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

PULMONARY HYPERTENSION A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCE...

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PULMONARY HYPERTENSION 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., 1960Pulmonary Hypertension: 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: 0-597-84571-9 1. Pulmonary Hypertension-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on pulmonary hypertension. 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 PULMONARY HYPERTENSION .................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Pulmonary Hypertension.............................................................. 4 E-Journals: PubMed Central ....................................................................................................... 61 The National Library of Medicine: PubMed ................................................................................ 64 CHAPTER 2. NUTRITION AND PULMONARY HYPERTENSION ...................................................... 111 Overview.................................................................................................................................... 111 Finding Nutrition Studies on Pulmonary Hypertension .......................................................... 111 Federal Resources on Nutrition ................................................................................................. 117 Additional Web Resources ......................................................................................................... 117 CHAPTER 3. DISSERTATIONS ON PULMONARY HYPERTENSION .................................................. 119 Overview.................................................................................................................................... 119 Dissertations on Pulmonary Hypertension ............................................................................... 119 Keeping Current ........................................................................................................................ 120 CHAPTER 4. CLINICAL TRIALS AND PULMONARY HYPERTENSION ............................................. 121 Overview.................................................................................................................................... 121 Recent Trials on Pulmonary Hypertension ............................................................................... 121 Keeping Current on Clinical Trials ........................................................................................... 128 CHAPTER 5. PATENTS ON PULMONARY HYPERTENSION ............................................................. 131 Overview.................................................................................................................................... 131 Patents on Pulmonary Hypertension......................................................................................... 131 Patent Applications on Pulmonary Hypertension..................................................................... 153 Keeping Current ........................................................................................................................ 182 CHAPTER 6. BOOKS ON PULMONARY HYPERTENSION................................................................. 183 Overview.................................................................................................................................... 183 Book Summaries: Online Booksellers......................................................................................... 183 Chapters on Pulmonary Hypertension ...................................................................................... 184 CHAPTER 7. PERIODICALS AND NEWS ON PULMONARY HYPERTENSION ................................... 187 Overview.................................................................................................................................... 187 News Services and Press Releases.............................................................................................. 187 Newsletter Articles .................................................................................................................... 192 Academic Periodicals covering Pulmonary Hypertension......................................................... 193 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 195 Overview.................................................................................................................................... 195 U.S. Pharmacopeia..................................................................................................................... 195 Commercial Databases ............................................................................................................... 196 Researching Orphan Drugs ....................................................................................................... 196 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 201 Overview.................................................................................................................................... 201 NIH Guidelines.......................................................................................................................... 201 NIH Databases........................................................................................................................... 203 Other Commercial Databases..................................................................................................... 205 The Genome Project and Pulmonary Hypertension .................................................................. 205 APPENDIX B. PATIENT RESOURCES ............................................................................................... 211 Overview.................................................................................................................................... 211 Patient Guideline Sources.......................................................................................................... 211 Associations and Pulmonary Hypertension............................................................................... 229 Finding Associations.................................................................................................................. 230 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 233

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Overview.................................................................................................................................... 233 Preparation................................................................................................................................. 233 Finding a Local Medical Library................................................................................................ 233 Medical Libraries in the U.S. and Canada ................................................................................. 233 ONLINE GLOSSARIES................................................................................................................ 239 Online Dictionary Directories ................................................................................................... 241 PULMONARY HYPERTENSION DICTIONARY................................................................... 243 INDEX .............................................................................................................................................. 333

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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 pulmonary hypertension 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 pulmonary hypertension, 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 pulmonary hypertension, 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 pulmonary hypertension. 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 pulmonary hypertension, 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 pulmonary hypertension. The Editors

1

From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON PULMONARY HYPERTENSION Overview In this chapter, we will show you how to locate peer-reviewed references and studies on pulmonary hypertension.

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

Hearing and Neurodevelopmental Outcome in Survivors of Persistent Pulmonary Hypertension of the Newborn Source: Pediatrics. 90(3): 392-396. September 1992. Summary: This article reports on a study that assessed neurodevelopmental outcome and hearing in infants who survived persistent pulmonary hypertension in the neonatal period, for which they were managed conservatively. A total of 27 of 34 infants with this diagnosis underwent neurological, intelligence, and audiologic testing between 10 months and 6 years of age. Children who were younger than 1 year of age at the initial hearing test were retested after they reached 2 years of age. The average IQ score was within the normal range (mean = 96.23). None of the children had sensorineural hearing loss. Severe neurologic abnormalities were seen in four children, three of whom had

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been severely asphyxiated at birth. Mild neurologic abnormalities were observed in five children. Two infants had bronchopulmonary dysplasia because they required supplemental oxygen for 29 and 66 days respectively, and had abnormal chest roentgenograms. The authors conclude that this study suggests that conservative management without induced alkalosis or respiratory paralysis is accompanied by no sensorineural hearing loss and a good neurologic outcome. 6 tables. 33 references. (AAM).

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

Project Title: A FUNCTIONAL GENOMICS HEART & LUNG DEVELOP. PROGRAM Principal Investigator & Institution: Hoffman, Eric P.; Director, Research Center for Genetic Me; Children's Research Institute Washington, D.C., Dc 20010 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: Drs. Eric Hoffman and Dietrich Stephan (whose primary interests are focused on muscle disease and leukemia) are PI and Co-PI on the Program's Expression Array Core and have extensive experience with all aspects of array use and data analysis. They have established collaborations with Dr. Michael Bitmer, Dr. Yidony Chen and the entire NHGRI array community. As a post-doctoral fellow in the laboratory of Dr. Jeffery Trent (member of this Program's External Advisory Committee), and a pioneer in DNA microarray technology, Dr. Stephan developed several alternative approaches to label total RNA for efficient signal detection under varying circumstances which have become the standard protocol used at NHGRI and has become a quite robust and reliable system for detecting signals over several orders of magnitude. In addition to building and using 7K expression arrays, Dr. Stephan was the first at NHGRI to develop genomic DNA microarray systems. Dr. Hoffman's laboratory is particularly interested in systematic assessments of the sensitivity and specificity of the Affymetrix vs. cDNA array approaches, and shows preliminary data pointing out the importance of redundant

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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

Studies

5

measurements, and correlative studies. Indeed, the proposed systematic comparison of the Affymetrix and cDNA array experimental platforms should be the first of this type of quality control of expression array data, and should prove highly valuable to both Program investigations and the research community at large. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACE HYPERTENSION

INHIBITION

IN

SINGLE

VENTRICLE/PULMON.

Principal Investigator & Institution: Gersony, Welton M.; Pediatrics; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 05-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant) The overall goal of this application is to examine treatment modalities which may improve the clinical care of two groups of patients with congenital heart disease: infants born with a single ventricle supplying blood flow to the lungs and body and children with pulmonary hypertension associated with congenital heart disease. The primary hypothesis in infants with single ventricle is that chronic angiotensin converting enzyme (ACE) inhibition favorably modifies the ventricular remodeling response to volume overload and improves ventricular function over the first year of life. Serial changes in ventricular geometry will be assessed using magnetic resonance imaging and compared with measurements of systolic and diastolic function, including the pressure/volume relation and the Tei index, and clinical outcome measures including post-operative course and changes in the Ross? heart failure classification. The beneficial effect of ACE inhibition is expected to occur prior to and following volume unloading surgery with the bidirectional Glenn shunt or hemi-Fontan. The primary hypothesis of the study in congenital heart disease associated with pulmonary hypertension is that the effect of long-term treatment with an oral prostacyclin analogue or an oral endothelin receptor blocker has a salutory effect on exercise capacity, longevity, and quality of life. It will also be determined whether any of these patients carry a defect of the primary pulmonary hypertension-1 gene. Each of these studies could potentially lead to a significant improvement in prognosis: in the single ventricle group by preventing a long-term deterioration in ventricular function and in the pulmonary hypertension patients by improving quality of life and survival without transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADAPTATIONS TO HYPOXIA Principal Investigator & Institution: Mcmurtry, Ivan F.; Professor; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-APR-1977; Project End 31-MAR-2003 Summary: This is a resubmission seeking renewal of a 25-year program encompassing 4 sub-projects. The present application sharpens the focus of the laboratory on the pulmonary circulation, by a multi-faceted study of the mechanisms of hypoxic pulmonary circulation, by a multi-faceted study of the mechanisms of hypoxic pulmonary hypertension (PH). The work is collectively founded on the hypothesis that PH smooth muscle cell (SMC) function. Studies of functional contributions explore the influence of hypoxia on the ratio of pulmonary vasoconstrictors/dilators and of altered ion channel function. Work exploring structural aspects tests the idea that there exist specific subpopulations of hypoxia-responsive SMCs responsible for a preponderance of

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remodeling of lung vessels in hypoxia and that hypoxic proliferative response is dependent on specific isoforms of protein kinase C. The projects share experimental models of hypoxic pulmonary hypertension in rats and cows, as well as 3 core laboratories. This project will test 3 specific aims: 1) If hypoxic pulmonary hypertension is associated with increased endothelial NOS but not ET-1 protein, whereas the opposite is true in genetic pulmonary hypertension; 2) If the mechanisms of action of nitric oxide synthase (eNOS) and ET-1 gene expression are hypoxia and hemodynamic stress, respectively in these models. This project will investigate 4 specific aims: 1) What changes in PA SMC ion channels develops as a result of hypoxic pulmonary hypertension; 2) How does Ca2+ enter the hypertensive PA SMC; 3) How do NO and cGMP regulate ion channels in the hypertensive PA SMC; and 4) Are changes in ion channel expression and regulation a direct result of chronic hypoxia. This project will test 3 hypothesis: 1) Gi coupled receptors activate the MAPK signaling pathway in selected populations of PA SMCs; 2) Hypoxia selectively stimulates in hypoxiaresponsive PA SMCs through MAPK-dependent mechanisms; and 3) Connective Tissue Growth Factor (CTGF), is expressed selectively in subpopulations of PA SMCs during hypoxia and contributes to the fibroproliferative response. This project will test 2 specific aims: 1) Are PKC-alpha expression and activation critical determinants of PA SMC proliferation to hypoxia in vivo, and 2) Are PKC-alpha expression and activation critical determinants of PA SMC proliferation to hypoxia in vitro. The 4 projects are highly interactive both conceptually, as well as in the performance and communication of experimental results. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AEROSOLIZED HYPERTENSION

PGE1

IN

NEONATAL

PULMONARY

Principal Investigator & Institution: Sood, Beena G.; Pediatrics; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: (prepared by applicant): The candidate, Beena Sood MD, is interested in pursuing an academic career in Neonatal-Perinatal medicine with the focus on patient oriented research. The areas of interest are the use of aerosolized medications I newborn, pulmonary biology, and pharmacologic manipulation of the pulmonary vasculature and ductus arteriosus. The candidate has been actively involved in research during her fellowship training. The institutional environment at the Wayne State University offers extensive resources available to the candidate The Division of Neonatal-Perinatal Medicine has a busy service both at Hutzel Hospital and Children's Hospital of Michigan. The career development plan includes formal mentorship, extensive coursework leading to a Master's of Science degree in Clinical Research Design and Statistical Analysis, conduct of clinical and complementary laboratory research related to the patient-oriented research. Dr. Sood's mentor, Seetha Shankaran, MD, is a renowned neonatologist with extensive experience in clinical research study design involved in several Multi center clinical trials through the NICHD Neonatal Research Network. She has established collaborative relationships with neonatologists throughout Michigan and the U.S. that will facilitate the studies proposed by Dr. Sood. JV Aranda MD, PhD and V Delaney-Black MD, MPH will be Consultants on the study. Dr Sood proposes a clinical trial for the use of aerosolized prostaglandin E1 (PGE1) as a selective pulmonary vasodilator in the treatment of persistent pulmonary hypertension (PPHN) in the newborn. T are two phases of the research plan. Initially, a phase I pilot study of aerosolized PGE1 in term and near- infants with PPHN will be conducted at the

Studies

7

Children's Hospital of Michigan (already under way) in collaboration with other hospitals in the Detroit area to establish the appropriate dosing of PGEl. In the second phase, a randomized controlled study of the optimum dose of aerosolized Prostaglandin E1 (PGE1) in the units will be conducted to evaluate efficacy. If effective, a proposal for using aerosolized PGE1 in neonatal PPHN as a multicenter study will be submitted to the NICHD Neonatal Network. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALPHA-ADRENOCEPTORS IN VASCULAR WALL GROWTH Principal Investigator & Institution: Faber, James E.; Professor; Cellular/Molecular Physiology; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2003; Project Start 01-APR-1999; Project End 31-MAY-2008 Summary: Alpha-1-adrenergic receptor (alpha 1A.R) activation by norepinephrine (NE) induces growth of smooth muscle cells (SMCs) and adventitial fibroblasts (AFBs) in cell culture. Although alpha1AR stimulation has been proposed to contribute to hypertensive wall hypertrophy and fibrosis, exacerbate atherosclerosis, and to worsen restenosis after angioplasty, until our studies there was no in vivo evidence that this was from a direct effect because of absence of local drug delivery systems that could prevent confounding systemic hemodynamic actions. We have devised a novel method that overcomes this problem. This, together with a unique organ culture method, selective alpha1AR subtype antagonists, and knockout mice devoid of catecholamine synthesis or specific alpha1AR subtypes, will be used to investigate the hvnothesis that stimulation of a snecific allpha1AR subtvne on SMCs and AFBs contribute importantlv to intimal lesion growth, fibrosis and vascular remodeling. Our previous and preliminary results have demonstrated that specific al AR subtypes mediate growth of SMCs and AFBs in vitro and in vivo, and strongly contribute to restenosis after angioplasty, outward hypertrophic remodeling and the vascular hypertrophy and lumen loss that causes pulmonary hypertension. Aim I will complete the work in these models, and extend it to hypertensive wall hypertrophy. Aim II will determine how NE exacerbates wall growth by in vivo examination of proliferation, apoptosis, and migration with immunohistochemistry and western blot. Aim III will test the hypothesis that injury induces neurite outgrowth and increased NE content and/or release. Aim IV will identify the intracellular kinase pathway mediating NE?s trophic activity and test the hypothesis that it proceeds through reactive oxygen species-and/or EGF-receptor transactivation-dependent pathways. These Aim IV studies will use organ culture of normal and balloon-injured rat thoracic aorta, with biochemical assays of intima-media and adventitia. This proposal examines a new fundamental concept, i.e., that catecholamines are important trophic factors for SMCs and AFBs. We propose that this mechanism links the sympathetic nervous system to adaptive vascular remodeling and to pathological disease progression. The results may identify novel vascular targets for alphal-AR subtype-specific antagonists with potential therapeutic application. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: ANGIOGENESIS IN HYPEROXIC LUNG FIBROSIS Principal Investigator & Institution: Douglas, Ivor S.; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2008

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Pulmonary Hypertension

Summary: (provided by applicant): This 5-year training program proposes the development plan for a career as an independent biomedical researcher in the area of lung injury and angiogenesis. The principal investigator, has completed Pulmonary and Critical Care Fellowship training through the ABIM Research Pathway. With the sponsors and experienced collaborators he will expand on his scientific skills in preparation for career progression as an independent physician-scientist. The program will emphasize skills in molecular biology of angiogenesis and macrophage regulation of fibrosis using a murine hyperoxia model. To advance his knowledge in computational biology he will attend courses in applied statistics. Steven Greenberg M.D. a macrophage biologist, and Paul Rothman M.D., a renowned immunologist in the area of molecular regulation of cytokine signaling, will provide sponsorship. The program will benefit from collaborative expertise of Jan Kitajewski PhD, an expert in angiogenesis and Patty Lee, M.D. who will provide consultative support for the hyperoxia studies. Additionally, George Yancopoulos, a world renowned investigator, will collaborate and serve with the sponsors, Drs. Kitajewski and Lee on an advisory committee every 8 weeks. This committee will review progress and provide close scientific support and career advice. Prolonged hyperoxia results in lung fibrosis in humans and mice. The accompanying vascular remodeling contributes to pulmonary hypertension, right heart failure, and premature death. This program addresses the questions: Do macrophage-derived angiogenic regulatory factors, particularly angiopoietin-2 (Ang-2), contribute to vascular remodeling in response to prolonged sublethal hyperoxia. Do these vascular alterations contribute, independently, to the development of lung fibrosis? And does macrophage-derived Ang-2 directly inhibit endothelial cell survival in response to hyperoxia? The role of macrophage-derived mediators in hyperoxic lung injury remains unclear. We demonstrate in preliminary experiments, increased Ang-2 mRNA and protein in response to hyperoxic exposure in RAW 264.7 and in a mouse model of sublethal hyperoxic lung fibrosis. These mice develop macrophage-predominant cellular infiltration, collagen deposition and pulmonary vascular regression that recapitulates features of subacute lung fibrosis in humans. The following specific aims will be accomplished: 1) The characterization of fibrotic and vascular remodeling responses in hyperoxia-exposed mice by immunohistochemistry, Western and Northern blotting and ELISA to quantify changes in markers of lung fibrosis, angiogenesis and expression of angiogenic regulators and their receptors. The effects on pulmonary vasculature will be evaluated by confocal microscopy. 2) Functional changes in response to altered expression of macrophagederived angiogenic regulators by angiogenesis assays. Macrophage-depleted mice will be used to assess the contribution of lung macrophages. 3) Lung targeted overexpression of Ang-1 or 2 by adenovirus transfection or blocking antibodies prior to hyperoxia to determine the contribution of Ang-2 to pulmonary vascular remodeling and fibrosis during prolonged sublethal hyperoxia. 4) Determine if Ang-2 mediated endothelial survival inhibition is PI3K/Akt dependent. Columbia University has an established record of successful mentorship and training for K08 Career awardees in their preparation for careers as independent. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIMITOGENIC MECHANISMS OF PKG IN VASCULAR SM CELLS Principal Investigator & Institution: Roberts, Jesse D.; Assistant Professor in Anesthesia & Pedi; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2005

Studies

9

Summary: Excessive smooth muscle cell (PASMC) proliferation causes abnormal pulmonary artery remodeling and hypertension in newborns with pulmonary hypertension and in infants and children with many forms of congenital heart disease. NO donors decrease mitogen-stimulated SMC proliferation in vitro. Recently inhaled nitric oxide (NO) treatment has been observed to decrease pulmonary artery cell proliferation in animals with vascular injury. Although studies suggest that NOsignaling decreases SMC proliferation via activation of cGMP-dependent protein kinase (PKG), the mechanism is incompletely understood. The BROAD, LONG-TERM OBJECTIVE of this proposal is to elucidate molecular mechanisms by which PKG activation inhibits PASMC proliferation. Specific aim 1 examines how PKG activation modulates the cell cycle progression of proliferating PASMC and identifies specific PKG-sensitive cell cycle regulators. Using flow cytometry, studies of [3H]thymidineincorporation into DNA, and assays of the activity and / or expression of cell cycle regulatory proteins, the antiproliferative mechanisms of PKG activation will be investigated in serum-stimulated PASMC. Specific aim 2 tests whether PKG activation modulates cascades in the mitogen-activated protein kinase (MAPK) signaling pathway. Using PASMC expressing PKG, proliferation assays, and specific inhibitors of MAPK signaling cascades, the effect of PKG signaling on the ERK, SAPK/JNK and p38signaling will be determined. Specific aim 3 identifies specific PKG- phosphorylation targets through which PKG decreases PASMC proliferation. For example, should PKG activation modulate the MAPK signaling cascade, the abundance and enzymatic activity of constituents of this pathway will be evaluated using PKG-expressing proliferating PASMC. These results will provide important insights into basic mechanisms of abnormal cell proliferation which is pathognomatic for pulmonary vascular disease. This award will permit the applicant to take advantage of an ideal research training environment for the acquisition of new knowledge and skills in cell and molecular biology. In addition, a carefully constructed training program has been developed that will permit successful development of an independent research career examining the basic mechanisms of pulmonary vascular diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: APPLIED GENOMICS IN CARDIOPULMONARY DISEASE Principal Investigator & Institution: Scott, Alan L.; Physiology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: The overall goal of the Animal/Proteomic Component of the "Applied Genomic Program in Cardiopulmonary Disease" is to define and test the relevance of disease specific gene candidates that predict lung and cardiac remodeling in animal models of cardiopulmonary diseases utilizing gene profiling approaches. Identification of susceptibility genes for human disease is hampered by variability in clinical phenotype, genetic heterogeneity in human populations and the experimental difficulty in addressing the molecular mechanisms underlying complex pathological processes in humans. Thus our strategy is to take advantage of the experimental tractability of murine models of disease to provide high quality of candidate genes underlying remodeling processes in multiple cardiopulmonary disease. To achieve this goal, we have assembled an outstanding group of investigators with broad and overlapping expertise with animal models of cardiopulmonary diseases including asthma, pulmonary fibrosis, cardiac failure, emphysema, hyperoxia-induced lung injury and pulmonary hypertension. Our preliminary data suggest that these models are predictive of human disease and that the gene profiling approach can successfully be

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used to identify genes important in human disease. The specific aims of this component are l) to define a set of predictor genes for tissue remodeling using Affymetrix 5000 predictor oligonucleotide microarrays (Mu19K) in each of the six animal models of disease; 2) to refine the number of candidate genes and to establish the kinetics of gene expression by constructing custom cDNA arrays for 1000-5000 predictor genes in each model; and 3) to compare and contract gene expression profiles between models and human systems in order to prioritize candidates for further analysis by proteomic and single nucleotide polymorphism (SNPs) approaches; 4) to utilize proteomic approaches to study the consequences of changes in gene expression at the cell and tissue level; and 5) to being to determine the functional relevance of this focused set of genes to remodeling processes by utilizing transgenic and knockout technologies. The combined (mouse and human) approach of this program to the identification of disease specific genes for lung and cardiac remodeling should greatly facilitate future disease discovery. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: APPLIED GENOMICS IN CARDIOPULMONARY DISEASE Principal Investigator & Institution: Haponik, Edward F.; Professor of Internal Medicine; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: The Clinical Core will serve as the coordinating center for patient recruitment, specimen procurement and data base management. It is the mission of this Core to identify and provide disease-specific candidate genes from patients with such clinical disorders as acute lung injury, COPD, cystic fibrosis, asthma, pulmonary hypertension, pulmonary fibrosis, ischemic heart failure and both lung and cardiac transplant rejection. This core will also be responsible for the establishment of a Cardiopulmonary Tissue Repository that will maintain an archive of cryopreserved tissues and maintain an accurate data base of patient demographic and clinical data for correlation with biological end points produced by cDNA microarray. Following patient consent and registration, tissue samples and peripheral blood are delivered to the Core laboratory. The freezing facility will also serve as a repository for cyropreserved human lung and cardiac specimens. The Core Investigators will meet regularly to review all diagnostic materials on each specimen procured including histochemical stains and biopsies in order to determine a precise diagnosis and relevant demographic and clinical data for entry into the Project's data base which will include critical variables for the analysis of the biological data obtained. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BASIS OF VARIABILITY OF LUNG GPCR SIGNALING Principal Investigator & Institution: Liggett, Stephen B.; Professor; None; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Many major signaling events in the lung are carried out by the superfamily of G-protein coupled receptors (GPCRs). These include bronchial smooth muscle relaxation and contraction, mucous secretion, ciliary beat frequency, inflammation, immune cell trafficking, pulmonary vascular tone and permeability, and alveolar fluid and electrolyte transport, as well as many yet to be defined functions. Approximately 75 GPCRs are estimated to be expressed in human lung. Within the next five years, the great majority of all therapeutic agents will target GPCRs. However, the physiologic, pathologic, and pharmacologic behavior of GPCR signaling displays

