessels. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vegetative: 1. Concerned with growth and with nutrition. 2. Functioning involuntarily or unconsciously, as the vegetative nervous system. 3. Resting; denoting the portion of a cell cycle during which the cell is not involved in replication. 4. Of, pertaining to, or characteristic of plants. [EU] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venereal: Pertaining or related to or transmitted by sexual contact. [EU] Venom: That produced by the poison glands of the mouth and injected by the fangs of poisonous snakes. [NIH] Venous: Of or pertaining to the veins. [EU] Venous blood: Blood that has given up its oxygen to the tissues and carries carbon dioxide back for gas exchange. [NIH] Venous Thrombosis: The formation or presence of a thrombus within a vein. [NIH] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Verruca: A circumscribed, cutaneous excrescence having a papilliferous surface; a small, circumscribed, epidermal tumor. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] 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]
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Vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. [NIH] Vinca Alkaloids: A class of alkaloids from the genus of apocyanaceous woody herbs including periwinkles. They are some of the most useful antineoplastic agents. [NIH] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Load: The quantity of measurable virus in the blood. Change in viral load, measured in plasma, is used as a surrogate marker in HIV disease progression. [NIH] Viremia: The presence of viruses in the blood. [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] Vitelline Membrane: The plasma membrane of the egg. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Vulgaris: An affection of the skin, especially of the face, the back and the chest, due to chronic inflammation of the sebaceous glands and the hair follicles. [NIH] War: Hostile conflict between organized groups of people. [NIH] Warfarin: An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. [NIH] Warts: Benign epidermal proliferations or tumors; some are viral in origin. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]
Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] Xenopus: An aquatic genus of the family Pipidae, occurring in Africa and distinguished by having black horny claws on three inner hind toes. [NIH] Xerostomia: Decreased salivary flow. [NIH]
Dictionary 297
X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Yolk Sac: An embryonic membrane formed from endoderm and mesoderm. In reptiles and birds it incorporates the yolk into the digestive tract for nourishing the embryo. In placental mammals its nutritional function is vestigial; however, it is the source of most of the intestinal mucosa and the site of formation of the germ cells. It is sometimes called the vitelline sac, which should not be confused with the vitelline membrane of the egg. [NIH] Zoonoses: Diseases of non-human animals that may be transmitted to man or may be transmitted from man to non-human animals. [NIH] Zoster: A virus infection of the Gasserian ganglion and its nerve branches, characterized by discrete areas of vesiculation of the epithelium of the forehead, the nose, the eyelids, and the cornea together with subepithelial infiltration. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]
299
INDEX 2 2-Aminopurine, 149, 211 A Abdominal, 81, 82, 96, 211, 243, 261, 270, 293 Abdominal Pain, 211, 243, 261, 293 Aberrant, 26, 130, 158, 211 Abscess, 82, 211 Acanthosis Nigricans, 169, 211 Accelerated phase, 69, 211 Acceptor, 211, 259, 269, 292 Acetylcholine, 211, 227, 268 Acetylcholinesterase, 141, 144, 159, 211 Actin, 14, 16, 36, 49, 211, 266, 279 Actinomycosis, 168, 211 Acute leukemia, 11, 88, 211, 277 Acute myelogenous leukemia, 62, 211 Acute myeloid leukemia, 10, 35, 211 Acute nonlymphocytic leukemia, 211 Acute renal, 49, 211, 249 Adaptability, 212, 225 Adaptation, 46, 212, 275 Adenine, 211, 212, 275, 279 Adenosine, 212, 271, 273 Adenosine Deaminase, 212, 271 Adenovirus, 44, 212 Adipose Tissue, 212, 259 Adjustment, 212 Adrenal Cortex, 212, 231, 232, 277 Adrenal Glands, 212, 214 Adrenergic, 212, 236, 239, 280 Adsorption, 46, 212 Adsorptive, 212 Adverse Effect, 77, 96, 134, 212, 285 Aerobic, 212, 263, 265 Aerosol, 25, 212 Afferent, 212, 241 Affinity, 7, 10, 11, 49, 154, 212, 213, 218, 260, 286 Agar, 213, 229, 274 Agarose, 10, 213 Agonist, 31, 127, 128, 131, 150, 157, 213, 236 Airway, 11, 213 Albumin, 19, 213, 274 Algorithms, 213, 221 Alimentary, 213, 256, 271 Alkaline, 213, 222, 290
Alkaloid, 213, 223, 228, 280 Alleles, 38, 213, 250 Allo, 28, 213 Allogeneic, 23, 90, 213, 246 Allograft, 23, 213 Alopecia, 213, 232 Alpha Particles, 213, 280 Alternative medicine, 174, 213 Amber, 214, 253 Ameliorated, 48, 214 Amenorrhea, 101, 214 Amino Acid Sequence, 134, 142, 144, 214, 216, 240, 244 Amino Acids, 128, 138, 144, 214, 244, 268, 269, 272, 276, 278, 285, 294 Amplification, 132, 214 Amygdala, 24, 214, 220, 258, 290 Amyloidosis, 169, 214 Anaemia, 92, 165, 214, 262 Anaesthesia, 76, 89, 214, 253 Anal, 214, 239 Analgesic, 214, 280 Analog, 214, 242, 252 Analogous, 214, 292 Analytes, 194, 214 Anaphylatoxins, 214, 229 Anaplasia, 215 Anatomical, 215, 218, 253, 271, 284 Androgens, 212, 215, 232 Anesthesia, 65, 87, 99, 213, 215, 238 Aneuploidy, 158, 215 Angina, 151, 154, 215 Angina Pectoris, 154, 215 Angiogenesis, 7, 39, 50, 215 Angioplasty, 32, 151, 215 Animal model, 31, 32, 35, 37, 38, 45, 53, 105, 158, 215 Anionic, 65, 215 Anions, 213, 215, 256 Anorexia, 215, 237, 243, 294 Antagonism, 31, 215 Anthracycline, 215, 233 Antiallergic, 216, 232 Antibacterial, 216, 287 Antibiotic, 23, 167, 215, 216, 233, 257, 271, 287 Antibodies, Anticardiolipin, 216, 217 Antibodies, Antiphospholipid, 216, 217
300 Thrombocytopenia
Antibody, 6, 8, 10, 18, 23, 26, 27, 28, 29, 32, 39, 46, 48, 54, 56, 57, 60, 65, 91, 119, 120, 126, 127, 128, 131, 135, 140, 146, 150, 213, 216, 229, 233, 239, 248, 250, 252, 253, 254, 255, 257, 261, 264, 280, 281, 283, 286, 297 Antibody therapy, 120, 216 Anticonvulsant, 216, 223, 295 Antigen-Antibody Complex, 216, 229 Antigen-presenting cell, 216, 234 Anti-inflammatory, 9, 216, 218, 232, 245, 277 Anti-Inflammatory Agents, 216, 218, 232 Antimetabolite, 216, 242 Antimicrobial, 41, 167, 216 Antineoplastic, 216, 217, 223, 232, 242, 251, 270, 271, 275, 296 Antineoplastic Agents, 217, 271, 296 Antioxidant, 9, 217 Antiphospholipid Syndrome, 167, 216, 217 Antipyretic, 217, 280 Antithrombotic, 32, 56, 65, 152, 217, 250, 291 Antiviral, 217, 253, 255 Anus, 214, 217, 222, 256, 272 Aorta, 217, 224, 231, 295 Aortic Aneurysm, 81, 217 Apheresis, 57, 217 Aplasia, 94, 120, 217 Aplastic anemia, 99, 133, 141, 217 Apolipoproteins, 217, 259 Apoptosis, 7, 8, 11, 12, 18, 20, 23, 50, 52, 105, 217, 224 Aqueous, 145, 217, 220, 233, 251, 257 Arachidonic Acid, 217, 252 Arenavirus, 34, 217 Arginine, 214, 217, 268, 293 Arterial, 8, 19, 28, 39, 52, 151, 152, 217, 218, 227, 251, 278, 289 Arteries, 217, 218, 221, 231, 259, 263, 266, 276, 294 Arterioles, 59, 218, 221, 223, 266 Arteriosclerosis, 218, 266, 291 Arteriovenous, 218, 291 Arteriovenous Fistula, 218, 291 Arthrosis, 218, 261 Aspirate, 118, 218 Aspiration, 218 Aspirin, 41, 70, 166, 218 Assay, 11, 43, 135, 151, 218 Astrocytes, 154, 218, 255