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substantial interindividual variability which is thought to be due to common variants (polymorphisms) of the genes encoding these receptors. Such polymorphisms have been estimated to account for as much as 50% of the variability in the response to therapeutic agonists and antagonists targeted to GPCRs. Indeed, with just one GPCR, the (2adrenergic receptor, we have shown that coding and promoter polymorphisms alter receptor expression, function, and regulation in vitro in cells, and in asthmatic patients, they are associated with clinical phenotypes and the response to beta-agonist therapy. The long-term goals of this proposal are to identify polymorphisms of up to 20 pulmonary GPCR genes, and by the use of recombinant expression techniques to delineate their biochemical and pharmacologic impact on cellular signaling relevant to lung homeostasis and pathobiology. In Aim 1, the polymorphisms of these 20 GPCR genes will be delineated in the promoter, 5' untranslated, coding, intron/exon junctions, and 3' untranslated regions from genomic DNA samples from a cohort of 60 ethnically diverse individuals. In Aim 2, the common combinations of polymorphisms (haplotypes) will be delineated in the population. In Aim 3, constructs will be developed and model cell systems utilized for recombinant expression of GPCR haplotypes to determine the biological effects of polymorphisms on receptor expression, signaling, or regulation. These studies will provide the basis for interindividual susceptibility and therapeutic responsiveness, the variability in pathobiology, and the potential for developing new treatment strategies, for a diverse range of lung diseases including asthma, pulmonary hypertension, pneumonia, pulmonary fibrosis, COPD, and pulmonary edema. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOLOGY OF MONOCROTALINE INDUCED PULMONARY HYPERTENSION Principal Investigator & Institution: Segall, Henry J.; Vet Molecular Biosciences; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2002; Project Start 01-JAN-1993; Project End 31-MAR-2006 Summary: Monocrotaline (MCT) induced pulmonary hypertension remains a principle model for the biology and development of intervention strategies for the human disease. Current concepts of pulmonary hypertension (PH) assign a primary pathogenetic role to the pulmonary endothelial cell in both human PH and that induced by MCT. Recently, a genetic lesion in the Bone Morphogenic Protein Receptor (BMPR) has been identified in humans with pulmonary hypertension The overall objective of this grant is to characterize the effects of MCT on the biology of the pulmonary endothelial cell and relate them to the initiating mechanisms of PH. Our previous work has demonstrated that several proteins with potential functional significance for endothelial cells have selective covalent interactions with the reactive intermediate of MCT metabolism, monocrotaline pyrrole (MCTP). This leads to our hypothesis that protein targets of MCT initiate vascular remodeling by altering endothelial cell function similar to endothelial dysfunction in persons with genetic susceptibility to primary pulmonary hypertension. Our specific aims are to further characterize the protein targets of MCT, to determine the functional significance of protein binding in endothelial cells, to evaluate proteins regulating endothelial cell barrier function as potential MCT targets and to determine whether the MCT model alters the BMPR signal pathway affected in humans with PH. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CALCIUM ENDOTHELIUM

REGULATION

IN

LUNG

MICROVASCULAR

Principal Investigator & Institution: Bhattacharya, Jahar; Professor; St. Luke's-Roosevelt Inst for Hlth Scis Health Sciences New York, Ny 10019 Timing: Fiscal Year 2002; Project Start 12-SEP-1997; Project End 31-JUL-2005 Summary: (Applicant's Abstract): Aims: The overall objective is to understand the in situ cell biology of lung endothelial cells. Here, The PI will determine the role of the endothelial cytosolic calcium concentration (EC[Ca2+]i) in proinflammatory responses in lung microvessels induced by sustained pressure stress. The specific aims are to define in lung microvessels: 1) the regulation of EC[Ca2+]i); 2) the regulation of leukocyte entrapment; 3) the generation of diffusible second messengers; and 4) the distribution of proinflammatory mRNA. The new hypotheses to be tested are that in lung microvessels, sustained pressure-stress causes: 1) increased expression of leukocyte adhesion receptors; 2) increased leukocyte entrapment; and 3) increase production of reactive oxygen species (ROS) and NO. Procedures: The isolated, blood-perfused rat lung will be used. Pressure-stress will be established by increasing the left atrial pressure for set periods. Arteriolar, septal and venular capillaries will be imaged by digital fluorescence microscopy. In these vessels, in situ quantifications will be obtained of EC[Ca2+]i by the fura 2-ratio method, EC exocytosis as determined by the fluorescence of FM1-43 at fusion-pores, ROS by the H202-sensitive dye DCFH and [NO] (NO concentration) by a potentiometric method. In addition, expression of leukocyte adherence receptors on the EC surface of lung capillaries will be determined by in situ immunoimaging. To determine the extent and within-capillary distribution of gene transcription responses, lung capillaries will be subjected to in situ PCR for detection of mRNA of selected leukocyte adhesion receptors and chemokines. Significance: Sustained high pressure is well known to be pathogenic in lung microvessels. However, relevant cellular mechanisms are not well understood. It is important to know the role of EC[Ca2+]i in this biology since high pressure increases EC[Ca2+]i and induces Ca2+ dependent expression of the leukocyte adhesion receptor, P-selection in lung venular capillaries. Increased EC[Ca2+]i may be common to many mechanisms that promote lung microvascular injury. Sustained EC[Ca2+]i increases, or EC[Ca2+]i oscillations in pathological conditions, may induce secondary effects such as generation of other second messengers and induction of gene transcription and consequently, lung vascular remodeling. The proposed studies are therefore novel and important, and will reveal a fundamental, new understanding of pressure-induced responses in the lung capillary. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CARDIOPULMONARY HYPERTENSION

EXERCISE

TESTING:

PULMONARY

Principal Investigator & Institution: Oudiz, Ronald J.; Associate Professor of Medicine; Harbor-Ucla Research & Educ Inst 1124 W Carson St Torrance, Ca 905022052 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: (Revised Abstract) Pulmonary arterial hypertension (PAH) is a devastating, rapidly progressive disease of the pulmonary vasculature that typically affects young women between the ages of 21 and 40. Untreated, the median survival time is 2.8 years. Only lung transplantation relieves the pulmonary hypertension. Methods currently used to assess the clinical course are either subjective or do not correlate well with symptoms and life expectancy. Right heart catheterization is widely-used to measure disease severity and response to therapy, but repeated catheterization causes morbidity

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and is a potential barrier to needed changes in therapy. Also, catheterization is performed at rest, not during exercise, when the patient is symptomatic. In contrast, preliminary data from the PI and his mentor show that noninvasive measures of aerobic function and ventilatory efficiency during exercise are closely related to disease severity and response to therapy in patients with PAH. This has broad implications for determining prognosis, selection of treatment, and making decisions on the timing of lung transplantation. The broad objectives of this proposal are to define optimal methods for noninvasively assessing patients with PAH, and to develop a prognostic model using cardiopulmonary exercise testing (CPET). The specific aims are: 1) To establish peak exercise oxygen consumption (peak VOz) and other CPET measurements as independent predictors of survival time, need for tung transplantation, or hospitalization for symptoms of PAH. 2) To use CPET parameters to further subclassify patients with NYHA II and III functional class symptoms, and patients with 6-minute walk distances of 250-400 m 3) To establish the relationship between peak VO2 and other CPET measurements in tracking the response to vasodilator therapy. This study will help determine the most useful parameter(s) to follow for making critical clinical decisions, including determining the need for and timing of lung transplantation. From our large PAH referral clinic, we will perform CPET in 72 human subjects with PAH, as defined by the World Health Organization. We will examine how the pulmonary vasculopathy of PAH affects exercise aerobic capacity and ventilatory efficiency in PAH, and how these important reflections of cardiac and pulmonary vascular function relate to clinical indices used in the conventional evaluation of these patients. Our hypotheses are based on the concept that CPET measurements provide objective, quantitative measures of disease severity and response to therapy. Therefore important therapeutic decisions can be based on objective measures of the circulatory and ventilatory responses to exercise, This proposal will enable the PI to participate in a structured, graded career development program leading to the acquisition of skills needed for a career in patient-oriented cardiovascular research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CGMP REGULATION IN THE DEVELOPING PULMONARY VASCULATURE Principal Investigator & Institution: Steinhorn, Robin H.; Professor; Pediatrics; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 01-AUG-1995; Project End 31-JUL-2005 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHRONIC HYPOXIA AND PULMONARY VASCULAR SMOOTH MUSCLE Principal Investigator & Institution: Shimoda, Larissa A.; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 08-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Prolonged exposure to decreased oxygen tension, as occurs with many pulmonary diseases, results in pulmonary hypertension, significantly worsening prognosis. The mechanism underlying the pathogenesis of this process remains unknown. Pulmonary arterial smooth muscle cell (PASMC) contraction associated with chronic hypoxia (CH) may be caused by elevated intracellular Ca2+ concentration ([Ca2+]i). In PASMCs, depolarization is observed with CH, fueling

14

Pulmonary Hypertension

speculation that [Ca2+]i is increased due to activation of voltage-gated Ca2+ channels or enhanced Na+/Ca2+ exchange. The endothelium-derived constricting factor, endothelin-1 (ET-1), may contribute to the pathogenesis of CHPH, since ET-1 increases [Ca2+]i. Following exposure to CH, the ET-1-induced rise in [Ca2+]i is reduced but contraction is maintained, suggesting activation of Ca2+-independent contractile pathways. This may be due to ET-1-induced activation of tyrosine kinases (TK). Hypoxic induction of ET-1 occurs via activation of the transcription factor, HIF-1, in systemic endothelium and in mice partially deficient for HIF-1, CH-induced pulmonary hypertension is markedly reduced. Therefore, we hypothesize induction of HIF-1 is an initiating step in the development of pulmonary hypertension, leading to elevated ET-1 levels. ET-1 then diffuses to PASMCs, activating three contractile mechanisms. First, ET1 decreases voltage-gated K+ channel expression, leading to depolarization-driven activation of Na+/Ca2+ exchange and elevation of resting [Ca2+]i. Second, ET-1 causes TK-mediated Ca2+ influx through L-type Ca2+ channels. Both of these mechanisms increase phosphorylation of myosin light chains (MLCs). Finally, ET-1 causes changes in Ca2+-sensitivity of the contractile apparatus via TK-mediated regulation of actin binding proteins. This final step allows actin to interact with the phosphorylated MLCs generated in steps 1 and 2, and results in contraction. To test these hypotheses, we will use a combination of techniques in our model of hypoxic pulmonary hypertension, including isometric tension recording in arterial segments, Northern and Western blot analysis, whole-cell patch-clamp and microfluorescence measurements, to accomplish the following Specific Aims: 1) confirm that HIF-1 regulates hypoxic induction of ET-1 in the pulmonary vasculature and identify the cell type(s) involved; 2) determine the mechanisms responsible for the CH-induced increase in resting [Ca2+]i and 3) determine the mechanisms by which ET-1 causes contraction during CH. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--LABORATORY FACILITY Principal Investigator & Institution: Meiselman, Herbert J.; Professor; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-MAR-2008 Summary: It is proposed to establish a Laboratory Core in order to support the research activities of the University of Southern California Comprehensive Sickle Cell Center (USC CSCC). This proposed Laboratory Core represents a consolidation of three ongoing activities of the present USC CSCC: 1) Biorheology-BiophysicsCore [H.J. Meiselman, PI]; 2) Diagnostic Laboratory [C.S. Johnson, Director]; 3) Haplotype Laboratory [A.L. Hiti, Director]. The specific aims of the Laboratory Core include: 1) For Project 1 (Dr. T. Fisher, PI), to provide relevant RBC rheologic and morpholgic data as aids in defining relations between blood group polymorphismsand specific markers of disease severity; 2) For Project 2 (Dr. C. Johnson, PI), to provide relevant RBC morphologic and rheologic data, specific ELISA assays, and RBC FACS analyses in support of studies exploring pulmonary hypertension; 3) For Project 3 (Dr. T. Coates, PI), to provide rheologic/morphologic data, biophysical techniques, and specialized hematological measurements in support of studies examining hypoxia-flow relations; 4) For Project 4 (Dr. P. Malik, PI), to provide hematological and rheological analyses for mouse and human RBC, hemoglobin analyses, and specific FACS assays, to help characterize RBC populations; 5) For Project 5 (Dr. V. Kalra, PI), to provide biophysical and rheological techniques such as RBC density fractionation and cyclic deoxygenation to aid studies of mechanisms of alveolar damage; 6) For all investigators associated with the USC CSCC, to provide relevant laboratory consultation, and to provide reference

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laboratory and consultative services to the local and regional medical community. It should be noted that this Laboratory Core represents a new, integrated approach to providing biochemical, biophysical, hematological, and rheological information to Center researchers. It is thus anticipated that this Core will increases the understanding of the patho-physiological events occurring in sickle cell disease, thereby leading to improved patient care. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--MOLECULAR PATHOLOGY Principal Investigator & Institution: Franklin, Wilbur A.; Professor; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: NO ABSTRACT PROVIDED Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CREB: HYPERTENSION

MOLECULAR

DETERMINANT

OF

PULMONARY

Principal Investigator & Institution: Klemm, Dwight J.; Associate Professor; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): Pulmonary hypertension is characterized by profound changes in the structure of the arterial wall due in large part, to the proliferation of smooth muscle cells. Insults to the cardiopulmonary system elicit changes in SMC phenotype through a variety of mechanisms including the production of proliferative and inflammatory cytokines by endothelial cells and platelets. The longterm goals of our research are to define the molecular mechanisms by which the cytokine, Platelet-derived Growth Factor-BB (PDGF-BB) regulates pulmonary artery (PA) SMC proliferation. Previously, we reported that levels of the transcription factor, cAMP-Response Element Binding Protein (CREB) are reduced in proliferating SMCs in PAs from hypertensive, neonatal cows, or in cultured SMCs treated with PDGF-BB. We also demonstrated that ectopic expression of constitutively active CREB isoforms in SMCs inhibits basal and PDGF-induced growth in vitro, whereas dominant negative CREB isoforms enhanced proliferation. PDGF appears to regulate CREB content at the level of gene transcription. Interestingly, PPARg agonists increased CREB content and blocked SMC proliferation in vitro and in rodent models of diabetic vascular disease. Recent preliminary studies indicate that CREB modulates cyclin D1 and Cdk-4 expression in SMCs. Based on these results, we hypothesize that PDGF-BB regulates SMC proliferation via associated signaling pathways and transcription factors that control CREB gene transcription, which in turn controls the expression of factors that govern cell cycle entry and progression like cyclin D1 and Cdk-4. To address this hypothesis we have designed three Specific Aims to 1) identify the intracellular signaling pathways and transcription factors that regulate CREB gene transcription in response to PDGF-BB, 2) demonstrate that CREB-induced changes in cyclin D1 and Cdk4 regulates SMC proliferation, and 3) demonstrate that PPAR agonists increase CREB content and prevent vascular remodeling in neonatal cows exposed to hypoxic conditions. These studies are significant since CREB has not been widely implicated in SMC function, in spite of the well-established role of cyclic nucleotides and PKA in controlling SMC proliferation. Likewise, the regulation of CREB activity has

16

Pulmonary Hypertension

traditionally been viewed as a function of phosphorylation status rather than changes in CREB content. Defining the expression and regulation of CREB in SMCs is crucial to developing a comprehensive model for its participation in controlling SMC proliferation. The proposed studies should provide new insights into the gene transcription events that control SMC growth and perhaps identify targets for new therapies designed to prevent or treat PH and related diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECTS HYPERTENSION

OF

BMPRII

MUTATIONS

IN

PULMONARY

Principal Investigator & Institution: Rodman, David M.; Professor; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2003; Project Start 19-SEP-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Primary pulmonary hypertension (PPH) is a potentially lethal disorder characterized by pulmonary vasoconstriction and vascular remodeling involving abnormal proliferation of fibroblasts, smooth muscle and endothelial cells. In the year 2000, mutations in the type 2 bone morphogenic protein receptor (BMPR2) were identified as the genetic basis for familial PPH and about 30% of sporadic PPH. BMP signaling had not previously been connected to pulmonary hypertension, and the mechanistic linkage is unknown. We hypothesize that in normal individuals the BMP pathway acts to down-regulate both inflammatory cytokinemediated positive feedback loops and vascular smooth muscle cell proliferation. Insufficient BMP pathway activity in individuals with BMPR2 mutations leads to insufficient damping of these auto-regulatory loops, resulting in the PPH phenotype. We provide preliminary evidence in cell culture systems supporting this hypothesis and have constructed a unique series of transgenic mice to further test the hypothesis. These mice express a human dominant-negative BMPR2 (dnBMPR2) using the tetracycline gene switch system, allowing both spatial and temporal control of expression. We have successfully bred smooth muscle cell and epithelial cell specific dnBMPR2 expressing mice, and are constructing endothelial cell specific mice at this time. Using our in vitro and transgenic models we will test the following three specific aims: 1: Test the hypothesis that the BMP pathway is a negative modulator of the cytokine interleukin-6 (IL-6) in PA SMC, leading to reduced IL-6-mediated signaling and proliferation. 2: Test the hypothesis that loss of PA SMC BMPR2 function in SM22-dnBMPR2 transgenic mice leads to an exaggerated pulmonary hypertensive response in vivo. 3: Test the hypothesis that loss of BMPR2 function in lung cell types other than SMC also contributes to the development of pulmonary hypertension. Upon completion of our studies, we will have tested the hypothesis that the link between BMP signaling and pulmonary hypertension involves both regulation of the critical cytokine, IL-6, as well as modulation of smooth muscle cell proliferation. We will have also tested the role of four pulmonary cell types, smooth muscle, endothelium, airway epithelium and macrophages in the link between BMPR2 and pulmonary hypertension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EICOSANOIDS AND PULMONARY VASCULAR TONE Principal Investigator & Institution: Pfister, Sandra L.; Pharmacology and Toxicology; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 01-JAN-1998; Project End 31-DEC-2003

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Summary: (Applicant's abstract): In recent years, the importance of various factors synthesized and released from the blood vessel endothelium that contribute to the regulation of vascular tone has become apparent. In pulmonary vessels, these investigators have identified an endothelium-dependent contracting factor as the vasoconstrictor thromboxane A2. There are a number of incidences where an increased synthesis of thromboxane A2 is associated with pulmonary disease, including pulmonary hypertension and sudden death. Therefore, the long term objective of the proposed studies is to investigate the hypothesis that arachidonic acid is metabolized by pulmonary blood vessels to thromboxane A2 and that thromboxane A2 is an important mediator involved in the regulation of pulmonary vascular tone under both normal and pathophysiological states. Specifically, it is known that arachidonic acid and methacholine-induced contractions of pulmonary arteries are mediated by thromboxane A2 and removal of the endothelial layer abolishes the contractions. Yet, endothelial cells isolated from pulmonary arteries do not synthesize thromboxane A2. Experiments described by specific aim 1 will investigate the hypothesis that thromboxane A2 synthesis in pulmonary vessels requires the interaction between the endothelial cells and adherent cells. Possible candidates for the adherent cells include platelets, polymorphonuclear leukocytes or monocytes. Studies have shown that thromboxane A2-induced platelet aggregation and vascular smooth muscle vasoconstriction is mediated via activation of a membrane-bound receptor. One limitation to studying the role of thromboxane A2 in pulmonary disease is the inability to differentiate the contribution of the platelet and the vascular smooth muscle receptor to the observed hemodynamic responses because the available thromboxane receptor antagonists are unfortunately non-selective and block both the platelet and vascular receptors. The investigators have identified a subset of rabbits that are deficient in vascular, but not platelet, thromboxane A2 receptors. Experiments described by specific aim 2 will use these rabbits to investigate the hypothesis that thromboxane A2 and its vascular receptor are important to the regulation of pulmonary vascular tone. Specifically, they will investigate the influence of age and gender on the vascular responsiveness to thromboxane agonist and thromboxane A2 receptor density, characterize the differences in receptor number and functional responses in vascular cells cultured from responder and nonresponder pulmonary arteries and assess the role of the vascular thromboxane A2 receptor in a model of pulmonary embolism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENDOTHELIAL HYPERTENSION

GENE

DELIVERY

FOR

PULMONARY

Principal Investigator & Institution: Curiel, David T.; Director; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2005 Summary: Pulmonary vascular disease constitutes a major cause of mortality, morbidity and healthcare expenditure. Although the underlying causes are mutifactorial, this condition is generally characterized by increased pulmonary vascular resistance, which develops on the basis of both vasoconstriction and arterial vascular remodeling. Within this context, pathobiologic changes in the pulmonary endothelium are understood to playa central role in the development of both of these characteristic disease features. Studies of pathologic material from patients have demonstrated dysregulated expression of factors relevant to vasomotor tone and vascular wall remodeling. It is clear. however, that a fuller understanding of these pulmonary endothelial abnormalities will be required to allow rational interventional strategies. In this regard,

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Pulmonary Hypertension

methods allowing specific and directed perturbations in gene expression profiles within pulmonary endothelium would potentially provide unique insight into disease pathophysiology. On this basis, it would be desirable to develop technologies to achieve the goal of transient alterations in gene expression patterns selectively within pulmonary endothelium. Such gene-based methods would allow rational analysis of candidate genes with respect to their role in the pathobiology of this condition. Of note, these same methods would potentially allow directed therapeutic interventions. We have recently developed methods to alter the tropism of Ad vectors. These modifications have allowed the achievement of cell-specific gene delivery to pulmonary vascular endothelium in vivo after systemic vascular administration of the vector. We will use these modified Ad vectors to deliver relevant genes to the pulmonary endothelium in rat models of pulmonary hypertension and thrombosis, as a means to discover new insights into the pathophysiology of pulmonary hypertension. In these analyses we will asses the impact of gene delivery on pulmonary vascular pressures, vascular remodeling and thrombosis. In addition, it is our hypothesis that we can further improve the targeting properties of adenoviral vectors by genetic means, thereby improving the efficiency and specificity for I pulmonary endothelial markers and generating agents of potential clinical utility. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EPITHELIAL DEVELOPMENT

MESENCHYMAL

INTERACTIONS

IN

LUNG

Principal Investigator & Institution: Vu, Thiennu H.; Anatomy; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-AUG-1998; Project End 31-JUL-2003 Summary: (Adapted from applicant's abstract) The applicant's goal is to become an independent clinician scientist who engages in basic research that has clinical relevance. The applicant has obtained both clinical and research training to prepare her for a career in medical research. She is interested in studying the development of the lung vasculature, since it not only addresses questions on fundamental developmental processes but may also provide insights into the pathogenesis of diseases in which abnormal vascular development is a component, such as cancer, vascular malformations, pulmonary hypertension, chronic inflammation, and abnormal lung repair following injury. The lung is one of the most highly vascularized tissues in the body, yet the mechanisms regulating the development of the pulmonary vasculature has been poorly characterized. The current application focuses on lung vascular development in the early embryonic period. The hypothesis is that epithelialmesenchymal interactions are important for the coordination between airway and vessel development, and he propose to study the molecular mechanisms of these interactions during early mouse embryonic development. Specifically, her will (1) define the processes of lung vascularization during early mouse embryonic development and characterize the temporal and spatial relationship between vessel and airway development, (2) identify molecular factors that may function in the development of the embryonic lung vasculature, and (3) determine the specific roles these factors play in the interactions between lung epithelium and mesenchyme that are necessary for vascular development. The applicant's long term goal is to understand the molecular mechanisms regulating lung vessel formation in normal development and in diseases. The current proposed study will add to the knowledge of the development of the lung vasculature during early organogenesis and help establish a firm foundation on which future studies can be based. Besides research, training activities include didactic studies,

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participation in seminars and conferences, formal presentations at local and national meetings, supervised preparations of manuscripts and grants, and regular meetings with a Scientific Advisory Council. The sponsor and the members of the Scientific Advisory Council have been chosen for their expertise in areas and approaches relevant to the proposed research. In addition, they are senior members of the faculty who will be able to guide the applicant in career development. UCSF is fully committed to the development of junior faculty researchers, and offers an excellent environment for the scientific development of a clinician scientist. (End of Abstract) Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HYPOXEMIA

FETAL

AND

ADULT

ADADPTATIONS

TO

LONG-TERM

Principal Investigator & Institution: Longo, Lawrence D.; Professor; Center for Perinatal Biology; Loma Linda University Loma Linda, Ca 92350 Timing: Fiscal Year 2002; Project Start 15-MAR-1995; Project End 31-DEC-2004 Summary: The overall theme of this proposal is to explore the fundamental mechanisms whereby the fetus and adult adapt to long-term, high altitude hypoxemia. In addition, we will examine several of these mechanisms in association with development of the fetus into an adult. This proposal is a broadly based, multidisciplinary program which uses physiologic, pharmacologic, biochemical, and molecular approaches to explore adaptations of the cardiovascular system, the cerebral blood vessels, uterine vessels, the fetal hypothalamic-pituitary-adrenal axis, and the myometrium in response to long-term hypoxemia. These studies will be conducted in fetal and adult sheep acclimatized to high altitude (3820 m/12,470 feet,) and in normoxic controls. They are based on eleven years of research by our group on the responses and acclimatization to high altitude hypoxia in the fetus and adult. The proposed studies examine a number of hypotheses regarding physiologic, biochemical, and molecular mechanisms. For example, in the heart we will test hypotheses regarding the roles of calcium channels, Ca2+-induced Ca2+ release, beta-receptor coupling to protein kinase A, and troponin and myosin ATPase isoforms in the responses to long-term hypoxemia. In the cerebral arteries we will test hypotheses regarding alpha adrenergic receptor subtypes, their coupling to second messengers, the relation to intracellular calcium modulation by protein kinase C the role of Ca2+ and K+ channels, vascular innervation, norepinephrine release and reuptake, relaxation mechanisms, et cetera, to long-term hypoxemia. In uterine arteries we will test several hypotheses regarding the mechanisms of modulation by cortisol, and how these mechanisms are altered by long-term hypoxemia. Finally, we also will test several hypotheses regarding the fetal hypothalamic-pituitary- adrenal responses to long-term hypoxemia, e.g., the role of adrenal adenylate cyclase, and glucocorticoid receptors, as well as signal transduction mechanisms in the myometrium. From a scientific standpoint, these studies will augment our understanding of the mechanisms whereby the fetus and adult successfully adapt to chronic hypoxemia. In addition, they will shed light on a number of aspects of development from fetus to adult. From a clinical standpoint, these studies relate to the problems of prolonged hypoxemia and successful high altitude acclimatization. For the fetus and newborn they also relate to responses to prolonged hypoxemia as occurs in women who live at high altitude, as well as those who smoke or are exposed to environmental pollution, as well as those who are anemic, or who have heart or lung disease or with "placental insufficiency." For the newborn infant these studies relate to problems such as pulmonary hypertension, persistent fetal circulation, altered cerebrovascular function, and intracerebral

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hemorrhage. Finally, the studies give promise of shedding light on the mechanisms of the Barker hypotheses of prenatal programming of adult disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FI02 AND BLOOD VESSEL FORMATION IN ADULT LUNG Principal Investigator & Institution: Jones, Rosemary C.; Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Injuries that trigger loss of small vessels and capillaries in the adult lung, and wall overgrowth in ones that survive ultimately restrict blood flow and increase vascular resistance and pressure to cause pulmonary hypertension (PH). The long-term goals of the present studies are to obtain data for circulating blood-derived cells that have the potential to form new vascular units in the adult lung, and the RTK-ligand signaling systems that regulate blood vessel formation, as a rational basis for strategies to promote (re)growth of vascular segments and block wall overgrowth. Our recent data in an in vivo model of vascular remodeling in PH indicate that the FiO2 triggers regression and growth of vessel and capillary units to match vascular density to the functional demands of the tissue. Because vessels of the normal alveolar-capillary membrane form the continuation of capillary networks many are simple endothelial-lined channels with few, if any, mural cells. As hyperoxia (FiO2 0.87) prunes these segments, mural cells develop around ones that survive, resulting first in wall support and then in wall overgrowth. The early stage of return to air (representing relative hypoxia to the hyperoxia-adapted lung) triggers further mural cell development and the formation of new vessels and capillaries throughout the alveolarcapillary membrane. Based on preliminary data, the hypotheses tested are that circulating endothelial progenitors (CEPs) form these new vascular networks, and that FiO2 -triggered increase in expression of RTKs for PDGF (PDGFR-alpha and R-beta) by interstitial fibroblasts and ANG- 1 (TIE-2) by local endothelial cells induces mural cell development, and increase in expression of RTKs for VEGF and ANG-2 (VEGFR-1, VEGFR-2 and TIE-2) by CEPs and endothelial cells the formation of vascular units. Blood-derived cells will be characterized by cell lineage analysis. The requirement of PDGFR-beta for mural cell development will be demonstrated by function-inhibition antibody studies. FiO2--induced vascular cell regression, unit pruning, by apoptosis, will be assessed by cell death assays, and the protection afforded by VEGF investigated. Quantitative data will be obtained by state-of-the-art high resolution immunogold labeling and digital imaging techniques for (i) fluorescein labeled/luciferase transfected blood-derived cells and (ii) RTK and ligand (PDGF-AA, PDGF-BB, VEGF, ANG-land ANG-2) expression levels in endothelial and mural cells of forming vascular units in growth responses triggered by the FiO2. These approaches will demonstrate a role for blood derived cells and RTK signaling triggered by an 'abnormal' FiO2 that lead to the formation of new vascular units and wall overgrowth, and provide data on which to base therapeutic approaches to prevent or correct the vascular remodeling that results in severe illness in human patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE THERAPY:TRANSLATING BASIC SCIENCE TO THE CLINIC Principal Investigator & Institution: Hammond, Kirk H.; Medicine; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-AUG-2006

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Summary: The purpose of this Program is to form efficient, interactive and mutually reinforcing program of basic, translational and clinical research in cardiovascular gene therapy. Our overriding goal is to translate basic bench discoveries in cardiovascular diseases into disorders affecting the heart is feasible but will require a multi-disciplinary approach with a global examination of new gene transfer and deleterious effects of transgenes to minimize potential and rigorous implementation of human clinical studies. We have brought together a group of leading basic, translational and clinical establishment of this new Program, the strong basic and clinical research environment at UCSD, and the historical and ongoing activities in gene therapy at this university will provide a superb environment to take a comprehensive and rigorous collaborations among scientists, provide them with high quality reagents, tools and services and promote the rapid translation of research in cardiovascular gene therapy. Dr. Hammond, the PI of the Program, will initiate a clinical trial in patients with severe heart failure (Project 1) using intracoronary (non- surgical) delivery of an adenovirus encoding Type VIII adenylyl cyclase to increase data supporting this approach over the last 5 years, and recently demonstrated the safety and efficacy of intracoronary gene transfer of adenovirus in treating human patients in a Phase I/Phase 2 blinded, placebocontrolled clinical trial. Other Projects will examine the effects of gene transfer on cardiovascular function and structure using in vitro and in vivo models. These studies are directed to obtain data supporting additional gene therapy studies. Other Projects are intended to facilitate gene transfer by providing high quality vectors (Core B), gene targeting to the cardiovascular system (Project 3), and the effects of gene transfer on cellular structure and function (multiple Projects with Core A). DR. Insel (Project 2) will transfect pulmonary artery smooth muscle cells with isoforms of adenylyl cyclase to alter signaling-exploring the potential for gene transfer in treating pulmonary hypertension. Dr. Friedmann (Project 3) will examine the in vivo fate of retrovirus and lentivirus vectors after systemic delivery, examining host immune responses. He also will use phage display libraries to identify tissue- targeting peptides for vector targeting, strategy that will be useful to multiple projects. Dr. Witztum (Project 4) will use gene transfer to arrest progression of atherosclerosis-vectors encoding single chain antibodies will be targeted against "oxidation-specific" epitopes of extracellular oxidized LDL. In summary, this Program will establish a comprehensive and rigorous program in translational research and clinical cardiovascular gene therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE TRANSFER TO ALTER TRANSPLANTED HEART FUNCTION Principal Investigator & Institution: Koch, Walter J.; W.W. Smith Professor of Cardiology; Surgery; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 01-JAN-1998; Project End 31-DEC-2004 Summary: (Verbatim from the applicant's abstract) This represents a competing renewal application to study gene transfer as a means to alter the function of transplanted hearts. Cardiac transplantation is limited by the limited supply of donor hearts and perioperative ventricular dysfunction. Ventricular dysfunction (including RV dysfunction due to recipient pulmonary hypertension) and allograft vasculopathy are major causes of cardiac transplant failure. Understanding signaling mechanisms may be important to improve graft function and survival. Signaling through G-protein coupled receptors (GPCR), especially BAR, is important for normal cardiac and vascular smooth muscle cell physiology. BAR signaling is often compromised in the transplanted human heart, and several agents implicated in allograft vasculopathy can signal through G proteins. Transgenic mice have been developed with altered BAR and G protein

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signaling, including mice in which BAR-kinase (BARK1) is overexpressed. Increased expression of a BARK1 inhibitor improves cardiac performance in heart failure and transplant models. The plans are to use viral-mediated gene transfer in rat and rabbit models and transgenic mice models to investigate mechanisms by which GPCR signaling affects graft function. The Aims are (1) to characterize BAR signalling in brain dead rabbit hearts and to try to improve function with adenoviral delivery of BAR signalling/inhibitory molecules; (2) to characterize BAR signalling and elucidate molecular defects in murine cardiac grafts, to use transgenic BAR signaling mutants to determine effects on graft function, and to use a rabbit model of heterotopic cardiac transplantation to study the effects of acutely manipulating BAR signalling; (3) to use a pulmonary artery banding model in rabbits to produce RV stress, as a condition to test BAR signalling and as a means to improve posttransplant RV dysfunction; and (4) to study the role of G protein signalling in mediating vascular smooth muscle (VSM) cell proliferation, and to use a rat aortic allograft model to test strategies to limit VSM hyperplasia in transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC AND ENVIRONMENTAL PATHOGENESIS OF PPH Principal Investigator & Institution: Loyd, James E.; Associate Professor; Medicine; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2003; Project Start 04-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Primary pulmonary hypertension (PPH) is a progressive, fatal disease, which threatens the lives of thousands of patients across all age groups. In a recent important advance, mutations in bone morphogenetic protein receptor 2 (BMPR2) have been associated with both familial and sporadic PPH. Our hypothesis is that other genes and biologic events participate in the development of familial PPH, because only 20% of persons with a BMPR2 mutation ever develop PPH. Our target goals are to identify the modifying genes and environmental features that regulate the clinical expression of mutations in BMPR2; to develop understanding about how BMPR2 mutations result in disease; and to identify the undiscovered mutations which cause PPH. The program forms a structural basis to enhance existing collaborations among experienced investigators from six disciplines to optimize progress in the study of PPH. The program will utilize the unique resources of our database and specimen bank developed from 116 PPH families across the US. In families with mutations not yet identified, we will search for alterations in the BMPR2 gene, including promoter and intronic regions, and search for chance recombination events which could confirm another locus near 2q33. Experimental approaches for identifying modifier genes will include genome wide single nucleotide polymorphism and microsatellite scans in large families with known mutations, examination of mitochondrial DNA haplotypes and candidate genes as modifiers, including NOS-1, NOS-3, and the serotonin transporter. We will study the perceived risks and benefits of genetic testing and counseling in many individuals in families at high risk for PPH. We will also identify genetic modifiers of BMPR2 in mouse models of pulmonary hypertension. We will determine the functional mechanisms by which variations found in the BMPR2 alleles alter BMP signal transduction by defining the biochemical effects of the mutant proteins on signaling pathways. The proposal emphasizes that the common themes, complementary expertise and unique technologies assembled into a coordinated program will be more creative, more productive and more likely to advance understanding of the molecular pathogenesis of PPH. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HEME OXYGENASE 1--LUNG VASCULAR CELL HYPOXIC RESPONSE Principal Investigator & Institution: Choi, Augustine M.; Professor; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-JAN-1999; Project End 31-DEC-2002 Summary: (Adapted from applicant's abstract): Hyperoxia is known to differentially regulate vascular tone contingent on the vascular bed involved. For example, hypoxia causes systemic vasodilation yet initially causes acute pulmonary vasoconstriction, and if sustained leads to profound remodeling of the pulmonary vasculature culminating in structural-based increases in pulmonary vascular resistance and in pulmonary hypertension. The molecular mechanisms underlying the differential vascular responses to hypoxia remain largely unknown. However, recent studies have demonstrated that hypoxia- inducible genes including endothelin-1, platelet-derived growth factor, vascular endothelial growth factor, and inducible nitric oxide synthase play important roles in the vascular cells' adaptive response to hypoxia. The applicant's laboratory has observed that hypoxic stress can result in marked induction of the stress inducible gene heme oxygenase-1 (HO-1) in systemic aortic vascular smooth muscle cells (aVSM) but not in pulmonary vascular smooth muscle cells (pVSM). The molecular basis by which hypoxia differentially regulates HO-1 expression in a VSM and pVSM is not known. Interestingly, carbon monoxide (CO), a major catalytic by-product of HO activity, is a gaseous molecule which can activate guanylyl cyclase and stimulate cGMP production, regulate vascular tone via vasodilatory effects and modulate gene expression, similar to the effects of nitric oxide. The functional role of HO-1 induction and thus CO in the vascular response to hypoxic stress is also poorly understood. Against this background, the applicants hypothesize that the differential expression of HO-1 in systemic and pulmonary vascular cells is mediated by distinct transcriptional regulation and that the HO-1 induction play an important role in mediating the lung's adaptive response to hypoxia. They will test their hypothesis by addressing the following SPECIFIC AIMS: (1) Determine the differential molecular regulation of HO-1 gene activation between hypoxic pulmonary vascular smooth muscle (pVSM) and aortic vascular smooth muscle (aVSM) cells. (2) Determine the differential molecular regulation of HO-1 gene activation between hypoxic pulmonary endothelial (pEC) and aortic endothelial (aEC) cells. (3) Determine the functional role of HO-1 and CO in vitro after hypoxia using the inducible tetracycline regulated expression system. (4) Determine the functional role of HO-1 and CO in vivo after hypoxia using genetically altered mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HEPARIN ON HYPOXIC PULMONARY HYPERTENSION AND REMODELING Principal Investigator & Institution: Hales, Charles A.; Professor of Medicine; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-JUL-1987; Project End 31-MAY-2005 Summary: Thickening of the media with intrusion on the vascular lumen contributes substantially to the pulmonary hypertension seen in primary or secondary pulmonary hypertension. Heparin has been shown to be antiproliferative and antihypertrophic for systemic and pulmonary artery smooth muscle cells (PASMC) in vitro and has been variably effective at inhibiting in vivo remodeling in several systemic and pulmonary models. We have found that commercial heparin lots vary widely in their

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antiproliferative activity. However, an effective antiproliferative heparin in vitro for PASMC proliferation can prevent hypoxic pulmonary hypertension in mice, rats and guinea pigs and can reverse it in guinea pigs even in the presence of continued hypoxia. We have also shown that heparin's ability to inhibit PASMC proliferation and in vivo pulmonary hypertension correlates with its ability to prevent mitogen stimulation of the Na+/H+ antiporter. We have found that highly specific antagonists of the Na+/H+ antiporter such as dimethyl amiloride (DMA) can inhibit PASMC proliferation in response to growth factors in vitro and can substantially prevent hypoxic pulmonary hypertension and remodeling in rats. As we dissect the chemistry of antiproliferative heparins we have shown, among other things, that the protein core is unimportant and that 3-0-sulfate is not an important feature in full-length heparin. We have made new heparin derivatives by O-acetylating heparin with butanoyl and hexanoyl which are more potent antiproliferative agents on PASMC than native heparins and are nonanticoagulant. We have found that in PASMC heparin stimulates the production of the cell cyclin kinase inhibitors p21 and p27 which are inhibitors of cell proliferation in other cells. With this progress we hope to continue our pursuit of an effective treatment for pulmonary hypertension with the following specific aims: 1) Continue examining strongly versus weakly antiproliferative heparins in order to discover the reasons for the differences with a goal of amplifying the antiproliferative potency and perhaps divorcing it from the anticoagulative and osteopenic properties. 2) Determine in the pig, as a preclinical trial in a large mammal, if heparin or heparin fragments or the Na+/H+ inhibitor DMA are effective at preventing hypoxic pulmonary hypertension and 3) Determine if heparin's mechanism of action in preventing SMC proliferation is via stimulation of the cyclin kinase inhibitors p21 and p27. Thus, this proposal may lead to new therapeutic agents for humans with pulmonary hypertension and may elucidate a new understanding of how heparin prevents PASMC growth. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HIV TAT EFFECT ON ENDOTHELIAL CELL FUNCTION Principal Investigator & Institution: Terada, Lance S.; Professor of Medicine; Internal Medicine; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 30-SEP-1998; Project End 31-JUL-2003 Summary: Infection of patients with Human Immunodeficiency Virus 1 (HIV) is associated with diverse alterations in endothelial function. These include syndromes marked by inappropriate endothelial cell (EC hyperplasia (primary pulmonary hypertension), incomplete differentiation (Kaposi's sarcoma), and acute inflammation (pneumonitis, myocarditis, encephalitis, pericarditis). Although these perturbations in EC function can be diffuse, direct infection of EC by HIV is unusual, may be restricted to certain vascular beds, and is generally abortive. Such endothelial alterations are therefore more likely to be the result of HIV-related circulating mediators, rather than of direct endothelial infection by retrovirus. We hypothesize that the secreted HIV transcription factor Tat acts to modify EC proliferation, differentiation, apoptosis, and expression of inflammatory molecules, and additionally, that these effects are modulated by the cytokines TNF alpha, IL-1 beta, and IFN gamma. We further hypothesize that the diverse and sometimes opposing effects of Tat are mediated by the oxidant-dependent differential activation of the various MAP Kinase signaling cassettes. Our preliminary data confirm that exposure of human EC to Tat acutely increases intracellular oxidant levels concomitant with activation of c-Jun amino terminal kinase (JNK). Further, Tat alters the TNF-alpha- mediated activation of JNK and the DNAbinding affinity of the transcription factor AP-1, a potential target of JNK. Our general

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objectives are to correlate oxidase assembly, oxidant production, MAPK activation, and DNA binding and promoter activation of transcription factors, with cell phenotype (proliferation, differentiation, apoptosis, inflammatory molecule expression, and leukocyte adhesion) in human EC exposed to Tat and cytokines, using a variety of interventions designed to dissect different signaling pathways. The significance of this work is to provide further insight into the cause of various AIDS-related vascular syndromes, as well as to understand the basis for fundamental EC functions in normal individuals. This may lead to specific treatments for HIV-infected patients, and may also suggest novel strategies for treatment of non-HIV related diseases through modulation of endothelial cell function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HYPOXIA-INDUCED MITOGENIC FACTOR IN PERINATAL LUNG Principal Investigator & Institution: Li, Dechun; Anesthesiology/Crit Care Med; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2007 Summary: (provided by applicant): The long-term interest of this research program is to understand and explore the cellular and molecular mechanisms of hypoxia-induced mitogenic factor (HIMF), a protein we found in a mouse model of hypoxia-induced pulmonary hypertension, in lung development and maturation. It was also called FIZZ1 (found in inflammatory zone) in an asthma model in the lung. HIMF belongs to a new family of cysteine rich cytokines known to be specifically expressed in hypoxic and inflammatory lung. Most importantly, HIMF is highly upregulated in the developing lung during the perinatal period. This proposal will focus on two major areas. First, it will address HIMF gene expression in the developing lung, especially during the perinatal period. Second, it will investigate the cellular and molecular mechanisms of action of HIMF gene product in lung development and maturation and its relation with bronchopulmonary dysplasia (BPD) and respiratory distress syndrome (RDS). The first aim will address the hypothesis that HIMF is expressed in the developing lung and regulates pulmonary vascular development, controls maturation of the parenchymal lung, and coordinates vascularization and alveolarization. We will investigate the temporal-spatial expression of HIMF in the developing lung and its relationship with vasculogenesis and alveolarization using histological and molecular biological techniques. The second aim will examine the hypothesis that HIMF plays an important role in the maturation of the lung; disrupting HIMF gene expression might result in delayed lung development/maturation, and bronchopulmonary dysplasia (BPD). This aim will define the roles of HIMF in vascularization and alveolarization during the perinatal period in cultured (in vitro) and transplanted (in vivo) embryonic and neonatal lungs treated with HIMF protein, HIMF neutralizing antibody, or HIMF gene knock down with RNA interference (RNAi) techniques. The third aim will address the hypothesis that HIMF gene expression in the developing lung is regulated by transcription factors, including C/EBPot and HIF-2a. It will utilize comprehensive promoter-reporter transfection studies, EMSA, footprinting, and overexpression studies to define the protein-DNA interactions critical to HIMF gene expression during the perinatal period. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HYPOXIA-INDUCED SMOOTH MUSCLE CELL PROLIFERATION Principal Investigator & Institution: Segel, Michael J.; New England Medical Center Hospitals 750 Washington St Boston, Ma 021111533