Asymptomatic, 14, 55, 167, 218, 220, 270 Ataxia, 189, 218, 290 Atherogenic, 51, 218 Atopic, 167, 218 Atrial, 86, 152, 218, 296 Atrial Fibrillation, 152, 218, 296 Atrium, 218, 224, 295 Atrophy, 189, 218, 267 Attenuated, 60, 219, 235 Attenuation, 24, 219 Atypical, 66, 164, 219, 254 Audiology, 118, 219 Autoantibodies, 8, 10, 11, 17, 45, 66, 88, 94, 216, 219 Autoantigens, 219 Autodigestion, 219, 270 Autoimmune disease, 17, 45, 139, 167, 168, 216, 219, 265, 273, 274 Autoimmunity, 7, 11, 17, 36, 77, 89, 219 Autologous, 7, 23, 79, 104, 219 Avian, 10, 219 B Babesiosis, 29, 219, 280 Bacillus, 219, 265 Bacteremia, 160, 219 Bacterial Infections, 164, 168, 219 Bacterial Physiology, 212, 219 Bacteriophage, 32, 219, 274, 292 Bacterium, 25, 28, 219, 224, 249, 265 Bacteriuria, 219, 294 Basal Ganglia, 218, 219, 243, 258 Basal Ganglia Diseases, 218, 219 Base, 42, 50, 55, 212, 220, 233, 234, 244, 257, 275, 289, 294 Basement Membrane, 220, 240 Basophils, 136, 220, 246, 258 Benign, 3, 48, 220, 243, 248, 267, 270, 281, 296 Bernard-Soulier Syndrome, 79, 220 Beta-Thalassemia, 22, 220 Bile, 220, 226, 227, 243, 250, 257, 259, 289 Bile Ducts, 220, 243 Bile Pigments, 220, 257 Biliary, 84, 220, 223, 270 Biliary Tract, 220, 223, 270 Bilirubin, 213, 220, 243, 251 Binding Sites, 6, 34, 146, 220 Biochemical, 5, 13, 16, 22, 39, 42, 50, 160, 166, 213, 216, 220, 242, 244, 245, 257 Biogenesis, 39, 42, 58, 220 Biological response modifier, 220, 221, 255 Biological therapy, 220, 247
Index 301
Biopsy, 100, 118, 208, 221, 272 Biosynthesis, 32, 51, 217, 221, 233, 285 Biotechnology, 16, 35, 59, 61, 165, 174, 185, 187, 189, 190, 221 Bioterrorism, 34, 221 Bladder, 221, 265, 278, 294 Blast phase, 211, 221, 227 Blastocyst, 221, 230, 269, 274, 293 Blasts, 11, 221 Bleeding Time, 220, 221, 290 Bloating, 221, 261 Blood Cell Count, 145, 198, 221, 248, 272 Blood Coagulation, 152, 154, 158, 221, 223, 241, 290, 291 Blood Coagulation Factors, 221 Blood Glucose, 221, 248, 254 Blood Platelets, 35, 42, 58, 140, 157, 159, 160, 221, 262, 275, 290 Blood pressure, 221, 224, 251, 252, 264, 286 Blood transfusion, 197, 221 Blood Volume, 130, 221, 276 Blood-Brain Barrier, 121, 221, 258 Blot, 120, 222 Body Fluids, 131, 150, 222, 236, 286 Bone marrow aspiration, 37, 208, 222 Bone Marrow Cells, 26, 136, 140, 157, 159, 222, 229, 246, 262, 265 Bone Marrow Transplantation, 21, 50, 129, 132, 141, 222 Bone scan, 222, 284 Bowel, 214, 222, 235, 257, 288, 294 Bowel Movement, 222, 235, 288 Brachytherapy, 222, 256, 257, 280, 297 Bradykinin, 222, 268, 274 Branch, 120, 121, 195, 205, 222, 233, 247, 260, 269, 271, 279, 286, 290 Breakdown, 222, 235, 243, 269 Breeding, 18, 222 Buccal, 164, 222, 250, 260, 288 Buccal mucosa, 164, 222 Bullous, 169, 222 Bypass, 74, 222, 291 C Cachexia, 145, 222 Calcium, 10, 49, 136, 222, 223, 229, 241, 270, 279, 285, 290 Calculi, 223, 246 Calpain, 14, 223 Camptothecin, 223, 256 Candidiasis, 164, 168, 223 Candidosis, 223
Capillary, 12, 113, 221, 222, 223, 244, 259, 295 Capsules, 223, 244 Carbamazepine, 68, 105, 223 Carbohydrate, 223, 231, 245, 276 Carbon Dioxide, 126, 223, 243, 274, 282, 295 Carboplatin, 104, 109, 121, 223 Carboxy, 128, 223 Carcinogenic, 223, 254, 268, 278 Carcinogens, 223, 268 Carcinoma, 164, 223 Carcinostatic, 134, 223 Cardiac catheterization, 151, 224 Cardiology, 63, 118, 224 Cardiopulmonary, 31, 58, 65, 76, 84, 87, 95, 151, 224 Cardiopulmonary Bypass, 31, 58, 65, 76, 84, 87, 95, 151, 224 Cardiorespiratory, 19, 224 Cardiovascular, 12, 53, 63, 66, 70, 74, 76, 86, 94, 151, 154, 195, 224 Cardiovascular disease, 151, 224 Carotene, 224, 282 Carrier State, 6, 224 Case report, 4, 100, 109, 110, 224 Case series, 87, 224 Caspase, 11, 18, 105, 224 Catheterization, 63, 66, 70, 74, 76, 86, 94, 104, 215, 224 Catheters, 69, 224, 253, 256 Cations, 224, 256 Cat-Scratch Disease, 168, 224 Causal, 224, 239, 249 Cause of Death, 152, 225 Caveolae, 39, 225 Caveolins, 225 Cell Adhesion, 25, 225, 255 Cell Count, 137, 158, 225 Cell Cycle, 5, 11, 37, 159, 225, 240, 279, 295 Cell Death, 11, 217, 225, 240, 244, 266 Cell Differentiation, 23, 133, 140, 225, 285, 287 Cell Division, 140, 157, 159, 189, 219, 225, 226, 233, 240, 247, 256, 264, 274, 284 Cell Lineage, 136, 153, 225 Cell membrane, 18, 225, 234, 247, 263, 273, 286 Cell Membrane Structures, 225 Cell proliferation, 40, 127, 133, 136, 218, 225, 255, 285 Cell Respiration, 225, 263, 282
302 Thrombocytopenia
Cell Size, 225, 242 Cell Survival, 144, 225, 247 Cell Transplantation, 225 Cellulitis, 168, 225 Cellulose, 225, 243, 274 Central Nervous System, 143, 144, 211, 226, 243, 245, 248, 258, 265, 277 Centrifugation, 226, 248 Centromere, 158, 226 Cerebellar, 218, 226, 281 Cerebral, 72, 218, 219, 221, 226, 231, 239, 240, 261, 279, 289 Cerebrovascular, 151, 220, 224, 226, 290 Cerebrum, 226, 293 Cervical, 8, 69, 197, 226 Cervix, 226 Character, 215, 226, 234 Cheilitis, 164, 226 Chemokines, 13, 15, 226, 260 Chemotactic Factors, 226, 229 Chemotaxis, 49, 226 Chemotherapeutics, 141, 226 Chemotherapy, 4, 10, 16, 23, 35, 42, 51, 71, 80, 88, 104, 109, 121, 129, 132, 134, 137, 139, 142, 144, 156, 157, 158, 160, 226 Chenodeoxycholic Acid, 51, 226 Chimeras, 10, 13, 40, 226 Chimeric Proteins, 41, 226 Choleretic, 226 Cholestanol, 51, 226 Cholesterol, 51, 220, 225, 226, 227, 231, 243, 251, 259, 274 Cholesterol Esters, 227, 259 Cholic Acid, 51, 227 Choline, 211, 227 Cholinergic, 24, 227 Chromatin, 133, 217, 227 Chromosomal, 35, 44, 158, 214, 215, 227, 244, 276 Chromosome, 5, 22, 23, 49, 98, 215, 226, 227, 248, 258, 264, 276, 284, 293 Chronic Disease, 222, 227, 258 Chronic granulocytic leukemia, 227 Chronic leukemia, 166, 227, 247 Chronic lymphocytic leukemia, 67, 92, 227 Chronic myelogenous leukemia, 69, 99, 211, 221, 227 Chronic phase, 211, 227 Chronic renal, 227, 276, 294 Chylomicrons, 227, 259 Cinchona, 227, 280 Circulatory system, 152, 227, 238