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Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2006 Summary: (provided by applicant): Medial smooth muscle cell (SMC) proliferation is a central event in hypoxic pulmonary artery remodeling. We hypothesize that hypoxia directly initiates a series of events in pulmonary artery SMC (PASMC) that lead to proliferation. We wish to characterize elements of this signaling cascade. We aim to: (1) Investigate the role of mitogen activated protein kinases (MAPK) by measuring MAPK phosphorylation in hypoxic PASMC, and by inhibition of MAPK pathways. (2) Clarify whether reactive oxygen species (ROS) or heme-like proteins play a role in the signaling pathway, by measuring intracellular ROS in hypoxic and normoxic PASMC, studying the effect of antioxidants on hypoxic PASMC proliferation, defining the specific RO involved, and also by studying the effect of CO, NO and CN. (3) Identify transcription factors (TFs) activated by hypoxia in PASMC. We hypothesize that GATA-4, HIF-1 and AP-1 are downstream effectors in this pathway. We will study DNA binding activity of these TFs in hypoxic PASMC by gel shift assay, study the effect of neutralizing these TFs on hypoxia-induced proliferation and screen for activation of unknown TFs by hypoxia, by studying the nuclear proteome of hypoxic PASMC. Understanding the mechanisms of hytpoxic remodeling will lead to novel therapeutic strategies for pulmonary hypertension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMPROVED PLASMID/LIPOSOME ADMINISTRATION TO THE LUNGS Principal Investigator & Institution: Sanders, Jonathan R.; Generx+, Inc. 3200 West End Ave, Ste 500 Nashville, Tn 372011322 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-DEC-2003 Summary: (provided by applicant): A major impediment to the successful use of aerosol gene therapy for the treatment of lung diseases is the lack of an efficient and safe aerosol delivery strategy. When the transgene vector is a cationic liposome/plasmid DNA complex, factors that must be considered in designing the optimal aerosol device are the intrinsic instability of the liposome/plasmid complex, physical disruption of the complex upon aerosolization, and maximizing the amount of the complex deposited in the lung while minimizing contamination of the environment with exhaled transgene vector. Under support of a Phase I SBIR, we have systematically evaluated how physical stability and the process of aerosolization affects transfection efficacy in airway cells in vitro. These data have permitted us to design a liposome/plasmid DNA aerosolization device for use in humans with pulmonary and pulmonary vascular disease, which we believe could deliver potentially therapeutic genes to the airspaces in a highly efficient and safe manner. The purpose of this Phase II application is to develop a prototype plasmid/liposome delivery device to the point that it is testable in humans. Specifically, we propose to use this strategy to deliver the gene encoding the cyclooxygenase (COX) enzyme to the distal airspaces of humans with primary pulmonary hypertension (PPH). In order to achieve this goal, we will quantify pulmonary deposition, distribution, and clearance profiles in normal sheep of aerosols with different particle sizes aiming to maximize distal deposition; test strategies for improving the physical stability of the complex; and using the optimized delivery system, determine the efficacy of delivering the COX gene to distal airspaces in reversing pulmonary hypertension in the sheep model of PPH. PROPOSED COMMERCIAL APPLICATIONS: This project is part of a geneRx+ program to develop aerosol devices to efficiently deliver plasmid DNA/fiposome complexes to the distal airspaces of the human lung in order to treat both primary and secondary pulmonary hypertension. The partnership between

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geneRx+ and Profile Therapeutics represents a unique alliance, the goal of which is to develop aerosol devices specifically designed to efficiently nebulize plasmid/liposomes complexes to humans. If our concepts prove correct, then these devices will become the industry benchmark for transgene/liposome aerosol delivery devices. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INOS GENE TRANSFECTION IN PULMONARY HYPERTENSION Principal Investigator & Institution: Chicoine, Louis G.; Pediatrics; University of New Mexico Albuquerque Controller's Office Albuquerque, Nm 87131 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: Pulmonary hypertension (PH) is a significant cause of morbidity and mortality affecting a broad range of patients. Neonatal pulmonary hypertension is the second leading cause for admission to neonatal intensive care units for respiratory support. In adults, PH causes significant morbidity and mortality in patients with chronic obstructive pulmonary disease. In all patients, PH is characterized by cellular proliferation and altered vasoreactivity in the pulmonary vascular bed. The objectives of this proposal are to evaluate the vasodilator efficacy and toxicity of NO produced by virally mediated inducible nitric oxide synthase (iNOS) gene transfection in the lung and to determine the effect of virally transfected iNOS on the pathogenesis of PH. The general hypothesis is that virally transfected iNOS will result in sufficient NO formation to modulate pulmonary vasoconstriction and attenuate pulmonary vascular changes associated with pulmonary hypertension, but insufficient NO formation to result in toxicity. Utilizing human iNOS gene and, as a control, the E. coli lac Z reporter gene coding for beta-galactosidase (beta-gal) adenovirus constructs our goals set forth in this proposal are: 1) to optimize iNOS gene delivery and expression in the rat lung, 2) to determine the role of transfected iNOS on the development of pulmonary hypertension, and 3) to compare intravascular and intratracheal delivery of the iNOS gene in terms of gene expression, vascular reactivity and toxicity. These goals are addressed in the following specific aims: Specific Aim number 1: Assess the effectiveness of adenovirusmediated iNOS gene transfection in attenuating acute pulmonary vasoconstrictor responses. Specific Aim number 2: Assess iNOS gene transfection-mediated effects on the development of chronic hypoxia-induced pulmonary hypertension. Specific Aim number 3: Assess the efficacy and toxicity of intravascularly and intratracheally administered adenoviral iNOS constructs. The methods will involve using adenovirus constructs containing the gene for iNOS or beta-gal that will be administered intravascularly; the lungs will then be studied to determine vascular reactivity, NO production, and localization of transfected iNOS. Some rats will be transfected and exposed to chronic hypoxia. Finally, intravascular and intratracheal delivery will be compared in terms of gene localization and toxicity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IONIC AND PHARMACOLOGICAL REGULATION OF VASCULAR CELLS Principal Investigator & Institution: Hume, Joseph R.; Professor & Chair, Dept. of Pharmacology; Pharmacology; University of Nevada Reno 204 Ross Hall Mailstop 325 Reno, Nv 89557 Timing: Fiscal Year 2002; Project Start 01-AUG-1993; Project End 31-JUL-2003 Summary: The long term goal of this project is to gain a more complete understanding of the role of ion transport pathways in the regulation of pulmonary and renal arterial

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tone. This renewal application is based upon several advances made during the previous funding period and focuses on characterization of the role of intracellular Ca2+ stores and selected sarcolemmal ion channels in excitation-contraction coupling of isolated pulmonary and renal arterial smooth muscle cells (PASMC and RASMC). A combination of experimental approaches will be utilized to obtain cellular and molecular information which will be related back to the physiology of intact pulmonary and renal arteries. We will specifically determine the physiological role, biophysical and pharmacological properties and the molecular identity of nonselective cation channels and volume-regulated chloride channels in these specialized vascular beds. We will also examine the properties of ryanodine- and inositol triphosphate (IP3)-sensitive Ca2+i stores in RASMC and PASMC and identify any physiologically relevant interactions which may occur between these two stores and possible effects of Ca2+ released from these stores on sarcolemmal ion channels. Finally, we will test the hypotheses that alterations of Ca2+i stores, pHi, sarcolemmal K+, Ca2+ and/or CI- channels represent critical early events in the initiation of hypoxic pulmonary vasoconstriction. Despite the clinical relevance of these two vascular beds to a number of important disease processes, relatively little information is presently available on the role of ion channels and Ca2+i stores in the control of pulmonary and renal vascular tone. This study will help fill the existing gap of knowledge regarding the role of ion channels and Ca2+i stores in vascular reactivity of the renal and pulmonary circulation. The medical significance of this project is that the results obtained have significant potential of revealing new, important cellular mechanisms responsible for pulmonary and systemic hypertension and could lead to the development of new drugs and therapeutic strategies to treat or prevent these conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISM OF APOPTOSIS IN LUNG VASCULAR SMOOTH MUSCLE Principal Investigator & Institution: Suzuki, Yuichiro J.; Assistant Professor; None; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-DEC-2003 Summary: (provided by applicant): Primary pulmonary hypertension (PPH) is rare, but often fatal, with increased incidence in users of appetite suppressants. It is characterized by increased lung vascular resistance due to thickening of pulmonary arterial walls. The cellular mechanisms that regulate smooth muscle cell number, however, have not been defined. Lack of such knowledge interferes with the development of new therapeutic strategies that are designed to prevent and/or treat this condition. My long-range goal is to identify the mechanisms for the regulation of apoptosis in human pulmonary artery smooth muscle cells (HPASMC). The objective of this application is to evaluate specifically the role of GATA transcription factors. The central hypothesis of the application is that GATA factors regulate apoptosis and survival. The hypothesis has been formulated on the basis of strong preliminary data, which suggest that i) GATA-4 and -6 are expressed in HPASMC, ii) apoptotic stimuli downregulate the GATA activity, and iii) serotonin and endothelin-1 exert anti-apoptotic signaling and enhance the GATA activity. The rationale for the proposed research is that, once knowledge of the mechanisms that regulate the lung vascular medial thickening has been obtained, it will lead to new strategies that can be used to prevent and/or treat PPH, thereby reducing the morbidity and mortality that are associated with this condition. I am uniquely prepared to undertake the proposed research because my lab has been studying GATA factors, and many of the techniques and reagents are already available. The central

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hypothesis will be tested and the objective of the application accomplished by pursuing two specific aims: 1) Identify the mechanisms of HPASMC apoptosis induced by nitric oxide and retinoic acid, and 2) Determine the mechanisms by which serotonin and endothelin-1 exert anti-apoptotic signaling. The proposed work is innovative, because it will investigate novel transcription factors in lung using an approach that has been used in the studies of cardiac muscle. It is my expectation that GATA factors are involved in the regulation of apoptosis of HPASMC. These results will be significant because they are expected to provide new agents for preventative and therapeutic interventions of PPH. In addition, it is expected that the results will fundamentally advance the field of lung cell biology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF DEFORMATION-INDUCED ATP RELEASE FROM RBCS Principal Investigator & Institution: Sprague, Randy S.; Internal Medicine; St. Louis University St. Louis, Mo 63110 Timing: Fiscal Year 2002; Project Start 15-AUG-2000; Project End 31-JUL-2004 Summary: When traversing microvascular beds, such as in the lung, red blood cells (RBCs) are subjected to mechanical deformation. Our previous findings that RBCs are required for flow-induced nitric oxide (NO) synthesis in the lung and that mechanical deformation of RBCs results in the release of adenosine triphosphate (ATP), a stimulus for endothelial NO synthesis, suggested a novel mechanism for the control of vascular resistance in the pulmonary circulation. In this construct, as the RBC is increasingly deformed by increments in the velocity of blood flow through a vessel and/or by reductions in vascular caliber, it releases ATP which stimulates the synthesis of NO resulting in relaxation of vascular smooth muscle and, thereby, an increase in vascular caliber. We propose that RBC-derived ATP contributes to the low vascular resistance of the healthy lung. Moreover, if deformation-induced ATP release from RBCs is an important determinant of vascular resistance in the lung, then a signal- transduction pathway for ATP release in response to this stimulus should be present in that cell. Here, we address the hypothesis that mechanical deformation of RBCs sets into motion specific signal transduction pathways which culminate in release of adenosine triphosphate (ATP). In this proposal we intend to 1) demonstrate that heterotrimeric G proteins are components of a signal transduction pathway for deformation-induced release of ATP from RBCs of rabbits and healthy humans, 2) establish that increases in intracellular cAMP are required for deformation- induced ATP release from these RBCs, 3) demonstrate that the activity of protein kinase A (PKA) is required for deformationinduced ATP release from RBCs of rabbits and healthy humans, 4) establish that ATP release from these RBCs requires the activity of the nucleoside transporter and 5) establish that deformation- induced ATP release from RBCs is decreased in humans with primary pulmonary hypertension and determine the associated defect(s) in the signal-transduction pathway for ATP release in these patients. The successful completion of the studies described in this proposal will define a new role for the RBC as a regulator of vascular resistance in the pulmonary circulation and may provide new insights into the pathophysiology of pulmonary hypertension. This hypothesis is the logical extension of our previous work and is consistent with a major focus of this group, namely, identification and characterization of those mechanisms responsible for the control of pulmonary vascular resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF HIGH FLOW INDUCED VASCULOPATHY Principal Investigator & Institution: Jacobs, Elizabeth R.; Professor and Chief Pulmonary & Critical; Medicine; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): Increased flow induces a series of vascular responses, the earliest of which are prodilatory and largely endothelial mediated, followed by the development of myogenic tone (which serves to return blood flow towards baseline) and enhanced reactivity to agonists. The mechanisms, which underlie this heightened response to contractile agents, are incompletely understood, but likely involve ion channel-mediated transduction of signals in endothelial and vascular smooth muscle cells. We have developed a model of high flow to isolated lung lobes of young pigs (created by an aorto-pulmonary anastomosis) which results in neointimal proliferation characteristic of clinical pulmonary hypertension and early enhanced reactivity which reactivity appears to be endothelial and L-type calcium channel dependent. Our preliminary data suggest that sustained flow results in increased expression of voltage-gated calcium channels and dysfunctions in NOS which may contribute to enhanced reactivity of shunted arteries. We hypothesize that acutely enhanced synthesis of endothelial-derived EETs increases opening of L-type calcium and decreases the opening of calcium activated K channels in subjacent PAVSMs following increased flow. The specific aims of the grant are threefold: (i) We will identify the contribution of the endothelial second messenger signaling pathways including PLC, EETs, NOS and Ca(L) and KCa ion channels in vascular smooth muscle cells to the tone and reactivity of PAs exposed to high or baseline flows. (2) We will characterize flow-induced changes in expression of eNOS levels in PAs as well as expression of Ca(L) and KCa type ion channels in pulmonary artery vascular smooth muscle cells. (3) We will examine flow-induced changes in activity of endothelial second messenger signaling cascades PLC, EETs, NOS, gating of Ca(L) and KCa channels in PAVSM, and effect of EETs on [Ca2+]i in PAVSMCs of shunted versus non-shunted pulmonary arteries. These studies should yield valuable information about cellular mechanisms which underlie high flow induced vasculopathy, which conditions complicate a number of clinically important conditions such as repair of congenital heart defects, pneumonectomies, and others. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MMP-2 IN NEONATAL HYPOXIC PULMONARY VASCULAR REMODELING Principal Investigator & Institution: Ambalavanan, Namasivayam; University of Alabama at Birmingham Uab Station Birmingham, Al 35294

Pediatrics;

Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): This proposal outlines a career development plan for the applicant, an academic neonatologist with a longstanding commitment to understanding the pathogenesis of neonatal pulmonary vascular remodeling and whose goal is to become an independent investigator. Under the mentorship of established investigators and a multidisciplinary advisory committee, the candidate will pursue a program of education (coursework, conferences, seminars) and a research project addressing the cellular and molecular mechanisms of neonatal hypoxia-mediated pulmonary vascular remodeling (HPVR), which predisposes to the important clinical problem of neonatal pulmonary hypertension. HPVR is characterized by thickening of

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small pulmonary arteries due to cellular proliferation and deposition of extracellular matrix (ECM) proteins. ECM protein deposition and turnover are regulated by matrix metalloproteinases (MMPs). The candidate has developed innovative neonatal mouse (in vivo) and cell culture (in vitro) models to evaluate neonatal HPVR. The candidate has made the novel observations that MMP-2 is the principal MMP both in vitro and in vivo and that hypoxia increases MMP-2 while concomitantly decreasing its inhibitor [tissue inhibitor of metalloproteinases (TIMP)-2]. In addition, the candidate has shown that specific ECM proteins including collagens (CN), periostin (PN), fibronectin (FN-1), and thrombospondin (TSP-1) are increased, while other ECM proteins either do not change [e.g. osteopontin (OPN)] or decrease [e.g. tenascin-c (TN-C)] in response to hypoxia. The objective of this project is to determine the mechanisms by which hypoxia alters ECM deposition during HPVR, with specific focus on the role of MMP-2 in this process. The Specific Aims are: (1) To test the hypothesis that chronic hypoxia-induced pulmonary arterial medial thickening, cellular proliferation, and ECM molecule deposition are decreased in neonatal C57BL/6 mice treated with MMP inhibitors (MMP2 I) and in MMP-2 -/- (MMP-2 null) mice as compared to neonatal wild-type (WT) mice, and (2) To test the hypothesis that hypoxia increases MMP-2 synthesis/activation and downstream ECM molecule expression by increasing endothelin-1 (ET-1) and activation of the phosphoinositide 3-kinase (PI3K) and mitogen activated protein kinase (MAPK) pathways. Determination of the mechanisms of ECM protein deposition in the neonatal pulmonary vasculature will provide essential information on normal pulmonary vascular development and lead to the development of new therapies for HPVR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROHORMONAL HYPERTENSION

ACTIVATION

IN

PULMONARY

Principal Investigator & Institution: Kawut, Steven; Medicine; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-AUG-2006 Summary: Candidate's Plans/Training: The candidate plans a career as an independent clinical investigator focusing on patient-oriented research related to pulmonary vascular disease. Training will include formal epidemiological course work in clinical research and closely mentored completion of the research protocol. Environment: The Center for Clinical Epidemiology and Biostatistics (CCEB) will provide formal coursework and structured mentoring. The CCEB, Pulmonary Vascular Disease Program, and General Clinical Research Center at the University of Pennsylvania Medical Center will provide research support. Research: Primary pulmonary hypertension (idiopathic) and secondary pulmonary hypertension (associated with portal hypertension, anorectic use, HIV, scleroderma, and other collagen vascular diseases) cause substantial morbidity and mortality. Although there are available therapies and interventions, they may be costly and risky in themselves. In addition, targeting therapy at the mechanism of morbidity and mortality and distinguishing highrisk patients have been suboptimal. There is evidence that certain vasoactive substances may play an important role in the disease process of pulmonary arterial hypertension. Studies have documented elevated levels of endothelin, natriuretic peptides, and norepinephine in patients with this disease. It is well known that these neurohormones play important mechanistic and predictive roles in left-sided heart failure. Similarly, there is much potential for these neurohormone levels in determining 1) the mechanism of disease and 2) the prognosis in pulmonary arterial hypertension. We propose an investigation of patients with pulmonary arterial hypertension to examine whether levels of these biomarkers at baseline and at six month

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Pulmonary Hypertension

follow-up are associated with right-sided heart failure and cardiovascular death. We will formulate prediction rules using neurohormone levels and clinical variables to improve prognostication and management in this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NITRIC OXIDE DIFFUSION AND REACTION WITH ERTHROCYTES Principal Investigator & Institution: Liao, James C.; Professor; Chemical Engineering; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 27-SEP-2000; Project End 31-JUL-2004 Summary: The broad, long-term goal of this project is to investigate the diffusion and reaction of nitric oxide (NO) in blood, particularly its interaction with red blood cells (RBCs). It is hypothesized that RBCs possess specific mechanisms that regulate the NO consumption rate through modulation of membrane permeability to NO. Specifically the following aims will be pursued. Specific Aim 1: Is NO consumption by RBC regulated by transmembrane diffusion? Specific Aim 2: Do any specific intraerythrocytic molecules participate in the regulation of NO quenching? Specific Aim 3: How does the regulation of NO consumption by RBCs affect vessel regulation? The first two aims will be addressed by use of a competitive experiment and a differential membrane bioreactor specifically designed to measure the NO-RBC reaction rate. Kinetic models will be used to analyze the data. Biophysical (EPR and fluorescence) and biochemical (characterization of enzymes, metabolites, and lipids) techniques will be applied to RBCs, RBC ghosts, and synthetic liposomes in order to answer these questions. The last aim will be addressed using isolated porcine coronary microvessels as a bio-assay to determine the functional role of NO quenching and its regulation. The hypotheses proposed above are a significant departure from the current understanding that NO consumption is not regulated and that the RBC membrane is "completely permeable" to NO. In addition to its contribution to fundamental physiology, the proposed work directly impacts multiple aspects of clinical medicine, including NO inhalation therapy and the design of blood substitutes. Furthermore, the proposed mechanism might contribute to the pathology of several diseases, such as essential and pulmonary hypertension, peripheral vascular disease associated with diabetes mellitus, sickle cell anemia, and other hereditary RBC disorders. In these situations, altered RBC membrane consumption by RBCs is essential to the development of clinical intervention and understanding of the complex roles that NO plays under physiological and pathological conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NITRIC OXIDE PRODUCTION AND REACTIONS IN THE LUNG Principal Investigator & Institution: Erzurum, Serpil C.; Professor; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: Primary pulmonary hypertension (PPH) is a fatal disease of unclear etiology, characterized by progressive increase in pulmonary artery pressure. The long term goal of this research is to determine the role of NO, oxidants and NO-oxidant chemical reaction products in pulmonary hypertension. Our preliminary data provide clear evidence that NO and NO reaction products (N03, S-nitrosothiols) are lower in lungs of PPH than healthy controls. We propose that the low levels of NO and its reaction products in PPH are due to decreased NO synthesis and increased NO consumption by