CIS, 21, 228, 282 C-kit receptor, 228, 287 Clinical Medicine, 50, 228, 277 Clone, 32, 51, 59, 228 Cloning, 20, 26, 50, 127, 132, 138, 221, 228 Clot Retraction, 228, 290 Coenzymes, 228, 268 Cofactor, 31, 34, 228, 268, 278, 290, 291 Cognitive restructuring, 228, 288 Cohort Studies, 228, 239 Colchicine, 228, 293 Coliphages, 219, 228 Colitis, 228 Collagen, 155, 220, 228, 231, 242, 244, 275, 278 Colloidal, 213, 229, 237 Colony-Stimulating Factors, 153, 229, 246 Combination chemotherapy, 121, 229 Combination Therapy, 46, 229 Combinatorial, 8, 229 Complement, 7, 10, 32, 214, 229, 244, 247, 255, 274 Complement Activation, 32, 214, 229 Complementary and alternative medicine, 109, 113, 229 Complementary medicine, 109, 229 Complementation, 40, 230 Complete remission, 48, 230, 282 Complete response, 230 Computational Biology, 185, 187, 230 Computed tomography, 230, 284 Computerized axial tomography, 230, 284 Computerized tomography, 48, 230 Conception, 230, 231, 241, 288 Concomitant, 45, 48, 136, 230 Condoms, 197, 230 Condyloma, 164, 230 Cones, 230, 282 Confusion, 230, 294 Congenita, 230, 280 Congestion, 230, 239 Conjugated, 48, 226, 227, 230 Conjunctiva, 230, 236, 254, 293 Connective Tissue Cells, 230, 231 Connective Tissue Diseases, 167, 217, 231 Constriction, 231, 257 Consumption, 19, 143, 220, 231, 234, 243, 282 Contamination, 44, 231, 249 Contraceptive, 152, 231 Contraindications, ii, 231 Control group, 231, 277
Index 303
Convulsions, 216, 231, 236, 277 Coordination, 231, 265 Cornea, 231, 236, 245, 288, 297 Coronary, 10, 12, 63, 66, 70, 71, 74, 85, 86, 104, 117, 154, 215, 224, 231, 251, 263, 266, 291 Coronary Artery Bypass, 85, 117, 231 Coronary Circulation, 215, 231 Coronary heart disease, 224, 231 Coronary Thrombosis, 12, 231, 263, 266 Cortex, 218, 231, 238, 240, 281 Cortical, 16, 231, 284, 290 Corticosteroid, 41, 45, 231, 277 Cortisol, 213, 232 Cortisone, 232, 277 Cost Savings, 16, 35, 232 Cranial, 232, 241, 248, 270, 272, 293 Creatine, 154, 232 Creatine Kinase, 154, 232 Creatinine, 232, 294 Critical Care, 75, 232 Crossing-over, 232, 281 Cross-Sectional Studies, 232, 239 Cryoglobulinemia, 75, 232 Curative, 232, 268, 290 Cutaneous, 71, 169, 223, 232, 236, 259, 273, 295 Cyclic, 70, 71, 140, 141, 188, 223, 232, 247, 268 Cyclophosphamide, 79, 121, 122, 145, 232 Cyclosporine, 72, 119, 232 Cyst, 218, 233 Cystathionine beta-Synthase, 233, 251 Cysteine, 223, 226, 233 Cytarabine, 11, 121, 233 Cytogenetics, 48, 233 Cytokine, 20, 23, 26, 30, 34, 35, 37, 46, 51, 93, 126, 127, 129, 132, 137, 139, 233, 255 Cytomegalovirus, 164, 168, 233 Cytoplasm, 133, 217, 220, 225, 233, 238, 239, 246, 264, 266 Cytosine, 149, 233 Cytoskeletal Proteins, 223, 233 Cytoskeleton, 6, 16, 36, 233, 255, 263 Cytotoxic, 26, 27, 145, 158, 233, 280, 281, 285 Cytotoxicity, 11, 145, 233, 257 D Daclizumab, 119, 233 Dactinomycin, 92, 233 Dalteparin, 71, 233 Databases, Bibliographic, 185, 233
Daunorubicin, 11, 233 Day Care, 198, 233 De novo, 46, 234 Decidua, 234, 274 Defense Mechanisms, 234, 255 Degenerative, 234, 249, 283 Dehydroepiandrosterone, 148, 234 Deletion, 58, 98, 134, 217, 234 Dendrites, 24, 234, 267 Dendritic, 24, 26, 30, 45, 149, 234, 262 Dendritic cell, 26, 30, 45, 149, 234 Dengue Virus, 71, 234 Density, 14, 226, 234, 242, 259, 269 Dental Care, 170, 234 Dentate Gyrus, 234, 250 Dentists, 163, 166, 234 Depolarization, 234, 285 Dermatitis, 234, 236 Dermatology, 74, 78, 82, 118, 234 Deuterium, 234, 251 Developed Countries, 31, 234 Diabetes Mellitus, 87, 139, 234, 245, 248 Diagnostic procedure, 125, 174, 234 Dialyzer, 234, 248 Diarrhea, 40, 60, 167, 197, 235, 261 Diarrhoea, 235, 243 Diastolic, 235, 251 Diffusion, 235, 247, 254 Digestion, 213, 220, 222, 235, 259, 288, 294 Digestive system, 123, 235, 243, 265 Digestive tract, 235, 286, 287, 297 Dihydroxy, 147, 148, 235 Dilatation, 215, 235, 295 Dilution, 27, 143, 235, 240, 274 Dimerization, 47, 235 Diploid, 215, 230, 235, 264, 274, 275, 293 Direct, iii, 9, 13, 25, 26, 40, 42, 58, 73, 100, 104, 129, 140, 228, 235, 236, 264, 280, 281 Discoid, 17, 154, 167, 235 Disease Progression, 235, 296 Disease-Free Survival, 88, 235 Dissociation, 213, 235 Distal, 231, 235 Docetaxel, 95, 111, 235 Dominance, 45, 235 Dopa, 236, 258 Dopamine, 236, 258, 273 Dose-limiting, 42, 236 Dosimetry, 48, 236 Drive, ii, vi, 103, 140, 166, 168, 169, 170, 197, 236 Drug Eruptions, 169, 236
304 Thrombocytopenia
Drug Interactions, 8, 178, 236 Duct, 224, 236, 283 Duodenal Ulcer, 145, 236 Duodenum, 220, 236, 288 Dura mater, 236, 262, 270 Dyes, 220, 236, 242 Dyskeratosis Congenita, 117, 118, 236 Dysplasia, 8, 96, 189, 236 Dystrophy, 189, 236 E Eclampsia, 130, 236, 277 Eczema, 13, 21, 36, 40, 49, 236 Edema, 236, 267, 277, 294 Effector, 26, 140, 211, 229, 236, 257 Efficacy, 16, 31, 32, 35, 43, 44, 46, 54, 55, 57, 74, 98, 117, 236 Ehrlichiosis, 25, 29, 237 Elastin, 229, 231, 237 Elective, 81, 237 Electrocoagulation, 228, 237 Electrolyte, 231, 237, 248, 263, 276, 286, 294 Electrons, 217, 220, 237, 256, 270, 280, 281 Electrophoresis, 39, 237 Embolectomy, 237, 290 Emboli, 237, 296 Embolism, 237, 279, 296 Embolization, 237, 296 Embolus, 237, 254 Embryo, 221, 225, 237, 238, 253, 263, 294, 297 Embryogenesis, 237, 287 Emesis, 145, 237 Encapsulated, 237, 259 Encephalitis, 237, 238, 257 Encephalomyelitis, 39, 238 Endarterectomy, 215, 238 Endemic, 238, 261, 287 Endocarditis, 223, 238 Endocrine System, 238 Endocrinology, 118, 238, 247 Endocytosis, 225, 238 Endoderm, 238, 297 Endometrium, 234, 238, 293 Endothelial cell, 7, 9, 14, 20, 26, 49, 52, 59, 154, 221, 238, 290 Endothelium, 14, 39, 238, 268 Endothelium, Lymphatic, 238 Endothelium, Vascular, 238 Endothelium-derived, 238, 268 Endotoxins, 229, 238 End-stage renal, 227, 238, 276
Entorhinal Cortex, 238, 250 Environmental Exposure, 238, 268 Environmental Health, 184, 186, 239 Enzymatic, 223, 224, 229, 239, 242, 250, 282 Eosinophil, 239, 246 Epidemiologic Studies, 168, 239 Epidermal, 164, 239, 262, 264, 295, 296 Epidermis, 239, 251, 280 Epidermoid carcinoma, 239, 287 Epinephrine, 212, 236, 239, 293 Epithelial, 11, 51, 164, 234, 236, 239, 249, 255, 260, 270 Epithelial Cells, 11, 239, 249, 255, 260 Epithelium, 220, 230, 238, 239, 270, 297 Epitope, 17, 45, 134, 239 Epoprostenol, 239, 252 Equine Infectious Anemia, 60, 239 Erythema, 74, 164, 239 Erythrocyte Indices, 221, 239 Erythrocyte Volume, 221, 239 Erythrocytes, 50, 126, 129, 139, 141, 142, 146, 214, 215, 219, 221, 222, 223, 239, 240, 249, 270, 281 Erythropoiesis, 137, 138, 240 Erythropoietin, 128, 129, 133, 137, 138, 139, 142, 153, 240 Escalation, 47, 240 Esophagus, 235, 240, 243, 273, 288 Essential Tremor, 189, 240 Estrogen, 240, 278 Etoposide, 121, 240 Eukaryotic Cells, 233, 240, 253, 268, 269 Evoke, 144, 240, 288 Excitability, 240, 280 Excitation, 240, 242 Exfoliation, 240, 266 Exhaustion, 215, 240, 261 Exogenous, 29, 39, 136, 212, 236, 240, 244 Exon, 33, 240 Extensor, 240, 279 External-beam radiation, 240, 256, 280, 297 Extracellular, 155, 218, 230, 238, 240, 242, 255, 269, 286, 290 Extracellular Matrix, 155, 230, 240, 242, 255, 269 Extracellular Space, 155, 240 Extracorporeal, 18, 31, 78, 241, 248, 273 Extracorporeal Circulation, 18, 241 Extravasation, 241, 248 Extremity, 69, 241 Eye Infections, 212, 241
Index 305
F Facial, 164, 168, 241, 271 Facial Nerve, 164, 241, 271 Factor V, 96, 194, 241 Factor VII, 96, 241 Factor VIIa, 96, 241 Family Planning, 185, 241 Fat, 212, 217, 222, 224, 227, 231, 237, 241, 259, 265, 283, 286 Fatty acids, 213, 241, 245, 259 Fatty Liver, 76, 241 Febrile, 29, 160, 234, 241, 249, 261 Feces, 226, 241, 288 Femoral, 224, 241 Femoral Artery, 224, 241 Fetal Death, 8, 241 Fetus, 20, 46, 64, 89, 91, 165, 240, 241, 252, 274, 294 Fibrin, 12, 31, 49, 152, 154, 155, 221, 228, 241, 242, 290, 291 Fibrinogen, 38, 42, 146, 147, 154, 155, 241, 274, 290 Fibrinolysis, 152, 242 Fibrinolytic, 43, 242 Fibroblasts, 231, 242, 255, 260 Fibronectin, 155, 242 Fibrosis, 33, 39, 189, 242, 283, 284 Filovirus, 34, 242 Flatus, 242, 243 Flow Cytometry, 11, 12, 26, 60, 147, 242 Fludarabine, 11, 67, 80, 92, 242 Fluorescence, 242 Fluorescent Dyes, 242 Fluorouracil, 110, 242 Foam Cells, 51, 242 Folate, 242 Fold, 31, 52, 140, 157, 159, 242 Folic Acid, 169, 242 Forearm, 221, 242, 281 Fractionation, 39, 41, 243 Fungi, 241, 243, 246, 263, 297 Fungus, 223, 243, 244 G Gallbladder, 211, 220, 235, 243 Gallstones, 226, 243 Gamma Rays, 243, 280, 281 Ganglia, 211, 219, 243, 267, 272 Ganglion, 243, 297 Gangrene, 100, 243 Gas, 18, 223, 235, 242, 243, 251, 261, 268, 282, 295 Gas exchange, 18, 243, 282, 295
Gastric, 145, 219, 243, 250 Gastrin, 243, 250 Gastroenteritis, 167, 197, 243 Gastroenterology, 40, 62, 65, 83, 87, 118, 243 Gastrointestinal, 40, 51, 143, 169, 222, 239, 243, 261, 288, 289 Gastrointestinal tract, 143, 243, 288 Gelatin, 244, 245, 290 Gene Expression, 19, 21, 36, 45, 46, 190, 244 Gene Targeting, 39, 42, 244 Genetic Code, 244, 268 Genetic Counseling, 118, 244 Genetic Engineering, 221, 228, 244 Genetic Techniques, 5, 244 Genetics, 22, 28, 40, 98, 99, 158, 212, 233, 235, 244 Genital, 244, 247, 294 Genitourinary, 244, 294 Genotype, 244, 273 Geotrichosis, 168, 244 Geriatric, 10, 244 Germ Cells, 158, 244, 269, 286, 290, 297 Gestation, 244, 272, 274, 277 Giant Cells, 244, 283 Gland, 168, 169, 212, 232, 244, 250, 260, 270, 271, 274, 278, 284, 288, 291 Glomerular, 20, 49, 244, 245, 256, 282 Glomerular Filtration Rate, 49, 244 Glomeruli, 244, 245 Glomerulonephritis, 97, 245, 252 Glomerulus, 244, 245, 267 Glucocorticoid, 245, 277 Glucose, 44, 189, 221, 225, 234, 245, 248, 254, 273 Glucose Intolerance, 234, 245 Glucuronic Acid, 245, 249, 252 Glutamic Acid, 242, 245, 278 Glycerol, 245, 273 Glycerophospholipids, 245, 273 Glycine, 226, 227, 245, 285 Glycogen, 44, 245, 273 Glycogen Storage Disease, 44, 245 Glycosaminoglycan, 24, 134, 245 Glycosidic, 245, 268, 273 Glycosylation, 128, 245 Gout, 168, 228, 246 Governing Board, 246, 277 Gp120, 15, 246 Grade, 36, 48, 57, 110, 246 Graft, 4, 85, 99, 145, 160, 246, 250, 253
306 Thrombocytopenia
Graft Rejection, 246, 253 Grafting, 117, 231, 246 Graft-versus-host disease, 99, 160, 246 Gram-negative, 224, 246 Gram-positive, 246, 265, 287, 288 Granule, 16, 234, 246 Granulocyte Colony-Stimulating Factor, 229, 246 Granulocyte-Macrophage ColonyStimulating Factor, 153, 229, 246 Granulocytes, 25, 43, 57, 126, 229, 246, 258, 266, 285, 296 Granulocytopenia, 30, 120, 197, 246 Granuloma, 167, 169, 246 Grasses, 242, 246 Gravis, 139, 247 Growth factors, 5, 35, 56, 133, 139, 144, 247 Guanylate Cyclase, 247, 268 Gynecology, 20, 41, 68, 75, 105, 118, 247 H Habitat, 247, 265 Haematemesis, 237, 247 Haematological, 105, 166, 247 Haematology, 62, 67, 70, 72, 73, 74, 78, 79, 80, 82, 84, 88, 90, 96, 98, 100, 101, 110, 111, 168, 247 Haematoma, 247 Haemodialysis, 84, 247 Haemolysis, 105, 247 Haemopoietic, 136, 247 Haemorrhage, 91, 96, 160, 247 Hair follicles, 247, 287, 296 Hairy cell leukemia, 95, 247 Half-Life, 16, 247, 252 Handwashing, 198, 247 Hantavirus, 25, 247, 248, 249 Hantavirus Pulmonary Syndrome, 25, 248 Haploid, 248, 274, 275 Haptens, 213, 248 Headache, 237, 248, 254 Heart attack, 224, 248 Hematocrit, 137, 221, 239, 248 Hematologic malignancies, 41, 248 Hematoma, 169, 248 Hematopoiesis, 11, 19, 20, 26, 30, 32, 46, 51, 99, 130, 136, 139, 145, 153, 248, 276 Hematopoietic Stem Cells, 4, 23, 26, 129, 141, 146, 153, 248 Hemochromatosis, 168, 248 Hemodiafiltration, 19, 248 Hemodialysis, 70, 167, 234, 248 Hemofiltration, 248
Hemoglobin, 136, 215, 220, 221, 239, 240, 248, 249, 258, 290 Hemoglobin M, 249 Hemoglobinopathies, 156, 168, 249 Hemoglobinuria, 32, 65, 189, 249 Hemolysis, 59, 101, 188, 219, 249 Hemolytic, 20, 23, 32, 49, 50, 52, 82, 101, 110, 122, 139, 167, 169, 197, 198, 249, 253, 290 Hemorrhage, 19, 45, 69, 137, 169, 237, 248, 249, 280, 288 Hemorrhagic Fever with Renal Syndrome, 25, 249 Hepatic, 20, 44, 51, 145, 213, 249 Hepatitis, 11, 62, 83, 87, 94, 98, 145, 160, 164, 169, 249, 254 Hepatitis A, 169, 249 Hepatitis Viruses, 164, 249 Hepatocytes, 9, 138, 249 Hepatomegaly, 249, 254 Hepatovirus, 249 Hereditary, 22, 35, 86, 92, 166, 167, 188, 194, 231, 246, 249, 267, 283, 290 Heredity, 244, 249 Herpes, 164, 250 Herpes Zoster, 164, 250 Heterodimers, 250, 255 Heterogeneity, 213, 250 Heterozygotes, 79, 235, 250 Hippocampus, 24, 234, 250, 258, 288 Hirudin, 31, 65, 79, 111, 250 Histamine, 215, 250 Histidine, 10, 250 Histiocytosis, 169, 250 Homeostasis, 27, 129, 136, 250 Homogeneous, 24, 250 Homologous, 19, 32, 37, 158, 213, 232, 244, 250, 284, 289 Homozygotes, 38, 50, 235, 250 Hormonal, 218, 232, 250 Hormone, 46, 130, 137, 213, 231, 232, 239, 240, 243, 250, 254, 262, 277, 278, 283, 285, 291 Host, 25, 26, 28, 30, 139, 145, 155, 160, 219, 223, 224, 228, 242, 249, 250, 252, 253, 296 Human papillomavirus, 164, 250 Humoral, 17, 26, 127, 129, 140, 142, 159, 246, 250, 253, 291 Humour, 250 Hybrid, 62, 228, 251 Hybridomas, 251, 255 Hydration, 198, 251
Index 307