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reactions with oxidant species, leading to alternative reaction endproducts. We show that NO reaction products are strongly correlated in an inverse relationship to pulmonary artery pressures in PPH. Theoretical modeling and simulation of our data suggest that progression and mortality in PPH will be predicted by NO reaction products. These data indicate a possible role for NO and oxidants in the pathogenesis of PPH. We will test our hypotheses with 4 aims. First, we will extend our preliminary findings and obtain longitudinal data on pulmonary artery pressures, cardiac output and lung diffusion capacity in 30 PPH patients. The values of these factors at specific time points will be modeled as linear functions of the corresponding levels of NO and NO reaction products to test our hypothesis that NO reaction products are predictive of progression of PPH. Second, low NO levels in PPH may result from decreased nitric oxide synthase (NOS) levels or activity. NOS expression for all 3 isoforms will be quantitated and localized in PPH lungs in comparison to controls. NOS activity will be measured and posttranslational mechanisms regulating activity evaluated. Third, low NO in PPH may also result from increased consumption. We propose that oxidative consumption of NO is increased in PPH due to alterations in the reducing-oxidizing (redox) environment of the lung. Since oxidative status of the lung cannot be assessed directly, we will test this hypothesis by measures of (i) nitrotyrosine formation; (ii) Nuclear Factor kappaB, a transcription factor activated in inflammation through oxidant mechanisms; and (iii) antioxidant levels. Finally, the concept that NO consumption through NO-oxidant reactions is dependent upon the redox environment will be tested in an in vitro cell culture system. Together, these experiments will define the mechanisms regulating NO levels and reactions in the lung, and provide a comprehensive picture regarding the role of NO and NO reaction products in PPH. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NITRIC OXIDE TOLERANCE IN SMOOTH MUSCLE Principal Investigator & Institution: Perkins, William J.; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: Nitric oxide (NO) is widely used by surgeons, anesthesiologists and critical care physicians managing critically-ill patients (e.g., inhaled NO for treatment of pulmonary hypertension and nitrovasodilators for decreasing afterload and for improving myocardial perfusion). Tolerance to these NO-based therapies occurs clinically and the extent to which this NO-induced NO hyporesponsiveness is due to decreased activity in the vascular smooth muscle NO-cGMP-cGK signaling system is unknown. The objective of this proposal is to determine the mechanisms by which chronic exposure to NO affects this signaling system in vascular smooth muscle. Two broad categories of mechanism for the development of chronic NO-induced NO hyporesponsiveness involving the vascular smooth muscle NO- cGMP-cGK signaling system are possible: 1) changes in [cGMP]i regulation and 2) reductions in the sensitivity to cGMP (cGMP sensitivity). To explore these mechanisms, we will utilize a cultured pulmonary artery preparation (PA) which permits experiments in fully functional, differentiated vascular smooth muscle cells. This cultured vessel preparation makes it possible to directly relate chronic NO-induced changes in the vascular smooth muscle NO-cGMP-cGK signaling system to chronic NO-induced decreases in NO responsiveness. Chronic NO exposure will be achieved using both NO-donors, and endogenously-derived NO following nitric oxide synthase gene transfer. Greater insight into the factors responsible for chronic NO-induced NO hyporesponsiveness will aid in the development of future NO-based therapeutic strategies. This is of particular

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Pulmonary Hypertension

relevance in the pulmonary circulation, in which inhaled NO is administered as a therapy for pulmonary hypertension, yet a large fraction of these patients are unresponsive to the NO. Methods used in the proposed studies include isometric force measurements, RT-PCR to isolate mRNA for all soluble guanylyl cyclase subunits (sGC) and cGMP-dependent protein kinase (cGK) isoforms, quantitative RT-PCR and immunoblotting to measure expression of each, and sGC and cGK enzyme activity measurement. We will use a combination of pharmacological probes and novel antisense oligomers to determine the mechanism by which chronic NO treatment decreases the expression and activity of sGC subunits and cGK isoforms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NONINVASIVE ASSESSMENT OF PRIMARY PULMONARY HYPERTENSION Principal Investigator & Institution: Shandas, Robin; Professor; Pediatrics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-MAY-2005 Summary: (Applicant's Abstract): This proposal addresses the problem of evaluating the efficacy of newly developed agents for the treatment of primary pulmonary hypertension. The use of catheter techniques to measure pulmonary vascular resistance severely limits routine evaluation of such treatments. We propose to develop, refine and test a non-invasive ultrasound based means of accurately evaluating pulmonary vascular resistance in children with primary pulmonary hypertension. The hypothesis for this project is based on the relationship between changes in downstream impedance within a fluid system and the characteristics of the pressure pulse propagation wave that develops within the arterial walls. We propose to show that downstream impedance affects the pulse propagation wave traveling within the main pulmonary artery and that changes in downstream impedance, as would occur with treatments such as inhaled nitric oxide or infused prostaclyin, can be followed by measuring pulse propagation characteristics. Furthermore, we propose that the pressure pulse propagation in the main PA affects local velocities, and that such changes in local velocities can be quantified as a velocity propagation using non-invasive ultrasound color M-mode imaging. This should significantly aid in evaluating new treatments for primary pulmonary hypertension and thereby expand treatment options and improve quality of life for patients. The aims of this project, therefore, are: 1. Demonstrate analytically that a fundamentally rooted mathematical and physical foundation exists for using velocity data to extract pressure pulse propagation characteristics for pediatric primary pulmonary hypertension. 2. Develop and test a method for using color Mmode velocity data to predict downstream impedance using highly reproducible in vitro models. 3. Determine clinical utility of the color M-mode approach using existing clinical protocols studying the efficacy of nitric oxide and/or 100 percent 02 treatment in the catheterization laboratory to reduce pulmonary vascular resistance in children with primary pulmonary hypertension. 4. Determine whether color M-mode measured velocity propagation (Vel-prop) predicts pulmonary vascular resistance in the clinical situation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: OPPOSING MODULATION OF K+ CHANNELS BY A REDOX SENSOR Principal Investigator & Institution: Weir, Edward K.; Professor/Chief of Cardiology; Medicine; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: (Scanned from the applicant's description): The ductus arteriosus (DA) is dilated in the hypoxic environment of the developing fetus. At birth the DA constricts in response to normoxia. In contrast, the pulmonary artery (PA) is dilated in normoxia and constricts in hypoxia. Although their responses to 02 are opposite, both vascular tissues have 02-sensitive K* channels expressed in their smooth muscle cells (SMC). In the DA, normoxia inhibits a K* channel to cause constriction, while in the PA hypoxia inhibits a similar channel. The mechanism by which these channels sense changes in 02 is unknown. It is hypothesized that: 1. A rise in 02 increases production of reactive 02 species in both the DA and the PA 2. A rise in 02 increases the levels of oxidized, cytosolic, redox couples in both the DA and PA. 3. An oxidized cytosol associated with normoxia, inhibits K channel activity in the DA SMC, resulting in membrane depolarization and increasesK channel activity in the PA, causing hyperpolarization. In contrast, a reduced cytosol associated with hypoxia increases K channel activity in DA SMC and inhibits K channel activity in PA SMC. 4. An oxidized cytosol associated with normoxia results in an increase in intracellular Ca2 and vasoconstriction in the DA and a decrease in Ca2i in the PA and vasodilation in the DA and increased [Ca2+]i and vasoconstriction in the PA. These studies will determine whether the different responses of the DA and PA to O2 are due to opposite modulation of K+ channel activity by the same cytosolic redox changes. Changes in O2 species and redox couples will be measured using chemiluminescence and 2', 7'-dichlorofluorescein and Amplex Red fluorescence. The effect of changing the redox status of the cytosol on K+ channel activity and membrane potential will be determined using patch-clamp techniques. Changes in [Ca2+]i in response to altering the redox status of the cell will be recorded using single-cell Ca2+ imaging techniques in combination with patch-clamping, while redox-mediated changes in tone will be determined in isolated DA and PA rings and whole rabbit lungs. Persistent patent ductus is a common congenital defect in newborns and treatment of pulmonary hypertension is extremely limited. An understanding of the mechanisms of O2-mediated changes in tone in the DA and PA would therefore be of significant medical importance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: OPTICAL COHERENCE TOMOGRAPHY FOR PULMONARY CIRCULATION Principal Investigator & Institution: Brezinski, Mark E.; Professor; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-AUG-1996; Project End 31-MAR-2006 Summary: (provided by applicant): This program is a continuation of NIH R29 HL.55686, extending optical coherence tomography (OCT) imaging to the evaluation of pulmonary arterial and venous circulation. OCT is a recently developed method of high resolution imaging which was developed for the evaluation of unstable plaque through this program. OCT is analogous to ultrasound, measuring the intensity of backreflected infrared light rather than sound. It's resolution, between 4 and 20 um, is up to 25 X higher than anything available in clinical medicine. Among the observations under NIH

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Pulmonary Hypertension

R29 HL1155686, OCT demonstrated a feasibility for the identification of vulnerable plaque, superior resolution to high frequency ultrasound (IVUS), and in vivo imaging in a rabbit model. In addition, a catheter based delivery system and high speed data acquisition system were developed. The technology is now being commercialized for in vivo human imaging. In this proposal, we will be extending OCT imaging to the pulmonary vasculature. In particular, in addition to +/-aracterizing normal pulmonary vasculature, a focus will be placed on the evaluation of pulmonary hypertension and the guidance of pulmonary vein ablation for atrial fibrillation. Pulmonary hypertension, an increase in pulmonary blood pressure, is a leading cause of mortality worldwide. Current methods of assessing the pulmonary vasculature are inadequate or dangerous. A method of high resolution assessment of the vasculature could be a powerful tool in the management of this disorder. Atrial fibrillation is a common disorder associated with a high incidence of stroke. It has recently been demonstrated that a significant portion of atrial fibrillation can be cured by ablation of foci in the pulmonary veins. However, this procedure is associated with a high incidence of pulmonary vein stenosis. A technology capable of controlling the degree of ablation could substantially improve the outcome of this procedure. The hypothesis of this proposal is that OCT demonstrates a feasibility for high resolution assessment of pulmonary vasculature, both for diagnosis and guiding interventions. The hypothesis will be tested through the following specific aims: Aim 1. Development of an OCT Imaging Catheter, Aim 2. Assessing the Pulmonary Veins Ablation in an Animal Model, Aim 3. Vascular Assessments In Vitro, Aim 4. OCT Elastography and Aim 5. OCT Imaging will be performed in an Animal Model of PTN. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PARTICLE-INDUCED CARDIAC EFFECTS IN SENESCENT MICE Principal Investigator & Institution: Tankersley, Clarke G.; Assistant Professor; Environmental Health Sciences; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2008 Summary: (provided by applicant): Plausible biological mechanisms remain elusive to explain the association between daily fluctuations in air pollution and increased mortality rates. Specifically, airborne particulate matter (PM) has been identified as the constituent of air pollution that is most culpable in correlating with increased mortality rates. Pathophysiologic mechanisms leading to tachycardia and bradycardia appear potential processes that increase PM-induced risk of mortality in humans and animal models. Because epidemiology studies also identify aging as a risk factor, we developed a unique model to define risk associated with terminal senescence based on a series of pathophysiological assays. HYPOTHESIS: Senescent-dependent changes in the neurohumoral regulation of the heart during PM exposure manifest acute instability in cardiac function resulting from imbalances in the autonomic nervous control and altered atrial natriuretic peptide regulation. Specific aim 1 characterizes specific pathophysiologic variables associated with loss of homeostasis in senescent mice of different inbred mouse strains. Specific aim 2 determines the interactive effects of terminal senescence and acute PM exposure on heart rate regulation and cardiac function. Here, we postulate that only terminally senescent animals are susceptible to the acute cardiac effects of PM exposure. Specific aim 3 determines the interactive role of innate susceptibility factors in acute PM-induced imbalances in autonomic neural regulation of heart rate, blood pressure and cardiac function. The focus of this aim considers PM-induced cardiac functional changes owing to genetic susceptibility factors.

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Specific aim 4 tests whether senescent-dependent susceptibility to PM-induced cardiovascular dysfunction evolves from adverse modifications in atrial natriuretic peptide (ANP) regulation. In the final aim, cardiac mechanisms surrounding right ventricular function and pulmonary hypertension are considered important factors in PM-induced susceptibility. The interaction between aging and PM exposure obliterates the cardioprotective effects of ANP leaving the heart acutely susceptible to instability. In summary, the proposed studies are significant because they represent a multidisciplinary approach that will advance our understanding of the adverse cardiac health effects of air pollution exposure in the elderly Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOBIOLOGY OF SEVERE PULMONARY HYPERTENSION Principal Investigator & Institution: Voelkel, Norbert E.; Professor; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 17-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant): This PPG application has evolved from three presently active R01 grants, which this application intends to replace. Severe chronic pulmonary hypertension (PH) - in spite of intravenous prostacyclin (PGI2) treatment remains an important and challenging clinical problem. Our four projects have been designed to investigate specific aspects of human PH including primary and neonatal pulmonary hypertension. We start with the concept that pulmonary arteries differ from systemic vessels in that their response to "stress" or "injury" is different. We further postulate that the adult lung circulation remodels with endothelial cell proliferation (Project 1), whereas the neonatal lung circulation remodels without endothelial cell proliferation (Project 2). Vascular endothelial growth factor (VEGF) and its receptor, KDR. are critically involved in the formation of plexiform lesions in adult PH whereas reduced VEGF/KDR signaling in the fetus leads to a vasculogenesis failure characterized by a muscularized, pruned vascular tree. Project 3 develops a prospectively designed new rodent model of endothelial cell-proliferative, severe PH that has been built on inhibition of the VEGF receptor KDP, and proposes that endothelial cell death selects for the emergence of resistant, proliferative endothelial cells at sites of high shear stress. We anticipate that this rat model will permit the systematic investigation of the interplay between altered vasoreactivity (vasoconstriction) and development of obliterative pulmonary vascular arteriopathy. The information gathered from this model will include lung tissue transcript information gathered using the microarray GeneChip technology and will be compared with the gene expression data obtained from human PPH and 2nd PH lungs (Project 1). The fact that endothelial cell proliferation in PPH is monoclonal encourages the search for gene mutations. One candidate mutated gene is the TGF-B-RII gene coding for the TGF-B-II receptor, which is involved in cell growth/death control. Lastly, a severe loss of prostacyclin receptor (PGII-R) expression in the resistance vessels of PPH lungs provides rationale and focus for the investigation of the role of PGI2 and its receptor in pulmonary vascular remodeling (Project 4). Vascular smooth muscle cells from genetically engineered mice (Lung-specific PGI2-synthase gene overexpression and PGI2-receptor knock-out) will be examined for PGI2-R-dependent and independent growth. We believe that this highly integrated program addresses central issues of the pathobiology of severe human pulmonary hypertension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PATHOPHYSIOLOGY AND TREATMENT OF PULMONARY HYPERTENSION Principal Investigator & Institution: Moon, Marc R.; Surgery; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2005 Summary: Chronic pulmonary hypertension (CPH) is a devastating disease - its progression is relentless, culminating in right heart failure (RHF) and death in the majority of patients. Unfortunately, our knowledge of the pathophysiologic sequelae that portend cardiac failure with CPH remains grossly inadequate to direct patient care for this increasingly important disease process. Furthermore, the mechanisms of action of common medical and surgical treatment options remain unknown, and the individual patient's response to therapy is unpredictable. Using a standard experimental model of CPH in animals, RHF will be created and studied with two novel techniques: 1.) Right atrial (RA) volume clamping, and 2.) Feedback-loop controlled pulmonary artery (PA) occlusion. The RA volume-clamping technique will permit, for the first time, isolation of the mechanics of RA function, including its contribution to cardiac output and compensatory role in CPH. In addition, feedback-loop controlled PA occlusion will permit differentiation of the indirect vasodilatory effects from the direct myocardial effects of popular therapeutic regimens on right heart mechanics. A series of experiments will assess the impact of common medical therapies and new, as of yet unproven, surgical therapies on right heart function and global cardiac performance. The proposed studies will address the following specific aims: l.) Define the pathophysiologic sequelae of CPH that produce RHF; 2.) Determine the balance between afterload reduction, changes in diastolic relaxation and compliance, and contractile inhibition with common, but poorly understood medical therapeutic agents; and 3.) Determine the physiologic consequences of graded atrial septostomy on right heart function and total cardiac output in subjects with varying degrees of CPH. The long-range goals of this project are to understand the physiologic sequelae of this crippling disease, guide appropriate medical and surgical therapy, and develop, new treatment strategies that will improve outcome for patients with CPH. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HYPERTENSION

PHARMACOGENETIC

THERAPY

OF

PULMONARY

Principal Investigator & Institution: Li, Song; Pharmacology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Pulmonary hypertension is a significant clinical entity severely affecting the longevity and quality of life for patients with either primary or secondary' forms of this disorder. Regardless of its underlying cause, pulmonary hypertension remains intractable to traditional pharmacotherapy. Recent basic genetic and preclinical pharmacological] studies suggest that newly developed agents modifying endothelin activity may have a potential role in pulmonary hypertension. Nonetheless, it is highly likely that general principles of pharmacology predictive of issues of non-specificity and adverse effects as well as target alterations leading to tachyphylaxis and desensitization will ultimately limit the use of new generation endothelin modifiers. In the current proposal, we suggest that advances in non-viral based genetic therapy may provide novel alternatives to traditional pharmacotherapy. In particular, delivery of antisense Oligodeoxynucleotides (ODN) to endothelin-1 lET-l)

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by immunoliposome can be used to down regulate pulmonary' endothelial ET-1 biosynthesis and similar application with RNA/DNA chimeric oligonucleotide may more permanently silence such expression. Accordingly, specific aims of this comprehensive proposal are: Aim 1: To develop an oligonucleotide-based approach to achieve efficient down-regulation of ET-1 in endothelial cells. ODN scanning arrays and ET-1 ELISA will be employed to identity - antisense ODNs that are highly efficient in inhibiting the ET-1 expression in mouse lung endothelial cells. In addition, RNA/DNA chimeric oligonucleotides will be investigated as an approach to achieve a long-term silencing of ET-1 in pulmonary endothelium. Aim 2: To develop novel delivery, systems to achieve efficient delivery of oligonucleotide to pulmonary endothelium with reduced toxicity. Aim 3: To investigate the biological effect of tissue-specific down-regulation of ET-1 in normal mice and in mice with PHT. The current proposal will lead to a better understanding of the roles of ET-1 in mouse hypoxia-induced pulmonary hypertension and provide experimental and preclinical support for rational pharmacogenetic approach to pulmonary hypertensive disorders. Down regulation of ET-1 biosynthesis by pulmonary endothelium by immunoliposome-mediated delivery of ODN may by itself, or in combination with" direct pulmonary vasorelaxants (e.g. nitric oxide and oxygen), provide an approach to prevent the progressive pathological aspects of PHT and ameliorate return towards more normal pulmonary vascular structure and function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RECEPTOR.

PHARMACOGENETICS

OF

THE

HUMAN

PROSTACYCLIN

Principal Investigator & Institution: Hwa, John; Pharmacology and Toxicology; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): Prostacyclin (PGI2), a derivative of arachidonic acid, plays an important role promoting vascular smooth muscle relaxation and preventing platelet aggregation. The actions are mediated through a poorly understood seven transmembrane domain spanning G-protein coupled receptor (GPCR), the prostacyclin receptor (IP). The clinical importance of this receptor stems from its involvement in cardiovascular diseases such as myocardial infarction, stroke, atherosclerosis, and hypertension. The potential use of prostacyclin in the treatment of pulmonary hypertension, and cancers (colon, breast and lung), is currently being intensely investigated. We have recently discovered eleven human prostacyclin receptor polymorphisms. Furthermore preliminary in vitro studies have revealed abnormal function in one of these polymorphisms (R212H). This has led to the hypothesis that such polymorphisms may play a critical role in cardiovascular disease. Through three Specific Aims the goal of this proposal is to understand the pharmacogenetic importance of hIP polymorphisms and in so doing to determine distinct features of this receptor, which enable it to bind a 20-carbon fatty acid (eicosanoid) and couple it to signal transduction pathways, leading to cardiovascular disease. Genomic screening and sequencing will be used to comprehensively search for new polymorphisms and assess association with clinical cardiovascular disease (Specific Aim #1). Novel polymorphisms found will be tested in vitro using site-directed mutagenesis, and structure-function studies (Specific Aim #2). Specific Aim #3 will focus on downstream signal transduction pathways in human vascular smooth muscle cells to determine mechanisms for cardiovascular defects. In addition to this proposed collaboration between the Pharmacology, Medicine (Statistics), Vascular Surgery, Cardiology and Pathology Departments here at Dartmouth, strong groups in protein structure-function and signal

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transduction, will be critical resources for addressing these Specific Aims. Achievement of these aims, should not only improve our understanding of the molecular genetics and structure-function of the prostacyclin receptor, but may also provide the critical biochemical understanding to explain interindividual differences in progress of cardiovascular disease and variable responses associated with prostacyclin analogue treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PKC VASODILATION

SIGNALING

IN

CAMP-INDUCED

PULMONARY

Principal Investigator & Institution: Barman, Scott A.; Pharmacology and Toxicology; Medical College of Georgia 1120 15Th St Augusta, Ga 30912 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-MAY-2005 Summary: (provided by applicant): Primary Pulmonary Hypertension (PPH) is a disease of unknown origin that results in narrowing Of the pulmonary vasculature causing high pulmonary blood pressure often leading to heart failure. Currently there is little knowledge on the cellular and molecular foundation of PPH. Normally, signaling mechanisms which elevate cAMP and cGMP in the pulmonary vasculature allow for the maintenance of a low pressure, high perfusion environment. It is well documented that the activation of the large-conductance, calcium-and voltage-activated potassium (BKca) channel is of primary importance in the regulation of pulmonary arterial pressure and inhibition of the BKca channel has been implicated in the development of pulmonary hypertension. Preliminary data from patch-clamp studies in pulmonary arterial smooth muscle cells (PASM) of the fawn-hooded rat (FHR), a recognized animal model of pulmonary hypertension, suggests that cAMP, an activator of cAMP-dependent protein kinase (PKA), opens the BKca channel through "cross-activation" of the cGMPdependent protein kinase (PKG). In contrast, protein kinase C (PKC) which causes pulmonary vasoconstriction, inhibits the BKca channel in FHR PASM, but activates the BKca channel in Sprague-Dawley (control) rats. Therefore, the hypothesis of the proposed studies is that cAMP-dependent vasodilators relax pulmonary arteries by opening BKca channels in pulmonary arterial smooth muscle by stimulating the activity of PKG, an effect inhibited by activation of PKC in FHR. This hypothesis will be tested by employing state-of-the-art techniques of electrophysiology, vascular contraction, and biochemistry/molecular biology to determine: 1) the effect of cAMP-dependent vasodilators on pulmonary arteries in vitro, 2) the effect of cAMP-elevating agents on whole-cell and single channel K+ currents from single myocytes isolated from pulmonary arteries, 3) cAMP-dependent "cross-activation" of PKG, and 4) the role of PKC on BKca channel activity and whether there is a direct interaction between PKG and PKC on BKca channel modulation. The long term goal of the proposed study is to understand how cAMP-elevating agents cause pulmonary arterial vasodilation by an endothelium-independent mechanism. It is believed that these studies will lead to the development of novel therapeutic agents that will help reduce the morbidity and mortality associated with PPH and other pulmonary vascular diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: POSITIONAL MAPPING FOR ALVEOLAR CAPILLARY DYSPLASIA Principal Investigator & Institution: Bejjani, Bassem A.; Professor; Health Research & Educ Ctr; Washington State University 423 Neill Hall Pullman, Wa 99164 Timing: Fiscal Year 2003; Project Start 23-APR-2003; Project End 31-MAR-2005