Hydrogen, 152, 211, 220, 223, 234, 251, 259, 264, 267, 269, 272, 279 Hydrogen Peroxide, 251, 259 Hydrolysis, 211, 212, 251, 273, 276, 278, 293 Hydrophobic, 245, 251, 259 Hydroxylysine, 229, 251 Hydroxyproline, 229, 251 Hydroxyurea, 5, 251 Hyperbilirubinemia, 251, 257 Hyperglycemia, 37, 158, 251 Hyperhomocysteinemia, 152, 233, 251 Hyperlipoproteinemia, 251, 259 Hyperpigmentation, 164, 168, 169, 251 Hyperplasia, 158, 164, 251 Hypersensitivity, 164, 167, 239, 251, 283 Hypertension, 39, 50, 130, 188, 224, 239, 248, 251, 277, 294 Hypertrophy, 251 Hyperuricemia, 246, 252 Hypoplasia, 37, 66, 158, 252 Hypotension, 74, 231, 252 Hypoxia, 20, 31, 50, 137, 252, 290 I Id, 106, 112, 198, 204, 206, 252 Idiotype, 45, 60, 252 Iduronic Acid, 31, 252 Iloprost, 68, 252 Immune Complex Diseases, 216, 252, 274 Immune function, 21, 252 Immune Sera, 252 Immune Tolerance, 20, 252 Immunity, 34, 36, 62, 252, 292 Immunization, 17, 96, 252, 253 Immunodeficiency, 6, 13, 14, 21, 26, 36, 40, 49, 60, 61, 91, 189, 252 Immunofluorescence, 252, 264 Immunogenic, 9, 29, 252 Immunoglobulin, 27, 38, 40, 45, 46, 93, 115, 151, 216, 253, 264 Immunologic, 6, 13, 25, 36, 38, 60, 139, 226, 252, 253, 281 Immunologic Diseases, 36, 252, 253 Immunology, 3, 8, 12, 22, 26, 40, 50, 65, 95, 104, 135, 149, 213, 242, 253 Immunosuppressant, 43, 242, 253 Immunosuppressive, 119, 232, 245, 253, 271 Immunosuppressive therapy, 253 Immunotherapy, 46, 134, 145, 220, 253 Immunotoxins, 253, 280 Impairment, 218, 219, 241, 253, 262
Impetigo, 164, 253 Implant radiation, 253, 256, 257, 280, 297 In situ, 21, 140, 159, 253 In Situ Hybridization, 21, 253 In vitro, 7, 8, 9, 10, 11, 16, 18, 19, 21, 25, 29, 35, 47, 53, 58, 59, 69, 81, 127, 128, 130, 138, 139, 144, 253 Incubated, 10, 253 Incubation, 253, 258 Incubation period, 253, 258 Indicative, 165, 253, 271, 295 Induction, 7, 34, 133, 215, 253, 278 Infarction, 151, 254, 276, 291 Infectious Mononucleosis, 90, 111, 254 Infertility, 144, 254, 294 Infiltration, 245, 254, 297 Influenza, 21, 81, 254 Infusion, 23, 59, 119, 254, 292 Ingestion, 26, 236, 254, 276, 290 Inhalation, 212, 254, 276 Initiation, 133, 254, 292 Inlay, 254, 282 Innervation, 241, 254 Insight, 7, 21, 30, 40, 46, 254 Insulator, 254, 265 Insulin, 37, 254, 257 Insulin-dependent diabetes mellitus, 254 Integrins, 11, 28, 49, 131, 150, 255 Intensive Care, 73, 75, 76, 82, 85, 255 Intercellular Junctions, 39, 255 Interferon, 5, 83, 87, 98, 101, 139, 255 Interferon-alpha, 98, 101, 255 Interleukin-1, 87, 88, 91, 129, 133, 134, 179, 255 Interleukin-11, 87, 88, 91, 179, 255 Interleukin-15, 129, 255 Interleukin-2, 139, 255 Interleukin-3, 133, 141, 146, 153, 229, 255 Interleukin-6, 141, 146, 255 Interleukins, 139, 255 Intermittent, 239, 256, 259 Internal Medicine, 10, 40, 43, 49, 64, 66, 72, 80, 91, 92, 93, 95, 97, 238, 243, 248, 256, 267 Internal radiation, 256, 257, 280, 297 Interphase, 256, 268 Interspecific, 33, 256 Interstitial, 39, 222, 240, 256, 257, 267, 282, 297 Intestinal, 51, 224, 226, 256, 261, 297 Intestines, 197, 211, 241, 243, 256, 274 Intoxication, 256, 296
308 Thrombocytopenia
Intracellular, 8, 11, 25, 26, 41, 144, 154, 168, 244, 254, 255, 256, 262, 268, 276, 285 Intracellular Membranes, 256, 262 Intraocular, 121, 256 Intravascular, 73, 77, 81, 256 Intravenous, 7, 38, 54, 115, 254, 256, 271 Intrinsic, 151, 213, 220, 256 Inulin, 244, 256 Invasive, 71, 104, 252, 256, 261 Involuntary, 220, 240, 256, 266, 291 Ion Channels, 218, 256 Ionizing, 213, 239, 256, 281 Ions, 14, 220, 235, 237, 251, 256, 279, 286 Irinotecan, 110, 256 Irradiation, 134, 144, 160, 256, 263, 297 Ischemia, 19, 151, 154, 218, 257 Islet, 37, 257 Isoenzyme, 232, 257 Ixodes, 29, 219, 257 J Jaundice, 84, 251, 257 Joint, 54, 218, 257, 289 K Kanamycin, 110, 257 Kb, 184, 257 Kidney Disease, 101, 123, 184, 189, 195, 257 Killer Cells, 257 Kinetic, 47, 256, 257 L Labile, 229, 241, 257 Lacrimal, 241, 257 Lactation, 79, 257, 278 Large Intestine, 235, 256, 257, 281, 286 Laxative, 213, 226, 257 Lectin, 257, 262 Lens, 230, 257, 282 Lentivirus, 6, 257 Lesion, 164, 231, 246, 258, 259, 293 Lethal, 42, 169, 258 Leucine, 38, 258 Leucocyte, 98, 129, 239, 258 Leukaemia, 135, 136, 258 Leukapheresis, 217, 258 Leukocytes, 49, 134, 136, 139, 142, 220, 221, 222, 226, 246, 255, 258, 264, 270 Leukocytosis, 132, 258, 276 Leukopenia, 75, 110, 145, 156, 175, 258 Leukoplakia, 164, 258 Levodopa, 97, 236, 258 Library Services, 204, 258 Ligament, 258, 278
Ligands, 6, 7, 13, 49, 127, 132, 140, 255, 258 Ligation, 36, 45, 258 Limbic, 214, 258 Limbic System, 214, 258 Linkage, 5, 17, 23, 62, 258 Lipid, 9, 20, 36, 37, 217, 218, 225, 227, 242, 245, 254, 259, 265 Lipid Peroxidation, 9, 259 Lipid Peroxides, 20, 259 Lipoprotein, 136, 246, 259 Lipoprotein Lipase, 136, 259 Liposomal, 46, 259 Liver scan, 259, 284 Liver Transplantation, 57, 73, 259 Localization, 10, 36, 73, 259 Localized, 22, 211, 214, 237, 247, 248, 254, 259, 265, 274, 284, 293 Locomotion, 259, 274, 279 Long-Term Care, 40, 259 Loop, 140, 159, 259 Low-density lipoprotein, 259 Lupus, 8, 17, 62, 88, 167, 168, 175, 197, 216, 217, 259, 289 Lutein Cells, 260, 278 Lymph, 226, 227, 238, 250, 254, 260, 282, 283, 288 Lymph node, 226, 260, 282, 283 Lymphadenopathy, 254, 260 Lymphatic, 238, 254, 260, 263, 286, 287, 291 Lymphatic system, 260, 286, 287, 291 Lymphoblastic, 70, 260 Lymphocyte, 6, 13, 20, 26, 40, 45, 79, 129, 142, 216, 255, 257, 260, 261 Lymphocytic, 34, 119, 120, 260 Lymphoid, 4, 11, 30, 40, 130, 216, 258, 260, 277 Lymphokine, 120, 260 Lymphokine-activated killer cells, 120, 260 Lymphoma, 48, 70, 71, 110, 121, 156, 164, 168, 189, 248, 260, 273 Lymphopenia, 12, 26, 132, 136, 260 Lymphoproliferative, 73, 75, 110, 260, 271 M Macrophage, 48, 138, 143, 229, 246, 255, 260 Macrophage Colony-Stimulating Factor, 229, 260 Macrophage Inflammatory Proteins, 143, 260 Maculopapular, 260, 274
Index 309
Magnetic Resonance Imaging, 91, 261, 284 Maintenance therapy, 61, 261 Malabsorption, 166, 189, 261 Malabsorption syndrome, 167, 261 Malaria, 60, 67, 88, 90, 93, 96, 97, 98, 105, 227, 261 Malaria, Falciparum, 261 Malaria, Vivax, 261 Malignancy, 100, 211, 261, 270 Malignant, 48, 84, 156, 189, 216, 250, 261, 265, 267, 281, 284 Malignant tumor, 261, 265 Malnutrition, 213, 218, 222, 261, 265 Mammary, 231, 259, 261 Mastication, 261, 293 McMaster, 104, 261 Meat, 198, 261 Mediate, 42, 140, 236, 257, 261 Mediator, 20, 50, 236, 255, 261, 275 Medical Records, 118, 261 Medicament, 129, 134, 153, 261 MEDLINE, 185, 187, 190, 261 Megaloblastic, 242, 262 Melanin, 262, 273, 293 Melanocytes, 251, 262 Melanoma, 189, 262 Melanophores, 262 Melanosis, 211, 262 Melanosomes, 33, 262 Membrane Proteins, 135, 225, 262 Meninges, 226, 236, 262 Meningitis, 34, 262 Menstruation, 137, 214, 234, 262 Mental Disorders, 123, 262, 279 Mental Health, iv, 4, 123, 184, 186, 262, 279 Mental Retardation, 61, 190, 262 Mentors, 50, 262 Mercury, 242, 262 Mesenchymal, 246, 260, 263 Mesoderm, 263, 293, 297 Metabolic disorder, 245, 246, 263 Metastasis, 263 Metastatic, 11, 82, 263 Methoxsalen, 263, 273 MI, 209, 263 Mice Minute Virus, 263, 271 Microbe, 155, 263, 292 Microbiology, 6, 26, 29, 34, 40, 50, 212, 219, 263 Microorganism, 228, 263, 271, 296 Microscopy, 39, 41, 220, 263, 268
Microtubules, 16, 263, 270 Microvilli, 14, 263 Migration, 14, 49, 263 Mineralocorticoids, 212, 231, 263 Minority Groups, 28, 263 Mitochondria, 11, 263, 269 Mitochondrial Swelling, 263, 266 Mitosis, 217, 264 Mitotic, 133, 158, 235, 240, 264, 296 Mitotic inhibitors, 235, 264 Mixed Connective Tissue Disease, 17, 264 Mobility, 21, 264 Mobilization, 36, 264 Modification, 144, 145, 244, 264, 280 Monitor, 232, 264, 268 Monoclonal antibodies, 13, 121, 128, 147, 233, 253, 264, 283 Monocytes, 51, 136, 149, 242, 255, 258, 264, 266 Monogenic, 37, 264 Mononuclear, 145, 246, 254, 260, 264 Monosomy, 215, 264 Morphogenesis, 16, 264 Morphological, 14, 39, 154, 237, 243, 262, 264 Morphology, 58, 247, 248, 264 Mucins, 264, 283 Mucociliary, 265, 285 Mucosa, 51, 169, 260, 265, 278, 288, 297 Mucositis, 51, 265 Mucus, 265, 294 Multiple Myeloma, 169, 265 Multiple Organ Failure, 18, 82, 265 Multiple sclerosis, 132, 265 Muscle Fibers, 265 Muscular Atrophy, 189, 265 Muscular Dystrophies, 236, 265 Mutagenesis, 12, 18, 21, 41, 265 Mutagens, 265 Myalgia, 25, 254, 265 Mycobacterium, 21, 168, 265, 293 Mycobacterium avium, 168, 265 Mycobacterium bovis, 21, 265 Myelin, 265 Myelodysplasia, 19, 265 Myelodysplastic syndrome, 70, 72, 156, 266, 286 Myelofibrosis, 266, 276 Myelogenous, 265, 266 Myeloid Cells, 23, 266 Myeloproliferative Disorders, 19, 266 Myelosuppression, 48, 266
310 Thrombocytopenia
Myocardial infarction, 8, 50, 151, 152, 154, 231, 263, 266, 296 Myocardial Ischemia, 215, 266 Myocardium, 215, 263, 266 Myofibrils, 223, 266 Myositis, 17, 266 Myotonia, 266, 280 Myotonic Dystrophy, 189, 266 N Nasal Mucosa, 254, 266 Natural selection, 220, 266 Nausea, 243, 266, 294 NCI, 1, 11, 54, 118, 119, 120, 121, 123, 183, 228, 266 Necrolysis, 164, 266 Necrosis, 76, 217, 254, 263, 266, 283 Need, 3, 15, 47, 55, 126, 140, 154, 159, 160, 163, 166, 175, 178, 179, 199, 212, 227, 245, 266 Neonatal, 12, 20, 38, 41, 47, 54, 61, 64, 69, 75, 80, 81, 82, 85, 86, 88, 91, 92, 93, 171, 267 Neoplasia, 189, 267 Neoplasm, 121, 267, 270, 284 Neoplastic, 135, 215, 251, 260, 267, 274 Nephritis, 23, 145, 267 Nephrology, 49, 70, 118, 267 Nephropathy, 257, 267 Nephrosis, 267 Nephrotic, 72, 267 Nephrotic Syndrome, 72, 267 Nerve, 212, 215, 218, 234, 241, 243, 254, 261, 265, 267, 270, 276, 282, 283, 284, 288, 293, 295, 297 Nervous System, 144, 189, 212, 226, 261, 267, 272, 295 Networks, 57, 267 Neural, 41, 144, 212, 250, 267, 286 Neurodegenerative Diseases, 132, 220, 267 Neurologic, 7, 52, 168, 267 Neurology, 68, 118, 267 Neuromuscular, 105, 211, 267, 294 Neuromuscular Junction, 211, 267 Neuronal, 132, 267 Neurons, 154, 234, 243, 258, 267, 289 Neuropathy, 8, 100, 168, 267 Neuropeptides, 223, 267 Neutralization, 32, 267 Neutrons, 213, 256, 267, 280 Neutrophil, 4, 268 Niacin, 169, 268, 293 Nickel, 10, 268
Nitric Oxide, 31, 268 Nitrogen, 213, 215, 232, 268, 293 Nuclear, 110, 118, 133, 219, 223, 237, 240, 243, 258, 264, 266, 268 Nuclear Medicine, 110, 118, 268 Nuclei, 133, 140, 157, 159, 213, 214, 237, 244, 258, 261, 264, 267, 268, 279 Nucleic acid, 127, 132, 149, 153, 233, 244, 253, 265, 268, 280 Nucleoli, 133, 268 Nucleus, 133, 217, 220, 227, 232, 233, 234, 240, 243, 264, 267, 268, 279, 290 O Obstetrics, 20, 41, 54, 61, 68, 73, 75, 105, 268 Oligopeptides, 160, 268 Oligosaccharides, 24, 268 Oncogene, 129, 189, 268, 287 Oncogenic, 35, 255, 257, 268, 279 Opacity, 234, 269 Open Reading Frames, 258, 269 Operon, 269, 282 Ophthalmology, 118, 269 Opportunistic Infections, 7, 164, 197, 269 Opsin, 269, 282 Oral Health, 163, 166, 167, 269 Oral Manifestations, 163, 164, 168, 169, 269 Organelles, 33, 226, 233, 262, 264, 269, 275 Osmosis, 269 Osmotic, 121, 213, 263, 269 Osteoblasts, 136, 269 Osteoporosis, 132, 269 Otorhinolaryngology, 118, 269 Outpatient, 55, 269 Ovary, 269, 288 Ovum, 234, 244, 269, 277, 278, 293 Ovum Implantation, 269, 293 Oxaliplatin, 95, 105, 269 Oxidation, 9, 211, 217, 249, 259, 269 Oxygenator, 18, 224, 270 P Pachymeningitis, 262, 270 Paclitaxel, 104, 109, 270 Palate, 270, 288 Palliative, 270, 290 Palsy, 168, 270 Pancreas, 211, 235, 243, 248, 254, 257, 270, 293 Pancreatic, 37, 189, 270 Pancreatic cancer, 189, 270 Pancreatitis, 61, 270
Index 311
Pancytopenia, 23, 26, 121, 156, 165, 270 Papilloma, 230, 270 Papillomavirus, 168, 270 Paralysis, 164, 270 Paranasal Sinuses, 270, 285 Parathyroid, 141, 146, 270, 290 Parathyroid Glands, 270 Parathyroid hormone, 141, 146, 270 Parenchyma, 137, 271 Parenteral, 236, 271 Parkinsonism, 258, 271 Parotid, 271, 284 Paroxysmal, 32, 65, 189, 215, 271 Partial remission, 271, 282 Particle, 271, 292 Parturition, 268, 271, 278 Parvovirus, 94, 263, 271 Patch, 258, 271 Pathogen, 25, 28, 29, 253, 271 Pathogenesis, 6, 7, 9, 13, 15, 20, 22, 25, 27, 29, 44, 49, 52, 59, 78, 79, 98, 155, 163, 271 Pathologic, 32, 38, 42, 87, 217, 221, 223, 231, 251, 271, 279, 295 Pathologic Processes, 42, 217, 271 Pathophysiology, 20, 31, 34, 39, 43, 79, 96, 166, 271 Patient Compliance, 16, 35, 271 Patient Education, 196, 202, 204, 209, 271 Pelvic, 197, 271, 278 Pelvic inflammatory disease, 197, 271 Penicillin, 135, 215, 271 Penis, 230, 271 Pentostatin, 95, 271 Peptide, 10, 17, 26, 36, 39, 42, 140, 144, 157, 159, 160, 272, 276, 278 Percutaneous, 66, 70, 71, 86, 104, 272 Perfusion, 18, 31, 73, 252, 272 Perianal, 230, 272 Pericardium, 272, 289 Perinatal, 31, 64, 82, 197, 272 Periodontal disease, 164, 272 Periodontitis, 164, 168, 272 Perioperative, 76, 272 Peripheral blood, 47, 79, 99, 104, 139, 141, 146, 255, 272, 273, 277, 290 Peripheral Nervous System, 267, 270, 272, 289 Peripheral stem cells, 246, 272 Pernicious, 169, 262, 272 Pernicious anemia, 169, 272 Petechiae, 68, 143, 247, 272 PH, 18, 43, 89, 272
Phagocytosis, 10, 272 Pharmaceutical Preparations, 226, 244, 272, 278 Pharmacodynamic, 24, 272 Pharmacokinetic, 8, 16, 24, 272 Pharmacologic, 39, 43, 215, 247, 273, 292 Pharynx, 254, 273 Phenotype, 18, 23, 58, 97, 120, 230, 273 Phenylalanine, 273, 293 Phospholipases, 273, 285 Phospholipids, 8, 65, 216, 217, 241, 259, 273 Phosphorus, 223, 270, 273 Phosphorylase, 223, 273 Phosphorylated, 36, 273 Phosphorylation, 18, 273 Photochemotherapy, 78, 273 Photocoagulation, 228, 273 Photopheresis, 78, 273 Photosensitizing Agents, 273 Physical Examination, 118, 119, 273 Physiologic, 18, 36, 153, 213, 221, 236, 247, 256, 262, 273, 281 Physiology, 4, 12, 130, 158, 224, 238, 243, 247, 248, 267, 273 Pigment, 61, 220, 262, 274 Pigmentation, 164, 251, 262, 274 Pilot study, 11, 274 Pituitary Gland, 231, 274 Pityriasis, 169, 274 Pityriasis Rosea, 169, 274 Placenta, 20, 46, 274, 277, 279, 294 Plant sterols, 50, 274 Plants, 145, 213, 221, 222, 223, 227, 245, 256, 257, 263, 264, 274, 292, 295 Plaque, 6, 215, 218, 274 Plasma, 8, 9, 10, 11, 15, 39, 43, 51, 54, 55, 57, 59, 82, 83, 127, 130, 133, 134, 138, 146, 213, 216, 221, 225, 227, 229, 238, 241, 242, 244, 245, 248, 249, 251, 258, 263, 265, 274, 275, 278, 281, 284, 296 Plasma cells, 216, 265, 274 Plasma Exchange, 15, 54, 55, 59, 82, 274 Plasma protein, 213, 238, 241, 274, 278 Plasma Volume, 221, 263, 274 Plasmacytoma, 51, 274 Plasmapheresis, 54, 57, 82, 217, 274 Plasticity, 23, 275 Plastids, 269, 275 Platelet Activation, 6, 28, 29, 32, 89, 130, 275, 285