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Summary: (provided by applicant): ACD is a rare and lethal developmental anomaly of the pulmonary vasculature. It is generally described as the failure of formation of the normal air-blood diffusion barrier in the newborn lung. ACD is usually associated with misalignment or displacement of the pulmonary veins. The disease presents very early in infancy, usually after a few hours of normal breathing ("honeymoon period"). Infants become critically ill very rapidly in the first days of life with severe hypoxemia and pulmonary hypertension. There is no cure for ACD. The disease is uniformly lethal. Standard therapies include mechanical ventilation, high concentrations of inspired oxygen, inhaled nitric oxide, and extracorporeal membrane oxygenation (ECMO) support. These therapies may prolong life by days to weeks, but they have led to no long-term survival. The purpose of this application is to map and clone the putative gene(s) responsible for ACD. We have established a close working relationship with the ACD Association, the only parent support organization, and have already collected 29 families, each with one or more infant with ACD in preparation for positional mapping and eventually cloning the ACD gene(s). Clinical records and pathological samples from affected individuals and DNA from affected and unaffected individuals were obtained. Our review of the pre- and postmortem records of affected individuals allows us to define better both the natural history of this condition and the associated anomalies with the ACD phenotype. Our collection of families corroborates the possible recessive nature of this condition and provides additional data for genetic and prenatal counseling. Analysis of the various associated anomalies allows us to formulate a hypothesis regarding possible candidate genes and/or signaling pathways. Finally, the material collected allows for positional mapping of the putative ACD gene as a first step towards understanding this condition. Support is requested to defray the costs of DNA preparation from peripheral blood samples and lung biopsies/autopsies, of positional mapping of the putative ACD gone(s), and of completing collection and analysis of the patient records. Cloning an ACD "gene" has implications for counseling, for prenatal testing, and for understanding the molecular pathophysiology of ACD and other organ malformation that are associated with this condition. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PRENATAL SET POINT FOR ADULT BLOOD PRESSURE Principal Investigator & Institution: Faber, Job J.; Professor; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: Late gestation fetal sheep will be treated to create systemic and pulmonary arterial hypertensions. One group will have high circulating angiotensin-II levels. There will be two normotensive control groups, one with normal and one with low angiotensin-II. The animals will be studied as fetuses, as newborns and as young adults. Circulatory measurements will include arterial pressures, right and left atrial pressures and cardiac outputs. We will also make plasma renin activity/renal ar6terial pressure response curves and measurements of glomerular filtration rates. Analytical measurements will include plasma renin activities, circulating angiotensin-II levels, catecholamines, plasma protein and blood hemoglobin concentrations, blood gases, osmolalities and electrolytes. Coronary pressure-flow relations will be determined under anesthesia with and without chemical dilation by means of adenosine infusions to determine coronary reserve. The animals will be killed for structural studies of heart and kidney. It is anticipated that prenatal hypertensions will produce lasting circulatory abnormalities later in life. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PREVALENCE OF SLEEP DISORDERED BREATHING IN CHILDREN Principal Investigator & Institution: Bixler, Edward O.; Professor; Psychiatry; Pennsylvania State Univ Hershey Med Ctr 500 University Drive Hershey, Pa 170332390 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): The objectives of this proposal are to: 1) establish the prevalence of different types of sleep disordered breathing (SDB) in a large general random sample of children; 2) identify important risk factors of SDB; (3) establish the family history of various risk factors associated with children with SDB; (4) assess the impact of SDB on clinical, psychometric and behavioral/academic outcomes; and 5) identify characteristics which will assist in identifying those children at risk for SDB for possible early intervention. Several studies evaluating select populations have suggested that various severe consequences are associated with SDB in children. These consequences include: cardiovascular complications such as pulmonary hypertension, cor pulmonale, and arrhythmia; behavioral abnormalities such as excessive daytime sleepiness, poor school performance, hyperactivity, aggressive behavior, and social withdrawal; and growth disturbances which at times are reversed by successful treatment. To date, there have been only four studies evaluating the prevalence of sleep apnea using objective sleep evaluation methods in general random samples of children. Three studies evaluated a limited age range of 6 mos to 6 yrs, while the fourth assessed a range of 2-18 years. These studies employed relatively small samples in their sleep laboratory phase (N=lO, 11, 132, and 126, respectively). Thus, they could not adequately assess clinical significance. None of these studies evaluated: general development (eg height, weight, age adjusted BMI); the effects of SDB on physical health (eg blood pressure); academic achievement; or electrophysiologic defined sleep stages as possible outcome measures. Only one study reported a possible association with daytime sleepiness and behavior. Thus, the prevalence and clinical impact of SDB in school age children is unknown. In order to establish the prevalence and clinical significance of SDB in children aged 6 - 12 years with reasonable precision, we propose to employ a protocol similar to that used to establish the prevalence and clinical significance in two previously NIH supported protocols in adults. The proposed study will employ a twophase protocol: 1) questionnaire completed by the parents of every child enrolled in local elementary school which will assess general sleep, behavior and learning problems; 2) a random sample (n= 1,000) selected from the first sample based on risk for SDB and evaluated in the sleep laboratory to determine the presence of SDB. The second phase will receive a thorough pediatric ENT and pulmonary evaluation and school records and behavior will be assessed. The parents of this group will be interviewed for the family history of risk factors associated with SDB in children. This strategy will yield adequate power to establish the prevalence and clinical significance of SDB in children. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PROSTACYCLIN SYNTHASE AND PROSTACYCLIN RECEPTOR IN PH Principal Investigator & Institution: Geraci, Mark W.; Director, Gene Array Facility; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: (provided by applicant) Severe pulmonary hypertension, including primary pulmonary hypertension (PPH), is an important clinical problem with few clinical treatment options. The chronic, intravenous infusion of prostacyclin (PGI2) has been

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established as the treatment of choice for patients with PPH. It is now clear that longterm benefits occur which obviate the need for transplant in many cases. The physiological effects of prostacyclin on platelet behavior, vascular tone control, and cell proliferation are well established; however, we do not know whether prostacyclin effects the vascular remodeling in chronic pulmonary hypertension. Our overall hypothesis is that prostacyclin, through membrane-receptor dependent and independent mechanisms, is an important modulator of pulmonary vascular remodeling. We have demonstrated loss of the prostacyclin receptor (PGIR) protein in the smooth muscle cells of precapillary resistance arteries in patients with PPH. We postulate that impairment of the prostacyclin signal transduction contributes to pulmonary vascular remodeling. We have generated transgenic animals with selective pulmonary prostacyclin synthase (PGIS) overexpression. These animals are protected from the development of hypoxic pulmonary hypertension, and show no acute vasoconstriction or chronic vascular remodeling. In contrast, PGIR knockout (KO) mice, in response to hypoxia, develop rapid pulmonary hypertension accompanied by vascular remodeling. Microarray analysis of the lungs from the transgenic animals demonstrates a change in the global pattern of gene expression, which may be responsible for the "protected" phenotype, including changes in PPARs and COX-2. Our underlying concept is that PGI2 exhibits both membrane-receptor mediated and nuclear-receptor-mediated actions. These alternative mechanisms could include direct effects on gene expression, signaling pathways not yet recognized, or changes in the level of other eicosanoids. Our goal is to examine, using both animal models and cell systems, the effects of PGIS and PGIR on vascular smooth muscle cell (VSMO) growth and differentiation. In Specific Aim 1, we will determine whether pulmonary vascular tone and remodeling are mediated through the PGI2 receptor using bitransgenic mice with PGIS overexpression, but lacking PGIR. Specific Aim 2 is designed to define the effect of PGIS and PGIR on the growth and remodeling of vascular smooth muscle cells. The results of this work are designed to elucidate new potential therapeutic targets for treating pulmonary hypertension, and broaden our understanding of vascular pathology in general. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PRX HOMEOSTASIS

HOMEBOX

GENES

IN

PULMONARY

VASCULAR

Principal Investigator & Institution: Jones, Peter L.; Assistant Professor of Pediatrics & Cell; Pediatrics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2006 Summary: (provided by applicant): Homeobox genes encode transcription factors that control local patterns of cell growth, differentiation, apoptosis and adhesion during development. Although homeobox genes are also expressed during post-natal development, relatively little is known about their regulation end functions in pulmonary vascular homeostasis and disease. Recent work in our laboratory has established that the expression of two paired-related homeobox genes, Prx1 and Prx2, is suppressed in normal adult pulmonary arteries (PAs). In contrast, these genes are expressed in the adventitia, and thereafter in the media, of hypertensive PAs where they co-localize with the pro-proliferative glycoprotein tenascin-C (TN-C). Since remodeling of the extracellular matrix (ECM) by proteases is critical to the pathogenesis of pulmonary vascular disease, we investigated whether changes in vascular smooth muscle cell (SMC) adhesion to the ECM regulate Prx1 and Prx2: SMCs cultured on

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native type I collagen (an alpha2beta1 integrin ligand that suppresses ERK1/2 MAPK activity) showed low levels of Prx1 and Prx2 mRNA expression. In contrast, cells maintained on denatured type I collagen (an alphavbeta3 integrin ligand that activates ERK1/2) showed high levels of expression of both genes. At a functional level, expression of Prx1 significantly increased SMC growth and TN-C gene transcription. These findings support the general hypotheses that Prx genes are regulated by changes in cell adhesion to the ECM, and that Prx proteins play key roles in remodeling PM by controlling cell growth and the expression of morphoregulatory molecules, including TN-C. To test this hypothesis, we will: (1) Determine how type I collagen, beta3 integrins and ERK1/2 MAPKs regulate Prx genes and their encoded proteins in PA adventitial fibroblasts and medial SMCs; (2) Elucidate how Prx proteins control the transcription of TN-C, and identify other gene targets that interact with Prx proteins, and (3) Ascertain how Prx gene expression in the adventitial layer of intact cultured PAs influences the behavior of surrounding adventitial fibroblasts and adjacent medial SMCs within intact PAs. Collectively, these study will identify gene and protein networks that are responsible for enhanced Prx1 and Prx2 expression, and will demonstrate how Prx gene targets, including TN-C, are controlled within remodeling PAs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PULMONARY ENDOTHELIAL FUNCTION DURING CHRONIC HYPOXIA Principal Investigator & Institution: Walker, Benjimen R.; Cell Biology and Physiology; University of New Mexico Albuquerque Controller's Office Albuquerque, Nm 87131 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: (Verbatim from the Applicant's Abstract): Recent studies suggest that chronic exposure to hypoxia causes upregulation of both endothelial and inducible nitric oxide synthase (eNOS and iNOS, respectively) within the lung. Responses to endotheliumderived NO (EDNO)-dependent dilators are enhanced the arterial vasculature of the lung under hypoxic conditions. However, the mechanisms by which eNOS and iNOS gene expression are increased in hypoxia-induced pulmonary hypertension are unclear. The two most likely possibilities are: 1) a direct effect of hypoxia on gene expression; or 2) an effect of altered mechanical forces secondary to pulmonary hypertension. In regulation of pulmonary NO and endothelin biosynthesis under these clinically relevant conditions. The specific aims are: Specific Aim 1 - Determine whether hypoxia per se or pulmonary hypertension is responsible for altered vasoreactivity and upregulation of eNOS and iNOS in lungs from chronically hypoxic rats; Specific Aim 2 - Determine whether pulmonary hypertension in the absence of hypoxia alters pulmonary vascular reactivity and expression of eNOS and iNOS; Specific Aim 3 - Determine the roles of increased shear stress, hypoxia and endothelin on eNOS and iNOS expression in cultured cells and in isolated arteries; and Specific Aim 4 - Examine the potential in vivo interactions between the endothelin and NOS systems in hypoxia-induced pulmonary hypertension. The proposed experiments utilize a variety of in vivo and in vitro approaches to examine questions central to the regulation of the pulmonary circulation under clinically relevant conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PULMONARY HYPERTENSION FOLLOWING INTERMITTENT HYPOXIA Principal Investigator & Institution: Fagan, Karen A.; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508

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Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Pulmonary hypertension (PHTN) is common in diseases characterized by chronic hypoxia (CH) (i.e. COPD, IPF) and occurs in 15-40% of patients with sleep apnea. Intermittent hypoxia (IH) mimicking the hypoxiareoxygenation cycles of sleep apnea causes systemic hypertension and altered regulation of systemic vascular tone. However, the effect of intermittent hypoxia on the pulmonary circulation is unknown. Recently, patients with sleep apnea-induced PHTN were found to have exaggerated hypoxic pulmonary vasoconstriction. Unlike in chronic hypoxia, hypoxia in sleep apnea is not continuous, thus the mechanisms causing sleep apneainduced PHTN are likely different from chronic hypoxia-induced PHTN. We therefore hypothesize that intermittent hypoxia leads to pulmonary hypertension by differential expression of genes important in regulating pulmonary vascular tone. Specifically, we hypothesize that oxidant stress in IH increases NOS and decreases SOD leading to PHTN through increased formation of peroxynitrite thus decreasing NO available for cellular effects such as attenuating vasoconstriction and mediating vasodilation. We further hypothesize that IH activates redox sensitive transcription factors leading to differential lung gone expression compared to CH. We will present data showing IHinduced PHTN in both rats and mice. We also will present data showing differential expression of NOS (nitric oxide synthase) and SOD (superoxide dismutase) in the lung following IH compared to CH, which may contribute to IH-induced PHTN through increased oxidant stress and decreased NO activity. This proposal will address the questions: 1) does repetitive hypoxia-reoxygenation causes pulmonary hypertension, 2) that despite increased NOS, NO appears to be insufficient to prevent IH-induced PHTN, 3) decreased SOD may contribute to IH-induced PHTN by increasing oxidant stress and formation of peroxynitrite, and 4) does IH leads to differential gene expression through activation of specific signaling pathways compared to CH. We will correlate physiologic measures of PHTN and pulmonary vascular tone with expression and activity of NOS and SOD, measurements of oxidant stress and NO, and activation of specific signaling pathways leading to altered gone expression in IH. This proposal, for the first time, will identify the consequences of IH in the pulmonary circulation. Understanding mechanisms contributing to the development of PHTN in IH may lead improved cardiovascular morbidity and mortality in this common disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PULMONARY HYPERTENSION IN GENETICALLY MODIFIED MICE Principal Investigator & Institution: Rabinovitch, Marlene F.; Dwight and Vera Dunlevie Professor; Pediatrics; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Idiopathic pulmonary hypertension (PH) is associated with progressive pulmonary vascular obliterative disease (PVOD) in otherwise healthy children and young adults. Some patients have an underlying genetic mutation causing loss of function of bone morphogenetic protein receptor II (BMP-RII) and some others have polymorphisms leading to heightened activity of the serotonin transporter (SERT). How these genetic abnormalities cause PVOD, is, however, unclear. Our recent studies in cultured human pulmonary artery (PA) smooth muscle cells (SMC) have shown that serotonin, likely in conjunction with SERT, increases expression of the calcium binding protein S100A4/Mts1 (Mts1). We further observed that recombinant Mts1 induces motility of PA SMC. Consistent with this, intense expression of Mts1 is apparent in PVOD in clinical tissue, in contrast to minimal expression in normal vessels. Also, 5-10% of transgenic mice that over-express Mts1 acquire PVOD as

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they age and all Mts1 overexpressing mice develop more severe PH than controls during hypoxia that does not regress with return to normoxia. Microarray analysis of DNA in lungs from Mts1 over-expressing vs. control mice shows a reduction in BMP-RI, the co-receptor of BMP-RII. We therefore propose that there are common and complementary molecular pathways linking BMP-RII, SERT and Mts1 in the pathophysiology of PVOD. Specific Aim I utilizes a variety of tools including short interference (si) RNA in cultured human PA endothelial and SMC to determine how BMP-RII, SERT and Mts1 might impact on vascular remodeling, either by inducing elastase activity and/or by promoting cell migration, proliferation, transdifferentiation, or propensity or resistance to apoptosis. These features will be correlated with the function of the transcription factor AML1, and with the genomic profiles of the cells. In Specific Aim II, transgenic mice with Mts1 over-expression will be investigated with respect to vascular reactivity and severity of PH in response to dexfenfluramine or inflammation. We also will produce and characterize a mouse with conditional global or SMC targeted deletion of BMP-RII, in terms of vascular cell structure, function, and propensity to PH. Genomic data from lung, endothelial and SMC from Mts1 overexpressing, BMP-RII deleted, and control mice will be correlated with function to identify common and complementary gene expression patterns related to PVOD. These studies should provide insights into the genetic basis for PVOD and information useful in developing strategies to arrest or reverse the process. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PULMONARY HYPERTENSION IN SCD Principal Investigator & Institution: Johnson, Cage S.; Professor of Medicine; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-MAR-2008 Summary: Chronic lung disease and pulmonary hypertension are complications of the sickle diseases that are increasingly recognized and are associated with considerable morbidity and mortality. Standard therapy with oxygen and a hypertransfusion regimen have not demonstrated efficacy in prolonging survival in such patients, indicating a need for new approaches to management. Both hydroxyurea and L-arginine have the potential for increasing endogenous production of NO within the pulmonary vasculature and may have beneficial effects on oxygenation and pulmonary vascular resistance in patients with chronic lung disease and pulmonary hypertension. In addition, hydroxyurea improves red blood cell hemorheological properties and microvascular blood flow and thus combined therapy may impact smooth muscle hyperplasia in damaged pulmonary microvasculature. We hypothesize that beneficial clinical responses may accrue to patients with sickle chronic lung disease and pulmonary hypertension as a result of increases in NO generated by oral administration of hydroxyurea and/or L-arginine. We further hypothesize that these beneficial effects are consequent to modulation of vasoactive peptides (ET-1) and adhesion molecules (I-CAM-I, V-CAM-I). The proposed research project is a phase II, randomized clinical trial designed to determine the effect of the NO donor L-arginine and hydroxyurea, either singly or in combination, on the biologic and clinical features of sickle cell disease patients with chronic lung disease and pulmonary hypertension. We further propose to characterize the effects of this treatment strategy on a broad range of RBC and hemorheologic properties in SCD,and to determine its efficacy in ameliorating chronic lung disease and pulmonary hypertension in these patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HYPERTENSION

RAFT/CAVEOLAR

MECHANISMS

IN

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PULMONARY

Principal Investigator & Institution: Sehgal, Pravin B.; Professor; Cell Biology and Anatomy; New York Medical College Valhalla, Ny 10595 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): This translational research proposal seeks to apply recent novel insights into the mechanisms of cell signaling at the level of the plasma membrane (the caveola/raft signaling hypothesis and the interleukin-6-raft-STAT3 signaling model) to an understanding of the pathogenesis of PH. Caveolin-1-containing detergent-resistant plasma membrane rafts are now recognized as specialized signaling organelles, including cytokine signaling. There is now growing evidence for a role of cytokines in the pathogenesis of lung diseases. As examples, elevated serum levels of IL6 have been observed in primary pulmonary hypertension (PH) and in PH associated with autoimmune diseases and AIDS. In a rat model, a single injection of the plant alkaloid monocrotaline (MCI) results within 48 hrs in endothelial cell damage, membrane leakage, upregulation of IL-6 mRNA and bioactivity but a marked downregulation of caveolin-1 in the lung, followed by development of PH 10-14 days later. The focus of the proposed studies is two-pronged: (a) to evaluate the hypothesis that pulmonary endothelial-cell raft/caveolar disruption by MCT is an initiating event in the pathogenesis of PH (Specific Aim I), and (b) to investigate the function of membrane rafts and of the newly discovered cytosolic caveolin-containing Palade complexes in IL-6-induced STAT3 signaling in lung-specific cells (Specific Aims II and III). Aim I will include investigations of the time-course, histologic location, and cellular and molecular mechanisms for the downregulation of caveolin proteins and gene expression, and of the integrity of caveolar/raft function in pulmonary vascular and parenehymal tissues of MCT-treated rats. Aim II includes molecular studies of the mechanisms of association of STAT3 with caveolin-1 and of STAT3 activation in plasma membrane rafts in pulmonary endothelial cells, alveolar type II-like epithelial cells and lung fibroblasts. Aim Ill includes studies of the protein components of STAT3containing cytosolic Palade complexes and their function in ferrying signaling molecules from the plasma membrane rafts to the cell interior. Mechanistic insights derived from this project are likely to suggest novel therapeutic approaches in the management of pulmonary hypertension. Moreover, the proposed studies are of particularly broad significance in that insights into the molecular mechanisms involved in raft-STAT signaling are likely to be applicable to cytokine-mediated activation of STAT transcription factors in perhaps all cell types, as well as to other signaling pathways localized in raft microdomains (eNOS and angiotensin II signaling). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REACTIVE OXYGEN SPECIES IN PPHN Principal Investigator & Institution: Black, Stephen M.; Associate Professor; Pediatrics; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: With the initiation of ventilation and oxygenation at birth, pulmonary vascular resistance decreases and pulmonary blood flow increases. There is evidence that increased endothelial NO synthase (eNOS) gene expression, eNOS activity, and NO production contribute to these changes. However, in a number of clinical conditions, there is failure of the pulmonary circulation to undergo this normal transition to postnatal life, resulting in persistent pulmonary hypertension of the newborn (PPHN).