312 Thrombocytopenia
Platelet Aggregation, 49, 69, 154, 215, 239, 252, 268, 275, 291 Platelet Factor 4, 27, 29, 91, 135, 275 Platelet Storage Pool Deficiency, 33, 275 Platelet Transfusion, 28, 47, 57, 75, 129, 160, 275 Plateletpheresis, 217, 275 Platinum, 259, 269, 275 Platinum Compounds, 269, 275 Ploidy, 47, 140, 157, 159, 275 Podophyllotoxin, 240, 275 Point Mutation, 36, 275 Poisoning, 243, 256, 262, 266, 276 Polyarteritis Nodosa, 167, 252, 276 Polycystic, 189, 276 Polycythemia Vera, 57, 71, 169, 276 Polymerase, 276, 282 Polymorphic, 27, 234, 276 Polymorphism, 23, 38, 276 Polypeptide, 128, 134, 139, 214, 228, 241, 276, 278, 290, 297 Polyploid, 157, 276 Polyploidy, 5, 140, 159, 276 Polysaccharide, 213, 216, 225, 245, 276, 278 Polytherapy, 105, 276 Posterior, 214, 218, 270, 276 Postmenopausal, 269, 276 Postnatal, 86, 276, 288 Postoperative, 3, 64, 265, 276 Postsynaptic, 276, 285 Post-traumatic, 169, 276 Potassium, 263, 276, 280 Potentiate, 133, 153, 255, 276 Potentiating, 145, 276 Potentiation, 277, 285 Practice Guidelines, 186, 198, 277 Precipitation, 14, 277 Preclinical, 44, 277 Prednisolone, 61, 89, 277 Prednisone, 54, 110, 119, 277 Preeclampsia, 20, 31, 277 Pre-Eclampsia, 130, 277 Pre-eclamptic, 236, 277 Preleukemia, 266, 277, 286 Prevalence, 59, 166, 277 Primary central nervous system lymphoma, 121, 277 Primary endpoint, 57, 277 Progeny, 32, 277 Progesterone, 41, 277, 278 Prognostic factor, 10, 52, 277 Progression, 6, 19, 159, 163, 215, 278
Progressive, 84, 168, 169, 225, 227, 240, 247, 265, 266, 267, 275, 278, 282 Prolactin, 46, 130, 278 Proline, 36, 38, 128, 229, 251, 278 Promoter, 9, 21, 32, 34, 278 Prone, 9, 131, 142, 150, 278 Prophylaxis, 88, 120, 278, 296 Propylene Glycol, 158, 278 Prospective Studies, 56, 278 Prostate, 189, 278 Protease, 14, 54, 154, 156, 229, 278 Protein C, 6, 9, 12, 135, 144, 145, 154, 156, 213, 214, 217, 219, 259, 278, 294 Protein Conformation, 214, 278 Protein S, 6, 12, 32, 49, 128, 165, 190, 221, 244, 278 Proteinuria, 265, 267, 277, 278 Proteoglycan, 275, 278 Proteolytic, 229, 241, 278 Prothrombin, 220, 241, 278, 290 Protocol, 8, 9, 15, 41, 48, 55, 56, 279 Protons, 213, 251, 256, 279, 280 Proto-Oncogene Proteins, 270, 279 Proto-Oncogene Proteins c-mos, 270, 279 Pruritic, 236, 279 Pseudopodia, 16, 279 Psoriasis, 39, 169, 273, 279 Psychiatric, 174, 262, 279 Psychiatry, 105, 279 Psychic, 279, 284 Psychomotor, 223, 279 Public Health, 29, 59, 186, 279 Public Policy, 53, 185, 279 Publishing, 59, 145, 279 Puerperium, 268, 279 Pulmonary, 18, 39, 63, 77, 85, 152, 160, 221, 231, 239, 248, 279, 295, 296 Pulmonary Artery, 221, 279, 295 Pulmonary Embolism, 77, 85, 152, 279, 296 Purines, 279, 285 Pustular, 253, 280 Putrefaction, 243, 280 Q Quality of Life, 10, 16, 35, 280 Quiescent, 27, 280 Quinidine, 135, 147, 227, 280 Quinine, 62, 73, 94, 135, 147, 227, 280 R Race, 236, 263, 280 Radiation therapy, 147, 157, 158, 240, 243, 256, 257, 280, 297
Index 313
Radioactive, 147, 222, 247, 251, 253, 256, 257, 259, 264, 268, 280, 281, 284, 297 Radioimmunotherapy, 48, 280, 281 Radioisotope, 48, 240, 280 Radiolabeled, 257, 280, 297 Radiological, 272, 281 Radiology, 87, 100, 118, 268, 281 Radiopharmaceutical, 32, 281 Radiotherapy, 134, 166, 222, 257, 280, 281, 297 Radius, 99, 188, 281 Randomized, 53, 55, 56, 57, 237, 281 Randomized clinical trial, 53, 56, 57, 281 Reactivation, 164, 281 Reactive Oxygen Species, 11, 281 Recombinant, 10, 12, 35, 38, 43, 44, 47, 65, 76, 80, 84, 88, 91, 96, 127, 132, 136, 179, 281, 295 Recombinant Proteins, 38, 281 Recombination, 19, 32, 158, 244, 281 Reconstitution, 27, 30, 145, 281 Rectum, 217, 222, 235, 242, 243, 257, 278, 281 Red blood cells, 136, 152, 197, 240, 249, 266, 281 Red Nucleus, 218, 281 Refer, 1, 222, 229, 243, 250, 259, 267, 280, 281 Refraction, 282, 287 Refractory, 11, 28, 43, 45, 74, 79, 92, 121, 196, 237, 282 Regeneration, 37, 281, 282 Regimen, 236, 271, 282, 283 Regional lymph node, 224, 282 Relapse, 54, 282 Remission, 54, 55, 59, 88, 261, 282 Remission Induction, 54, 282 Renal failure, 66, 101, 139, 167, 249, 282 Repressor, 35, 269, 282 Reproductive cells, 244, 282 Resolving, 104, 282 Respiration, 223, 264, 282 Respiratory failure, 63, 248, 282 Restoration, 129, 281, 282, 296 Reticular, 133, 282 Retina, 230, 257, 282, 283 Retinal, 61, 282 Retinoblastoma, 189, 282 Retinol, 282, 283 Retinopathy, 39, 273, 283 Retreatment, 48, 283 Retroviral vector, 7, 12, 283
Rheumatic Diseases, 22, 283 Rheumatism, 65, 66, 283 Rheumatoid, 91, 132, 139, 168, 283 Rheumatoid arthritis, 91, 132, 139, 168, 283 Riboflavin, 169, 283 Ribonuclease, 264, 283 Ribonucleoside Diphosphate Reductase, 251, 283 Rigidity, 271, 274, 283 Risk factor, 23, 52, 56, 92, 239, 251, 283 Rituximab, 43, 48, 54, 65, 73, 80, 92, 95, 110, 121, 283 Rod, 219, 283 S Saline, 264, 274, 283 Saliva, 163, 283 Salivary, 164, 168, 169, 233, 235, 241, 270, 283, 288, 296 Salivary glands, 164, 233, 235, 241, 283 Saphenous, 231, 283 Saphenous Vein, 231, 283 Sarcoidosis, 94, 283 Sarcoma, 164, 165, 168, 284 Scans, 48, 118, 284 Schizoid, 284, 296 Schizophrenia, 284, 296 Schizotypal Personality Disorder, 284, 296 Scleroderma, 17, 167, 264, 284 Sclerosis, 65, 167, 189, 218, 265, 284 Screening, 26, 39, 64, 67, 118, 121, 144, 228, 284, 294 Sebaceous, 284, 296 Secretion, 7, 20, 36, 37, 140, 232, 250, 254, 256, 257, 263, 264, 265, 284, 295 Secretory, 12, 260, 284 Sediment, 284, 294 Segregation, 219, 281, 284 Seizures, 17, 223, 271, 284 Semen, 278, 284 Semisynthetic, 223, 240, 253, 284 Senescence, 26, 284 Senile, 269, 284 Sepsis, 19, 34, 284 Septic, 82, 285 Sequencer, 12, 285 Sequencing, 12, 23, 33, 138, 285 Serine, 128, 154, 156, 233, 279, 285, 293 Serositis, 23, 285 Serotypes, 234, 285 Serous, 238, 285
314 Thrombocytopenia
Serum, 8, 20, 47, 93, 127, 134, 138, 188, 213, 214, 229, 232, 252, 259, 263, 264, 281, 285 Sex Determination, 189, 285 Shock, 34, 82, 249, 285, 293 Side effect, 44, 54, 119, 121, 134, 151, 155, 177, 179, 212, 220, 232, 236, 252, 266, 285, 292 Signal Transduction, 40, 42, 52, 58, 225, 285 Signs and Symptoms, 166, 276, 282, 285, 294 Sinusitis, 168, 285 Skeletal, 44, 215, 232, 265, 266, 280, 285 Skeleton, 17, 211, 257, 285 Skull, 285, 289 Small cell lung cancer, 104, 286 Small intestine, 220, 226, 227, 236, 250, 256, 286, 293 Smoldering leukemia, 266, 286 Smooth muscle, 214, 223, 231, 242, 250, 286, 289 Social Environment, 280, 286 Social Support, 286, 288 Social Work, 118, 286 Sodium, 87, 121, 239, 246, 263, 280, 286, 295 Sodium Channels, 280, 286, 295 Soft tissue, 222, 285, 286 Solid tumor, 4, 71, 88, 165, 215, 286 Solvent, 245, 269, 278, 286 Soma, 286 Somatic, 32, 40, 45, 129, 142, 158, 237, 250, 258, 264, 272, 286 Somatic cells, 129, 142, 264, 286 Specialist, 199, 286 Specificity, 17, 26, 27, 52, 131, 140, 150, 213, 277, 286 Spectrum, 26, 30, 167, 286 Sperm, 215, 227, 282, 287, 293 Spinal cord, 69, 218, 226, 227, 236, 238, 243, 262, 267, 270, 272, 277, 287 Spirochete, 28, 94, 287, 289 Spleen, 21, 133, 143, 158, 166, 214, 233, 260, 276, 283, 287 Splenectomy, 38, 43, 45, 74, 89, 95, 96, 287 Splenomegaly, 254, 276, 287 Sporadic, 267, 283, 287 Squamous, 164, 168, 239, 287 Squamous cell carcinoma, 168, 239, 287 Squamous cells, 287 Staging, 284, 287 Standard therapy, 45, 54, 273, 287
Staphylococcus, 155, 243, 253, 287 Staphylococcus aureus, 155, 243, 253, 287 Steatosis, 241, 287 Stem Cell Factor, 153, 228, 287 Stem cell transplantation, 4, 15, 24, 28, 57, 90, 104, 287 Stem Cells, 23, 40, 122, 128, 132, 136, 139, 141, 144, 146, 240, 272, 287 Stent, 76, 94, 104, 288 Sterile, 270, 288 Sterility, 232, 254, 288 Steroids, 15, 37, 148, 231, 234, 245, 288 Stimulant, 128, 250, 288 Stimulus, 45, 236, 240, 254, 256, 288, 290 Stomach, 211, 219, 235, 240, 243, 250, 256, 266, 273, 286, 287, 288 Stomatitis, 164, 168, 288 Stool, 118, 198, 257, 288 Streptococci, 253, 288 Stress, 59, 144, 164, 197, 232, 243, 266, 283, 288 Stress management, 197, 288 Stroke, 8, 123, 152, 154, 184, 224, 288 Stroma, 271, 288 Stromal, 7, 13, 14, 51, 132, 222, 288 Stromal Cells, 7, 222, 288 Subacute, 94, 254, 285, 288 Subclinical, 55, 254, 284, 288 Subcutaneous, 39, 95, 225, 236, 271, 288 Subiculum, 250, 288 Submandibular, 168, 288 Subspecies, 286, 289 Substance P, 281, 284, 289 Supplementation, 110, 289 Support group, 197, 289 Suppression, 145, 232, 289 Suppurative, 225, 289 Symphysis, 278, 289 Symptomatic, 270, 289 Synaptic, 285, 289 Synergistic, 153, 271, 278, 289, 291 Synostosis, 61, 188, 289 Syphilis, 164, 289 Systemic disease, 169, 289 Systemic lupus erythematosus, 17, 22, 45, 65, 66, 97, 139, 167, 175, 197, 216, 217, 252, 264, 289 Systolic, 251, 289 T Tachycardia, 219, 289 Tachypnea, 219, 289 Taurine, 226, 227, 289
Index 315
Telangiectasia, 189, 289 Temporal, 23, 26, 32, 214, 250, 289 Temporal Lobe, 214, 289 Testicular, 37, 158, 289 Testis, 37, 289, 290 Tetany, 270, 290 Thalamic, 218, 290 Thalamic Diseases, 218, 290 Thalassemia, 101, 170, 220, 290 Therapeutics, 16, 25, 142, 178, 290 Threonine, 128, 279, 285, 290 Threshold, 240, 251, 290 Thrombasthenia, 19, 188, 290 Thrombectomy, 86, 237, 290 Thrombin, 12, 31, 58, 100, 104, 152, 154, 155, 156, 241, 275, 278, 290 Thrombocytes, 105, 126, 129, 136, 138, 143, 275, 290 Thrombocytosis, 168, 290 Thromboembolism, 63, 77, 152, 290 Thrombolytic, 152, 290 Thrombomodulin, 12, 156, 278, 290 Thrombopenia, 217, 290 Thrombophilia, 53, 290 Thromboplastin, 241, 291 Thromboses, 217, 291 Thrombus, 58, 100, 137, 152, 231, 254, 266, 275, 290, 291, 295 Thymus, 30, 252, 260, 291 Thyroid, 270, 291, 293 Thyroid Gland, 270, 291 Thyroxine, 213, 273, 291 Tic, 56, 291 Tick-Borne Diseases, 219, 291 Ticlopidine, 52, 291 Time Management, 288, 291 Titre, 73, 291 Tomography, 48, 291 Tonic, 145, 291 Tonicity, 249, 292 Tooth Preparation, 212, 292 Topical, 251, 273, 292 Topoisomerase inhibitors, 256, 292 Torsion, 254, 292 Toxaemia, 277, 292 Toxic, iv, 26, 49, 135, 164, 168, 169, 227, 233, 238, 239, 246, 252, 253, 259, 267, 275, 292 Toxicity, 8, 9, 11, 35, 43, 44, 48, 49, 120, 121, 155, 236, 263, 292 Toxicology, 67, 186, 292
Toxins, 216, 221, 237, 238, 245, 253, 254, 264, 280, 292 Trace element, 268, 292 Transcription Factors, 5, 11, 19, 34, 36, 292 Transduction, 41, 285, 292 Transfection, 11, 221, 292 Transfer Factor, 252, 292 Transferases, 245, 292 Transfusion, 12, 15, 23, 43, 53, 54, 55, 56, 57, 60, 82, 83, 93, 104, 112, 135, 147, 160, 197, 292 Transgenes, 19, 44, 292 Translating, 50, 292 Translational, 52, 292 Translocation, 16, 292 Transmitter, 211, 218, 236, 256, 261, 293 Transplantation, 5, 12, 15, 28, 37, 69, 78, 227, 252, 293 Trauma, 55, 57, 137, 169, 220, 248, 266, 270, 290, 293 Trauma Centers, 55, 293 Treatment Failure, 72, 293 Triad, 21, 49, 167, 293 Trigeminal, 168, 293 Trisomy, 215, 293 Trophoblast, 20, 221, 293 Trypsin, 293 Tryptophan, 229, 293 Tubercle, 265, 293 Tuberculosis, 112, 122, 164, 231, 259, 265, 293 Tuberous Sclerosis, 189, 293 Tubulin, 42, 263, 293 Typhoid fever, 82, 293 Tyrosine, 18, 236, 293 U Ulcer, 225, 236, 293 Ulceration, 164, 168, 169, 293 Ulcerative colitis, 132, 169, 293 Umbilical Arteries, 294 Umbilical Cord, 105, 294 Unconscious, 234, 252, 294 Unnecessary Procedures, 5, 294 Uraemia, 270, 294 Urea, 294 Uremia, 197, 282, 294 Urethra, 271, 278, 294 Uric, 246, 252, 280, 294 Urinalysis, 118, 294 Urinary, 133, 219, 223, 244, 294 Urinary tract, 219, 294
316 Thrombocytopenia
Urine, 127, 219, 221, 229, 232, 249, 278, 283, 294 Urogenital, 143, 244, 294 Urology, 118, 294 Uterus, 226, 234, 238, 262, 277, 294, 295 V Vaccine, 26, 279, 294 Vacuoles, 238, 269, 294 Vagina, 143, 223, 226, 262, 295 Vaginal, 197, 295 Vaginitis, 223, 295 Valproic Acid, 96, 295 Varicella, 164, 168, 295 Vasculitis, 75, 270, 276, 295 Vasoactive, 50, 295 Vasodilation, 252, 295 Vasodilators, 268, 295 Vector, 9, 10, 21, 25, 44, 47, 292, 295 Vegetative, 276, 295 Vein, 69, 218, 256, 268, 271, 283, 294, 295 Venereal, 289, 295 Venom, 67, 295 Venous, 8, 55, 69, 100, 111, 151, 152, 154, 217, 218, 221, 275, 278, 291, 295, 296 Venous blood, 221, 275, 295 Venous Thrombosis, 111, 151, 152, 154, 291, 295, 296 Ventricle, 214, 250, 279, 289, 295 Venules, 221, 223, 238, 295 Verruca, 164, 295 Vertebrae, 287, 295 Vesicular, 250, 295 Veterinary Medicine, 185, 295 Vinblastine, 293, 296 Vinca Alkaloids, 296
Vincristine, 105, 110, 293, 296 Viral, 8, 13, 26, 34, 44, 45, 60, 129, 164, 168, 169, 237, 239, 244, 254, 268, 291, 292, 296 Viral Load, 8, 296 Viremia, 6, 296 Virulence, 219, 292, 296 Viscera, 286, 296 Vitelline Membrane, 296, 297 Vivo, 4, 6, 8, 9, 11, 12, 13, 15, 16, 18, 20, 23, 25, 27, 29, 30, 35, 36, 39, 40, 42, 44, 46, 47, 59, 69, 129, 130, 136, 138, 139, 144, 153, 249, 253, 259, 296 Vulgaris, 164, 296 W War, 247, 296 Warfarin, 76, 100, 196, 296 Warts, 250, 275, 296 Withdrawal, 101, 145, 296 Wound Healing, 143, 158, 168, 169, 255, 296 X Xenograft, 215, 296 Xenopus, 10, 296 Xerostomia, 164, 168, 169, 296 X-ray, 118, 134, 230, 242, 243, 256, 268, 280, 281, 284, 297 X-ray therapy, 257, 297 Y Yeasts, 223, 243, 273, 297 Yolk Sac, 19, 297 Z Zoonoses, 219, 297 Zoster, 168, 297 Zymogen, 156, 278, 297
Index 317
318 Thrombocytopenia
Index 319
320 Thrombocytopenia