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PPHN complicates more than 1 in 1000 live birth and up to 10% of admissions to intensive care units. PPHN causes substantial morbidity and mortality in otherwise normal term infants. Newborns who die of PPHN have decreased endogenous NO production and an increase in circulating endothelin (ET-1) levels. In addition these children have an increase in pulmonary arterial medial smooth muscle cell thickness and extension of muscle to normally non muscular arteries. The anatomic changes in the pulmonary vessels in newborns with PPHN are thought to be intimately associated with the morbidity and mortality associated with PPHN. However, the mechanisms producing this abnormal smooth muscle cell (SMC) development and the reduction in ENOS gene expression and NO production are not well understood. We hypothesize that the increased circulating levels of ET-1 in infants with PPHN activates the ETS subtype receptor located in the SMC layer leading to an increase in the production of reactive oxygen species (ROS) in these cells. This increase in ROS then stimulates SMC proliferation while decreasing endogenous ENOS expression in endothelial cells by inhibiting the transcription of its gene. To test these hypotheses we will investigate the following: 1) How does ET-1 stimulate ROS generation in SMCs? 2) Are the increased levels of ROS induced by ET-1 linked to an increase in SMC proliferation? 3) Does ROS reduce, while antioxidants increase, eNOS gene expression in endothelial cells? The successful completion of these studies will lead to a better understanding of the mechanisms responsible for the development of PPHN and may lead to new treatments for infants born with pulmonary hypertension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF HYPOXIA INDUCIBLE FACTOR-1 BY NITRIC OXIDE Principal Investigator & Institution: Palmer, Lisa A.; Assistant Professor; Pediatrics; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2005 Summary: Hypoxia inducible factor-1 (HIF-1) is a transcription factor involved in the regulation of genes induced by low levels of oxygen. Regulation of HIF-1 is primarily determined by the stability of the HIF-1alpha subunit. In normoxia, HIF-1alpha mRNA is made but the protein is rapidly degraded by the ubiquitin-proteasome pathway. Nitric oxide (NO) has been shown to induce HIF-1 expression in normoxia. Our preliminary evidence suggests that S-nitrosylation reactions stabilize HIF-1alpha by inhibiting elements of the ubiquitin activating system. Because 1) the pulmonary vascular endothelium is not exposed to the profound levels of hypoxia often required to induce HIF-1 in vitro; 2) hemoglobin deoxygenation is associated with the transfer of nitrogen oxides to the vascular endothelium at pO2s more relevant to intravascular pathophysiology; and 3) downstream effects of HIF-1alpha stabilization on gene expression are implicated in the pathophysiology of pulmonary hypertension, we propose to clarify the mechanism by which NO activates HIF-1alpha in vitro and in vivo by testing the following hypotheses: Hypothesis number 1.: The expression of HIF-1 is regulated by nitric oxide (NO) in normoxia by S-nitrosylation of protein thiols. Hypothesis number 2. NO modifies HIF-1alpha stability in normoxia by modifying ubiquitin-dependent degradation through S- nitrosylation of HIF-1alpha and one or more enzymes of the ubiquitin activating pathway. Hypothesis number 3. Snitrosoglutathione, and/or other related nitrogen oxides arising from hemoglobin deoxygenation induce HIF-1 expression in vivo. In testing this third hypothesis, we will control the effects of hypoxia on the gamma glutamyl transpeptidase knockout mouse. We have shown that this animal has attenuated responses to deoxyhemoglobin, that

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appear to involve decreased bioactivation of S-nitrosoglutathione. Taken together, these hypotheses represent a completely novel direction in the study of abnormal gene regulation in the pulmonary vascular endothelium. At the completion of this project, we believe we will have identified several new targets for the prevention and treatment of hypoxia- induced and primary pulmonary hypertension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF KV CHANNELS BY ANOREXIGENS Principal Investigator & Institution: Takimoto, Koichi; Pharmacology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): Voltage-gated K+ (Kv) channels in pulmonary arterial smooth muscle cells (PASMCs) have been implicated in the initiation of pulmonary hypertension: inhibition of these channels results in membrane depolarization and an increase in intracellular Ca2+ concentration, leading to vasoconstriction and cell growth/remodeling. The use of anorexic agents (phentermine, fenfluramine and their related drugs) is associated with an increased incidence of pulmonary hypertension. These drugs also decrease the activity and expression of Kv channels in PASMCs. Thus, understanding the mechanisms by which these identified stimuli produce alterations in the function and level of these channels may provide clues for prevention and treatment of primary pulmonary hypertension. The anorexic agents reduce Kv channel activity at multiple steps. They acutely inhibit 4-aminopyridine (4AP)-sensitive Kv current in PASMCs. Furthermore, long-term treatment of PASMCs with fenfluramine leads to decreases in Kv current density and the expression of Kv1.5 mRNA. Lung tissues from patients with primary, but not secondary, pulmonary hypertension also exhibit reduced expression of Kv1.5 mRNA. These findings suggest acute and long-term exposures to these drugs influence 4-AP-sensitive Kv channels at plasma membrane and transcription of Kv channel subunit genes, respectively. Using Xenopus oocyte expression system, we found that fenfluramine and phentermine inhibit Kv1.5, Kv2.1 and Kv4.2, but not Kv3.1b, current. Using cultured rat PASMCs and heterologous expression systems, we have analyzed molecular mechanisms underlying the anorexigen-induced changes in the activity and expression of Kv channels. First, exposure to fenfluramine decreased endogenous Kv2.1 proteins in PASMCs. The drug also reduced heterologously expressed Kv2.1, but not Kv1.5 or Kv4.3, proteins in a mammalian cell line. In addition, the non-selective kinase inhibitor staurosporin mimicked and occluded the fenfluramine-induced decrease in the channel protein level in PASMCs. Second, the anorexic drugs caused significant decreases in the level of endogenous Kv1.5 mRNA and reporter gene expression driven by the Kv1.5 promoter in PASMCs. Reductions in the channel promoter activity were also seen in A7r5 smooth muscle cells, but not in CHO or HEK293 cells. Finally, fenfluramine and phentermine rapidly and reversibly inhibited Kv1.5, Kv2.1 and Kv4.2, but not Kv3.1b, currents in Xenopus oocytes. Thus, the anorexigen-induced pulmonary hypertension may be mediated by their multitude of actions to produce acute and long-term inhibition of PASMC Kv channels. Hence, this proposal is to identify molecular mechanisms for anorexigen-induced inhibition of Kv channels at the three levels: a slow decrease in Kv2.1 proteins, inhibition of Kv1.5 gene transcription and blockade of Kv currents at plasma membrane. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REGULATION OF NITRIC OXIDE SYNTHASE IN DEVELOPING LUNG Principal Investigator & Institution: Shaul, Philip W.; Professor; Pediatrics; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-APR-1993; Project End 31-MAR-2006 Summary: (Scanned from the applicant's description) Nitric oxide (NO), produced by endothelial NO synthase (eNOS), plays a key role in pulmonary vasodilation at birth and in the genesis of persistent pulmonary hypertension of the newborn (PPHN). Studies in fetal sheep have shown that the hormone estrogen, which rises markedly in the fetal blood during parturition, causes pulmonary vasodilation due to nongenomic effects on NO production. Estrogen also reverses the vascular abnormalities in a lamb model of PPHN. We have shown in ovine fetal pulmonary artery endothelial cells (PAEC) that estradiol (E2) cause eNOS activation through novel nongenomic actions of estrogen receptor (ER) a and calcium-mediated signaling. The OBJECTIVE of this proposal is to determine the molecular mechanisms by which E2 causes nongenomic eNOS activation in fetal PAEC. Four Aims will be addressed in primary and immortalized PAEC, and transfected COS-7 cells. We have new evidence that a subset of ERa is localized to PAEC plasma membrane (PM) where they modulate eNOS activity. AIM 1 is to determine the mechanisms underlying ERa PM function, testing the hypotheses that E2 causes internalization of PM ERa, that processes needed for genomic ERa function are not required, and that specific ERa domains are involved in PM function. We also have preliminary evidence that fetal PAEC express ERb, and that eNOS stimulation by E2 Is greater after ERb overexpression. AIM 2 is to determine the role of ERb in eNOS activation, testing the hypotheses that a subset of PM ERb is capable of nongenomic function, and that neither ERa nor dimerization are needed for PM ERb action. In further initial studies, E2 activation of eNOS was blocked by pertussis toxin. AIM 3 is to determine the role of G proteins in eNOS activation by E2, testing the hypotheses that G proteins are critically involved, that downstream signaling is mediated by Gai, and that E2 causes ERa-Gai interaction on PM. Finally, in recent studies we have detected ERa protein in PAEC caveolae, which compartmentalize signaling molecules on the PM including eNOS, and have found that E2 causes potent, ER-dependent eNOS activation in isolated caveolae membranes. AIM 4 is to characterize an E2-eNOS signaling module in PAEC caveolae, testing the hypotheses that known signaling proteins are coupled in caveolae, and that a caveolae-associated calcium pool is released by E2 to activate eNOS. Unknown components will be identified by ERa immunoprecipitation and microsequencing and yeast two-hybrid screening. These studies will fill major gaps in our understanding of NO production in the developing lung as well as our knowledge of nongenomic E2 actions in the coronary and uterine circulation and in nonvascular cells. Ultimately, we may be able to take greater therapeutic advantage of the effects of E2 on the pulmonary and also coronary and uterine circulations, thereby optimizing the vascular health of both the fetus and the mother. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REGULATION OF PULMONARY RESISTANCE VESSELS Principal Investigator & Institution: Aschner, Judy L.; Pediatrics; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004

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Summary: Alkalosis is a selective dilator stimulus for the pulmonary circulation. Achievement of an alkalotic pH has, for years, been a mainstay of therapy for infants with Persistent Pulmonary Hypertension of the Newborn (PPHN). At the cellular level, very little is known about the signaling mechanisms mediating alkalosis-induced pulmonary vasodilation. The long-term objective of our laboratory is the elucidation of cellular mechanisms regulating vascular tone and reactivity in the newborn pulmonary circulation. Our overall hypothesis is that there are unique endothelial-dependent signaling mechanisms at the level of the pulmonary resistance circulation that mediate the dilatory response to alkalosis. At the core of our methodology is measurement of vascular responses in pressurized and perfused pulmonary resistance vessels (PRV) isolated from newborn piglets, the first time this technique has been applied to the neonatal lung. Our preliminary data demonstrate that PRV mimic the unique responses of the intact lung to alkalosis, providing an excellent model for the study of pHdependent vasoactive responses. This proposal will investigate the following' specific hypotheses: (a) In the pulmonary circulation, alkalosis mediates vasodilation by a mechanism which is endothelial-dependent. (b) Alkalosis activates endothelial cell K+ channels, resulting in membrane hyperpolarization and increased Ca++ influx. (c) The resulting increase in intracellular Ca++ activates the nitric oxide (NO) pathway and the prostaglandin (PG) pathway stimulating synthesis and release of NO and prostacyclin (PGI2), respectively, thus mediating vascular smooth muscle relaxation. To test these hypotheses the following specific aims will be addressed: (1) Determination of the mechanism by which the endothelium mediates the response of PRV to alkalosis. (2) Examination of the effects of alkalosis on K+ conductance, membrane potential and intracellular Ca++ concentrations ([Ca++]i) in PRV and cultured pulmonary microvascular endothelial cells. By understanding the mechanism by which alkalosis causes pulmonary vasodilation, pharmacologic strategies can be formulated to mimic, enhance or prolong this dilator effect, while minimizing the lung and brain injury associated with hyperventilation and low PCO2, respectively. It is anticipated that these studies will enhance our knowledge of the biochemical pathways regulating perinatal transitional physiology and contribute to the development of safer, more effective strategies for the treatment of infants with PPHN. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RELATIVE HYPERTENSION

ARGININE

DEFICIENCY

IN

PULMONARY

Principal Investigator & Institution: Badesch, David B.; Professor, Pulmonary Critical Care Medic; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: Pulmonary hypertension (PH) affects patients of all ages, both sexes (with a predilection toward young females), is highly lethal, and frequently requires complicated, invasive, and expensive therapy. Abundant evidence supports the broad importance of nitric oxide (NO) in the maintenance of normal vascular function, and more recently of vascular structure. Evidence in a wide array of vascular disorders also suggests that availability of L-arginine, the sole substrate for NO generation, limits NO generation. Under such circumstances NO production may be enhanced by administration of exogenous arginine. These considerations could be of direct and potentially practical importance in the pathophysiology and treatment of PH, but have not been extensively evaluated. Accordingly, this proposal tests the hypothesis that patients with PH have a chronic relative deficiency of NO synthase substrate (arginine).

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Pulmonary Hypertension

Thus increased generation of NO in response to increased shear stress and flow would be limited by substrate availability. We further hypothesize that chronic supplementation with L-arginine or protection of NO from oxidant degradation, would augment NO activity, ameliorating pulmonary vascular injury and structural remodeling, with consequent clinical improvement in PH as measured by exercise capacity and cardiopulmonary hemodynamics. This work could define simple, inexpensive, low risk measures which might contribute to the treatment of PH. The specific aims are to determine whether: 1. NO activity (NOx, citrulline) is increased in patients with various forms of PH (PPH and SPH). 2. Levels of L-arginine (nitric oxide synthase substrate) are reduced in patients with various forms of PH. 3. Treatment of PPH with prostacyclin increases NO activity and/or decreases NOS substrate (arginine) levels. 4. L-arginine levels can be augmented in patients with PPH by chronic L-arginine supplementation, or by the administration of antioxidant vitamins. 5. Raising L-arginine levels in patients with PPH results in augmentation of NO activity (NOx, citrulline), short- term biologic effect as assessed by improvement in measures endothelial cell function, and long-term biologic effect as assessed by improvement in the 6-minute walk test and cardiopulmonary hemodynamics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RIGHT VENTRICULAR DYSFUNCTION AND TREATMENT Principal Investigator & Institution: Semigran, Marc J.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114

Assistant

Professor;

Timing: Fiscal Year 2002; Project Start 12-APR-1999; Project End 31-MAR-2004 Summary: Heart failure represents the results of a variety of cardiovascular diseases in which the initial insult to the myocardium may either be identifiable, such as a myocardial infarction, or unknown, such as in dilated cardiomyopathy. In either case, the occurrence of injury to the myocardium leads to an inexorable course of myocardial dysfunction. While most previous investigations have concentrated on the abnormalities in left ventricular function, there is evidence that right ventricular (RV) function is a more important determinant of patients symptoms and prognosis. Few therapies currently exist to improve RV performance, as currently used systemic vasodilator therapy can cause hypotension when nonselective pulmonary vasodilators are added to a patient's therapeutic regimen. Nitric oxide (NO) activates vascular smooth muscle cell soluble guanylate cyclase leading to vasodilation. The vasodilator effect of NO is limited in time by its rapid binding to, and inactivation by hemoglobin. In preliminary studies, inhaled NO has been demonstrated to be a selective pulmonary vasodilator which can improve cardiac performance and exercise capacity in heart failure patients. The goal of this proposal is to combine type 5 (cGMP- specific) phosphodiesterase inhibiton with inhaled NO to: 1. Assess the acute alterations in right ventricular function, overall cardiac performance and exercise capacity in heart failure patients treated with the combination of inhaled NO and the type 5 phosphodiesterase inhibitor sildenafil. 2. Assess the acute and chronic effects of selective pulmonary vasodilation with inhaled nitric oxide and type 5 phosphodiesterase inhibition on pulmonary artery resistance and morphology in patients with pulmonary hypertension due to pulmonary vascular disease or to left heart failure. 3. Assess the effects of acute and chronic pulmonary vasodilator and the subsequent decrease in wall stress on the activity of proteins which regulate myocyte apoptosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RISK FACTORS FOR PULMONARY HYPERTENSION OF THE NEWBORN Principal Investigator & Institution: Mitchell, Allen A.; Professor/Director; Slone Epidemiology Unit; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAR-2004 Summary: (Adapted from Investigator's Abstract) Persistent pulmonary hypertension of the newborn (PPHN), previously called persistent fetal circulation, is a birth defect affecting approximately 1 in 1250 liveborn term infants; even with complex and highrisk interventions, PPHN results in substantial mortality and morbidity. This defect results from the inappropriate muscularization of fetal pulmonary vessels, and experimental and human evidence consistently suggests that maternal cigarette smoking and antenatal exposure to non-steroidal anti-inflammatory drugs (NSAIDs), particularly aspirin or ibuprofen, may play a role in the etiology of this condition. Because these exposures are quite prevalent (e.g., ibuprofen is currently taken in the first trimester or later in pregnancy by 15% and 3.2% of women, respectively), testing these hypotheses is of considerable public health importance. The investigators propose to conduct a multicenter case-control study of PPHN in relation to maternal exposure to smoking and NSAIDs. They will also assess other potential antenatal risk factors and collect and store buccal cell specimens for future analyses. There will be 560 case infants with PPHN and four controls per case (2240). All controls will be drawn from the birth hospitals of cases; half the controls will have malformations other than PPHN, and half will have normal formations. Cases and controls will be identified within 5 months of birth at 88 birth and tertiary hospitals in the areas surrounding Boston, Philadelphia, and Toronto. Mothers of subjects will be interviewed by telephone within six months of delivery; a standardized questionnaire will inquire in detail about demographic factors; reproductive, medical, and pregnancy illness histories; medication use (including a detailed focus on use of over-the-counter analgesic/antipyretic medications), smoking, and nutrition. Because of emerging genetic research suggesting an effect of NSAIDs on pathways possibly related to the etiology of PPHN, buccal swabs will also be collected and stored for future analyses. Exposure prevalences will be compared between mothers of cases and controls and relative risks will be estimated, controlling for potential confounding factors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RODENT MODEL OF SEVERE PULMONARY HYPERTENSION Principal Investigator & Institution: Tuder, Rubin M.; Associate Professor; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: (provided by applicant): This project replaces the R01 grant: "VEGF protects against pulmonary vascular remodeling". Endothelial cell (EC) dysfunction plays an important role in the development of severe pulmonary hypertension (SPH). We have proposed that one of the most characteristic cellular features of SPH is the finding of EC clusters (tumorlets) in medium-size pulmonary arteries. Since these proliferated ECs express markers of angiogenesis, we have postulated that this EC growth occurs due to disordered angiogenesis. The VEGF receptor 2 (VEGFR-2) regulates several fundamental properties of ECs that impact on EC survival and nitric oxide and prostacyclin. We hypothesize that VEGF has a central role in the maintenance of the pulmonary endothelium. In this revised proposal, we seek to demonstrate that the

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blockade of the VEGFR-2 in combination with chronic hypoxia or monocrotaline causes severe pulmonary hypertension. We postulate that the combination of VEGFR-2 blockade and chronic hypoxia promotes death of normal pulmonary ECs and the selection of an abnormal, apoptosis-resistant, proliferating EC. Our experimental approach is based on in vivo studies with mice and rats with hypoxia- and monocrotaline-induced pulmonary hypertension (PH), ex vivo, in isolated perfused rat lungs, and, in vitro, using endothelial and lung smooth muscle cell cultures. Specifically, we propose to answer whether: 1. VEGF receptor blockade with SU5416 or ZK202650 in rats exposed to normoxia, or chronic hypoxia, or monocrotaline causes severe pulmonary hypertension associated with EC proliferation; and 2. The combination of VEGF receptor 2 blockade and chronic hypoxia leads to EC injury and EC death prior to the development of EC proliferation and SPH. Since we have successfully completed many of the originally planned experiments, we now propose experiments to confirm the specificity of our findings with SU5416 with a second, chemically unrelated VEGF receptor blocker, ZK202650, and we further probe the impact of abnormal VEGF/VEGF receptor signaling in the development of pulmonary hypertension in the transgenic mice expressing only the 188 amino-acid form of VEGF(VEGF188/188 mice) (Aim 1). In addition, we develop a novel approach to test whether apoptosis of normal lung ECs induces an apoptosis-resistant EC and SPH (Aim 2). This rodent model shares several of the key cellular and molecular features with human SPH. This proposal will allow us to better understand the natural history of human SPH associated with EC proliferation (secondary PH, project I and how alterations in pulmonary EC function affect pulmonary vascular tone and VSMC growth and hypertrophy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF FACIT COLLAGENS IN HYPERTENSION Principal Investigator & Institution: Gerecke, Donald R.; Pharmacology and Toxicology; Rutgers the St Univ of Nj New Brunswick Asb Iii New Brunswick, Nj 08901 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2006 Summary: (Applicant's abstract) Pulmonary hypertension may be either a primary event, or secondary to other injury. In either case it is an important clinical problem in which the walls of injured blood vessels rapidly thicken. Part of this rapid thickening is caused by the de novo synthesis of the extracellular matrix components that help define the medical and adventitial layers of the blood vessels. This thickening in turn can result in decreased lumen diameter, increasing resistance to blood flow and ultimately raising arterial pressure. In animals, the damage is reversible if the disease has not progressed and if the underlying cause is removed. This hypertension regression has been well documented in animal models, but little is known about the normal mechanisms regarding this remodeling of the vessels. In particular, the rat model of hypoxic pulmonary hypertension is frequently used as it has in common many of the features of the human disease. Collagens play a major role in the development of mature, functional tissues. The extracellular matrix of connective tissue is composed, in part, of heterotypic collagen fibrils. Ultrastructurally, various connective tissue have different collagen fibrillar arrangements and alignments, however, despite the appearance of the fibrils, the types of collagens found in the fibrils are frequently the same, their spatial arrangements determined by molecules associated with the surfaces of fibrils or fibril bundles that establish and/or stabilize the various spatial arrangements. Such molecules would be expected to contain at least two domains: One domain that anchors the molecule to the surface of the fibril and a second domain to assist in various interactions with other fibrils or other matrix components. Proteins with such characteristics include

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collagens IX, XII, and XIV, which are classified as Fibril Associated Collagens with Interrupted Triple-helices (FACITs). Of this class of molecules, collagens XII and XIV are found in a variety of tissues that contain type I collagen and sit on the surface of the collagen I fibrils in an unknown capacity. We hypothesize that types XII and XIV collagen are recruited to temporarily stabilize fibril interactions under conditions of stress, such as hypoxia. This fibril stabilization would allow the tissue architecture to withstand the forces generated by a rapid increase in fibrillar collagen content and rapid cell proliferation. We also hypothesize that the types XII and XIV collagen are responsible for the reversibility of the vessel wall changes. These molecules are easily removed from fibril surfaces, allowing more permanent stabilizers to take their places (such as fibril fusion or lysly crosslinking), which are fibril adaptions that make the vessel changes permanent. We propose to examine the role of these collagens in the hypertensive rat model using a variety of biochemical and molecular biological techniques. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF TGF-ALPHA IN PULMONARY VASCULAR DISEASE Principal Investigator & Institution: Le Cras, Timothy D.; Assistant Professor; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 45229 Timing: Fiscal Year 2003; Project Start 10-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Pulmonary hypertension plays a major role in the morbidity and mortality of a number of acute and chronic lung diseases including bronchopulmonary dysplasia. While clinical studies have implicated transforming growth factor-alpha (TGF-alpha) in the pathogenesis of these diseases, the role of TGFalpha, its cellular targets, and the signaling pathways involved are unclear. Preliminary data accompanying this application demonstrate that epithelial expression of TGF-alpha causes severe reductions in pulmonary artery number, vascular remodeling, and pulmonary hypertension as early as 2 weeks of age in transgenic mice. We also have preliminary evidence to suggest that this is mediated in part by autocrine signaling through EGF receptors on distal epithelial cells, and reductions in vascular endothelial growth factor-A (VEGF-A). Using both in vitro and in vivo approaches, this proposal will test the central hypothesis that epithelial expression of TGF-alpha disrupts vascular growth and causes vascular remodeling and pulmonary hypertension through EGF receptor-dependent autocrine-paracrine signaling. In the first phase we will define when pulmonary growth is disrupted by TGF-alpha, whether acute or chronic expression of TGF-alpha is necessary, and whether TGF-alpha causes vascular remodeling and pulmonary hypertension independent of reductions in vascular growth (Specific Aim 1). In the second phase we will define the role of indirect signaling through the epithelium versus direct signaling to the vascular endothelium (Specific Aim 2) using a dominant negative (mutant) EGF receptor to block TGF-alpha signaling in specific cellular compartments. In the third phase we will define whether TGF-alpha, regulates expression of VEGF-A in type II epithelial cells in vitro and in vivo, and whether reductions in VEGF-A contribute to the pathogenesis of pulmonary vascular disease (Specific Aim 3). The overall goal of this proposal is to define the timing, cellular targets, and mechanism by which TGF-alpha disrupts pulmonary vascular growth and causes pulmonary hypertension and vascular remodeling. This information will serve as a basis for developing therapeutic strategies aimed at improving lung growth and preventing pulmonary hypertension in premature babies and adults. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF VEGF IN NEONATAL PULMONARY HYPERTENSION Principal Investigator & Institution: Grover, Theresa R.; Pediatrics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Dr. Theresa Grover is an Assistant Professor of Pediatrics and a board-certified neonatologist at the University of Colorado Health Sciences Center. She developed an interest in the regulation of pulmonary vascular growth and function during her fellowship training at UCHSC. She has extensive experience in whole animal studies of fetal and neonatal pulmonary blood flow in the lamb and has developed a focused interest in the role of growth factor modulation of pulmonary vascular growth and function in the perinatal circulation. Her immediate goals are to learn the theories and practice of molecular and cell biology in order to provide better mechanistic understanding of the physiologic and structural changes seen in the whole animal studies. Her long-term goals are to use whole animal, molecular and cell culture techniques to focus on independent investigation of the regulation of pulmonary vascular growth and vasoreactivity in the perinatal lung. The research environment at UCHSC will provide an ideal setting in which to foster Dr. Grover's career development. She has chosen leaders in the field of pulmonary vascular biology to serve as her advisory committee. Dr. Steven Abman (mentor) has extensive experience in animal and clinical studies of pulmonary vasoreactivity. Dr. Kurt Stenmark's work has focused on cellular and molecular changes of smooth muscle cells in pulmonary hypertension. Dr. Russ Anthony is a PhD physiologist at Colorado State University and has extensive experience in studying the molecular endocrinology of pregnancy and placental angiogenesis. Dr. Grover will work directly with Drs. Abman, Stenmark, and Anthony to apply molecular and cell biology techniques learned through intensive course work to her studies of the effects of vascular growth factors on the fetal and neonatal pulmonary circulation. Dr. Grover will also enhance her career development through regular interactions with members of the Cardiovascular Pulmonary Research Laboratory (CVP) and the Perinatal Research Facility (PRF). Dr. Grover proposes to study the effects of VEGF treatment on pulmonary vascular structure and function in an experimental model of PPHN. She will examine the mechanisms responsible for structural vascular remodeling and endothelial cell dysfunction and apoptosis in neonatal pulmonary hypertension. These studies will provide an integrated approach to the hypothesis, incorporating whole animal physiology coupled with molecular and cellular studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SIGNALING PATHWAYS IN HUMAN VASCULAR SMOOTH MUSCLE CELLS Principal Investigator & Institution: Beasley, Debbie S.; New England Medical Center Hospitals 750 Washington St Boston, Ma 021111533 Timing: Fiscal Year 2002; Project Start 13-SEP-2001; Project End 31-JUL-2005 Summary: It has long been thought that hypoxia is a stimulus for human vascular smooth muscle cell (HVSMC) proliferation occurring in pulmonary hypertension, however, the mechanisms involved are unknown. Based on our novel finding that hypoxia directly stimulates proliferation in cultured HVSMC, the main objective of this proposal is to determine the role of hypoxia-inducible transcription factors (HIFs) in the O2-dependent regulation of HVSMC proliferation. Numerous studies have demonstrated a crucial role of HIF-1, a dimer consisting of alpha and beta subunits, in

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hypoxia-inducible gene transcription. Our preliminary data indicate that hypoxia induces increased nuclear levels of HIF-1alpha and HIF-2alpha protein (by Western blot analysis), increased nuclear HIF complexes which bind to a hypoxia response element (by EMSA), and enhanced HIF-dependent reporter gene expression, in HVSMC. Furthermore, transient overexpression of HIF-1alpha or HIF-2alpha stimulates HVSMC proliferation. Based on these findings, the proposed studies will test the hypothesis that hypoxia induces human VSMC proliferation via upregulation of HIFs, and will further explore the role of downstream signaling pathways in their mitogenic effect. Transient and stable transfection techniques, adenoviral vectors, antisense oligonucleotides, electrophoretic mobility shift assays, Western blot and promoter activity analysis will be used to address the following specific aims: to determine whether HIF transcription factors mediate the proliferative responses of human VSMC to hypoxia; to characterize HIF-dependent gene promoters that are involved in the subsequent mitogenic effect. Elucidating the roles of hypoxia-inducible transcription factors in human VSMC proliferation will enhance our understanding of the pathogenesis of vascular diseases such as pulmonary hypertension, and may lead to identification of novel therapeutic targets for pharmacologic intervention in this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STIMULATION OF SMC GROWTH BY SEROTONIN Principal Investigator & Institution: Fanburg, Barry L.; Professor; New England Medical Center Hospitals 750 Washington St Boston, Ma 021111533 Timing: Fiscal Year 2002; Project Start 01-JUL-1984; Project End 31-AUG-2007 Summary: (provided by applicant): There is considerable evidence now available that supports an important rote for the serotonin (5-HT) transporter, a member of the NaCldependent transporter gene family, in the development of pulmonary vascular remodeling and hypertension. Transcription of this transporter is stimulated by hypoxia and the transporter participates in 5-HT-induced pulmonary artery (PA) smooth muscle cell (SMC) hyperplasia/hypertrophy. Based on our studies done largely during the last funding period, we hypothesize that there are specific intermediate intracellular signaling pathways through which the mitogenic action of 5-HT occurs (denoted in Figure 1). We plan in this proposal to further study these intermediate signals by: 1) examining the PA SMC NAD(P)H oxidase that is stimulated in response to 5-HT transport; 2) characterizing the role of Src-Fak non-receptor kinases in signal transduction, cyclin D1 gene regulation, cell growth and cytoskeletal reorganization produced by 5-HT; 3) evaluating transcription factors (in particular STAT and GATA) that may be linked to 5-HT transporter stimulation of SMC growth; and 4) assessing the role of a concomitant 5-HT4-like receptor action on the same SMC that can convert the growth stimulatory effect to a growth inhibitory one. For these studies we will use bovine PA SMCs, with which we have had considerable experience, but will shift to PA SMCs of the human, rat and mouse species as needed to answer specific questions, or where reagents being used require specific species homology. Methodologies will include, but not be limited to, Western and Northern analyses, electrophoretic mobility shift assays, immunoblotting, PCR technology, lipid-mediated transient transfections, adenoviralmediated gene transfer, and use of reporter gene constructs, all of which are ongoing in our laboratory. We anticipate that a fuller understanding of the intracellular processes responding to 5-HT transporter activation may allow development of new strategies for treating pulmonary hypertension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TARGETING ACTIVE ADAPTORS TO CONTROL ENDOTHELIAL DAMAGE Principal Investigator & Institution: Wei, Sheng; Interdisciplinary Oncology Prg; University of South Florida 4202 E Fowler Ave Tampa, Fl 33620 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2009 Summary: (provided by applicant): Upon cell-cell contact, one of the mechanisms of immune cells to cause tissue damage is by delivery of lytic granules containing preformed effector molecules--perforin proteins and granzyme proteases. The presence of granzymes and perforin in the extracellular milieu not only reflects the presence of activated CTL and NK cells but also significantly contribute to inflammatory reaction. These protein enzymes can cause circular pore-like lesions on the membrane surface of endothelial cells and induce target cell death leading to local tissue damage and chronic vascular cell damage. Increased granzyme level is closely correlated with the inflammatory activity in autoimmune diseases (e.g. rheumatoid arthritis) and virallyinfected lung and heart diseases. A clear understanding of the pathophysiology of inflammation mediated tissue damage would greatly facilitate management of this disease. The signal transduction pathways in effector lymphocytes, which trigger the redistribution of the lytic granules towards the target endothelial cells, are not well defined. Identification of key signaling molecules which specifically control this lytic process could enable pharmaceutical disruption of this process, thereby reducing the tissue damage mediated by activated lymphocytes. In this proposal, we will use a human primary pulmonary endothelial cell line, CRL- 2598, as the trigger to activate the lytic signal cascade in NK cells. Using biochemical and gene delivery approaches, we will directly test the hypothesis that the early signals via NK activation receptors and their associated adaptor proteins, DAP12 and DAP10, will play a specific role in control of granule movement in NK cells. Blocking of this initial step, at the level of the adaptor proteins, will inhibit granule exocytosis. More importantly, we will test our hypothesis on LGL leukemic patients with primary pulmonary hypertension (PPH) and determine if DAP10 and/or DAP12 critically control NK cell- mediated endothelial cell damage and death. A better understanding of the signaling pathways that control granule movement and exocytosis will offer new opportunities, e.g. design of DAP10 and DAP12 antagonists, for therapeutic intervention to specifically control lymphocytemediated tissue damage. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE HOMEOSTASIS

ROLE

OF

CARBON

MONOXIDE

IN

VASCULAR

Principal Investigator & Institution: Christou, Helen; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2002; Project Start 15-JAN-2000; Project End 31-DEC-2004 Summary: (Adapted from applicant's abstract) The long term goal of the research is to gain insight into how vascular tone and structure are regulated at the cellular and molecular level. Important insights into the pathogenesis of diseases of disrupted vascular homeostasis, such as atherosclerosis and pulmonary hypertension, would be gained by an elucidation of the cellular and molecular vascular homeostatic mechanisms. Complex circuits involving vascular cell interactions and feedback regulatory loops are known to control vascular tone and structure. The central hypothesis of this proposal is that the production of endogenous carbon monoxide (CO) in the vasculature represents an adaptive response to hypoxia. Endogenous CO is

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largely the product of the enzymatic activity of heme oxygenase (HO). The inducible form of this enzyme, HO-1, is expressed by hypoxic vascular smooth muscle cells (SMCs) which release CO in the vasculature. Smooth muscle cell-derived CO may affect vascular cell function in autocrine and paracrine ways. The applicant proposes to investigate the role of CO in vascular homeostasis using cell culture and transgenic animal techniques. The specific aims of the proposed project are: (I) to study the molecular mechanisms by which CO regulates gene expression (ii) to determine the role of SMC-derived CO in endothelial-smooth muscle cell interactions in the setting of hypoxia and (iii) to validate the role of CO in the regulation of pulmonary vascular tone and structure in vivo. The experimental design involves use of in vitro single-cell type and co- culture systems in conjunction with regulated overexpression of HO-1 by transfected SMCs. Aspects of endothelial cell function to be studied include gene expression, proliferation and barrier function. Similarly, SMC gene expression, growth and proliferative response to mitogenic stimuli will be examined. A transgenic mouse model approach will be used to examine the role of CO in pulmonary vascular homeostasis under hypoxia in vivo. The human Surfactant Protein-C (SP-C) promoter will be used to target expression of the HO-1 transgene to the lung and the animals will be assessed as to the development of pulmonary hypertension in response to hypoxia. The above studies should enhance the understanding of vascular homeostasis and the role of CO. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: UNIQUE MECHANISM FOR REABSORPTION OF EDEMA IN THE LUNG Principal Investigator & Institution: Effros, Richard M.; Professor and Chief; Medicine; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: New insight concerning transvascular formation and reabsorption of pulmonary edema has been provided by novel stop-flow procedures developed in our laboratory. These studies indicate that elevations in pulmonary vascular pressures result in leakage primarily from the venous side of the pulmonary exchange vessels but not rom the arterial side. They have also shown that when perfusion is briefly interrupted, excess interstitial fluid can be forced back into the vasculature of isolated rat lungs by simultaneously raising airspace and pleural pressures. Reabsorption of fluid under these circumstances can occur even in the presence of very low protein concentrations in the perfusate. This observation indicates that strictly hydrostatic pressure gradients can effect reabsorption of edema from the pulmonary interstitium, a phenomenon which has not been documented in other organs. However no fluid reabsorption occurs unless the lungs are inflated, suggesting that fluid returns to extraseptal vessels which ar e kept open when the lungs are inflated. We hypothesize that the unique capacity of the lung to reabsorb edema fluid under these circumstances is based upon the fact that lung inflation prevents compression of extraseptal portions of the venous microvasculature, which are pulled open as the lungs are inflated. This study will utilize the uptake of 201/Tl from the perfusate to calculate the fraction of samples collected from the pulmonary outflow which were within the pulmonary exchange vessels during the stop-flow interval. Experiments will be conducted to compare the sites of edema formation, solute exchange, and fluid reabsorption with hypertonic solutions of small and large molecules. It is anticipated that hypertonic solutions of small molecules will result in cellular dehydration all along microvasculature whereas the sites of fluid reabsorption with protein and other macromolecules will depend upon their molecular

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size. We will also seek to confirm that NO production is greater in venous at suites which inhibit edema formation and will investigate the effects of NO on transvascular fluid transport. The effects of lung injury caused by high vascular pressures, over distention of the lungs, acid aspiration and infections of the oleic acid will be investigated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VASCULOGENESIS FAILURE IN NEONATAL PULMONARY HYPERTENSION Principal Investigator & Institution: Abman, Steven H.; Professor, Pulmonary Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: (provided by applicant): Persistent pulmonary hypertension of the newborn (PPHN) is characterized by failure of the pulmonary circulation to achieve or sustain the normal decrease in pulmonary vascular resistance (PVR) at birth. Mechanisms that contribute to the pathogenesis and pathophysiology of PPHN are uncertain, but include abnormalities of vascular function ("maladaptation"), structure ("maldevelopment"), and growth ("underdevelopment"). Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and a critical trophic factor for the maintenance of normal endothelial function. Past studies in mouse models of lung development have clearly shown that VEGF plays an essential role in vasculogenesis and angiogenesis during the early embryonic period, but little is known about the role of VEGF and its KDR receptor in vascular growth and endothelial function in the pulmonary circulation during late gestation. The endothelial cell plays a central role in the regulation of the normal fetal and transitional pulmonary circulations, especially through production of nitric oxide (NO). NO modulates basal PVR in the normal fetus, contributes to the fall in PVR at birth, and is decreased in experimental models of PPHN. However, mechanisms that regulate endothelial function and NOS expression in the perinatal lung are poorly understood. In vitro studies suggest that VEGF mediates endothelial cell growth through NO-dependent mechanisms, and that VEGF can upregulate NO synthase (NOS) expression in some settings. Whether the VEGF-KDR system plays a critical role in angiogenesis, endothelial cell survival and function, and the regulation of NOS expression during late fetal life is unknown. Therefore, we hypothesize that the VEGFKDR axis is critical for normal lung vascular growth, and that disruption of VEGF production or activity impairs pulmonary vascular development, leading to decreased endothelial cell growth and function, and failure of postnatal adaptation at birth. To test these hypotheses, we propose to investigate the following specific aims: 1) to define normal temporal and cell-specific changes in VEGF-KDR expression during lung maturation in the fetal and postnatal lung; 2) to determine whether abnormal hemodynamic stress disrupts normal vascular growth in utero, decreases VEGF and KDR expression and activities, and contributes to failure of postnatal adaptation at birth; 3) to determine whether inhibition of VEGF or the KDR receptor disrupts lung vascular growth, alters vasoreactivity, and causes pulmonary hypertension; and 4) whether VEGF treatment improves endothelial function and vascular growth in experimental PPHN. Studies will utilize the chronically-prepared fetal lamb model to provide an integrative physiologic approach that combines whole animal physiology with molecular, biochemical, and morphometric studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VESSEL ATHEROGENESIS

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Principal Investigator & Institution: Rumschitzki, David; Chemical Engineering; City College of New York 138Th St and Convent Ave New York, Ny 10031 Timing: Fiscal Year 2002; Project Start 10-APR-2002; Project End 31-MAR-2006 Summary: Atherosclerosis is a disorder of the large arteries that begins with the accumulation of lipoproteins in the artery wall and develops into lesions. This accumulation is associated with high plasma lipoprotein concentrations, and thus lipoprotein transport into and accumulation in the artery wall has been the focus of intense study. If lipoprotein transport and accumulation in the vessel wall is the key to atherosclerosis, then a good understanding of these processes should explain why different vessels have different susceptibilities to disease and why these susceptibilities vary with conditions such as transmural pressure. In particular, the pulmonary artery (PA) and the large veins such as the inferior vena cava and the saphenous vein are exposed to much lower transmural pressures than the large arteries and are normally resistant to atherosclerosis. But, the PA becomes disease prone under pulmonary hypertension and large veins when exposed to artery pressure. We have developed an endothelial cell-level approach to the transport into and accumulation in the aortic wall, which seem to have vessel-in-dependent features. This proposal extends that approach to a more general venue for a detailed understanding of how the transmural pressure, vessel ultrastructure and endothelial cell turnover influence transport and accumulation in the low-pressure PA and the large vein (inferior vena cava). It does not treat vessel remodeling. The theory aims to model the roles of vessel structure and pressure conditions on the transport processes of lipoproteins in relation to atherosclerosis. The proposed research is designed by combining animal experimentation and theoretical modeling, each guiding the other, to understand these roles. In particular, the theory should be able to explain Tompkins' decade-old profiles of the tracer concentration-vsdepth into the vessel wall that coarser theories less in tune with the vessel's histology could not. It also tests the hypothesis that the kinetics of lipid binding to arterial extracellular intimal matrix and accumulation there is vessel independent; vessel dependence would derive solely from the vessel's peculiar transport problem that supplies free LDL to the tissue and its proteoglycan type/amount. The long-term goal is to be able to predict a vessel's lipid accumulation patterns based on its ultrastructure and conditions, e.g., transmural pressure. The hypothesis is that this will correlate with susceptibility to atherosclerosis and, if so, can contribute to an understanding of the effect of blood pressure on atherogenesis in certain vessels. The ultimate goal of the proposed research is to provide information needed for the prevention and treatment of atherosclerosis in humans. 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

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Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.

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Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “pulmonary hypertension” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for pulmonary hypertension in the PubMed Central database: •

Acute hemodynamic effects of inhaled nitric oxide, dobutamine and a combination of the two in patients with mild to moderate secondary pulmonary hypertension. by Vizza CD, Rocca GD, Roma DA, Iacoboni C, Pierconti F, Venuta F, Rendina E, Schmid G, Pietropaoli P, Fedele F.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96124

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Anorexigen-induced pulmonary hypertension and the serotonin (5-HT) hypothesis: lessons for the future in pathogenesis. by Eddahibi S, Adnot S.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=64820

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Bone morphogenetic proteins, genetics and the pathophysiology of primary pulmonary hypertension. by Caestecker MD, Meyrick B.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59576

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Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice. by Zhao YY, Liu Y, Stan RV, Fan L, Gu Y, Dalton N, Chu PH, Peterson K, Ross J Jr, Chien KR.; 2002 Aug 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123264

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Dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary hypertension. by Bonnet S, Dumas-de-La-Roque E, Begueret H, Marthan R, Fayon M, Dos Santos P, Savineau JP, Baulieu EE.; 2003 Aug 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=170945

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Functional Heterogeneity of Bone Morphogenetic Protein Receptor-II Mutants Found in Patients with Primary Pulmonary Hypertension. by Nishihara A, Watabe T, Imamura T, Miyazono K.; 2002 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124142

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Genomic approaches to research in pulmonary hypertension. by Geraci MW, Gao B, Hoshikawa Y, Yeager ME, Tuder RM, Voelkel NF.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59578

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Group B streptococcal phospholipid causes pulmonary hypertension. by Curtis J, Kim G, Wehr NB, Levine RL.; 2003 Apr 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154302

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Heterozygous deficiency of hypoxia-inducible factor --2[alpha] protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia. by Brusselmans K, Compernolle V, Tjwa M, Wiesener MS, Maxwell PH, Collen D, Carmeliet P.; 2003 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155039

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With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.

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Hypoxia due to patent foramen ovale in the absence of pulmonary hypertension. by Maraj R, Ahmed O, Fraifeld M, Jacobs LE, Yazdanfar S, Kotler MN.; 1999; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325672

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Iliac arteriovenous fistula due to spinal disk surgery. Causes severe hemodynamic repercussion with pulmonary hypertension. by Machado-Atias I, Fornes O, GonzalezBello R, Machado-Hernandez I.; 1993; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325056

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Inhaled nitric oxide in persistent pulmonary hypertension of the newborn refractory to high-frequency ventilation. by Al-Alaiyan S, Neiley E.; 1999; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=29006

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Inhaled nitric oxide reverses cell-free hemoglobin-induced pulmonary hypertension and decreased lung compliance. Preliminary results. by Figueiredo LF, Mathru M, Jones JR, Solanki D, Kramer GC.; 1997; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28996

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Ketanserin in the treatment of protamine-induced pulmonary hypertension. by van der Starre PJ, Solinas C.; 1996; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325377

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Lipid X ameliorates pulmonary hypertension and protects sheep from death due to endotoxin. by Golenbock DT, Will JA, Raetz CR, Proctor RA.; 1987 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=260732

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Nitric oxide for the evaluation and treatment of pulmonary hypertension in congenital heart disease. by Kovalchin JP, Mott AR, Rosen KL, Feltes TF.; 1997; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325473

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Nonlinear indicial response of complex nonstationary oscillations as pulmonary hypertension responding to step hypoxia. by Huang W, Shen Z, Huang NE, Fung YC.; 1999 Mar 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26697

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Pentoxifylline Therapy A New Adjunct in the Treatment of Pulmonary Hypertension? by Park IS, Leachman RD.; 1988; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=324819

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Pulmonary hypertension associated with COPD. by Naeije R, Barbera JA.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137368

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Pulmonary Hypertension Syndrome in Broilers Caused by Enterococcus faecalis. by Tankson JD, Thaxton JP, Vizzier-Thaxton Y.; 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98767

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Upregulation of nitric oxide synthase in mice with severe hypoxia-induced pulmonary hypertension. by Fagan KA, Morrissey B, Fouty BW, Sato K, Harral JW, Morris KG Jr, Hoedt-Miller M, Vidmar S, McMurtry IF, Rodman DM.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59521

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Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. by Petkov V, Mosgoeller W, Ziesche R, Raderer M, Stiebellehner L, Vonbank K, Funk GC, Hamilton G, Novotny C, Burian B, Block LH.; 2003 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154449

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

A 38-year-old man with pulmonary hypertension, who had undergone atrial septal closure 26 years previously. Author(s): Satoh T, Yagi T, Kato S, Azuma K, Kataoka M, Takahashi T, Sato A, Okita H. Source: The Keio Journal of Medicine. 2003 December; 52(4): 250-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14748478

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A study of clinical efficacy of sildenafil in patients with primary pulmonary hypertension. Author(s): Sastry BK, Narasimhan C, Reddy NK, Anand B, Prakash GS, Raju PR, Kumar DN. Source: Indian Heart J. 2002 July-August; 54(4): 410-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12462670

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Acquired pulmonary vein stenosis as a cause of life-threatening pulmonary hypertension. Author(s): Jaillard SM, Godart FR, Rakza T, Chanez A, Lequien P, Wurtz AJ, Storme L. Source: The Annals of Thoracic Surgery. 2003 January; 75(1): 275-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12537232

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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Acute hemodynamic effects and home therapy using a novel pulsed nasal nitric oxide delivery system in children and young adults with pulmonary hypertension. Author(s): Ivy DD, Parker D, Doran A, Parker D, Kinsella JP, Abman SH. Source: The American Journal of Cardiology. 2003 October 1; 92(7): 886-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14516902

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Acute hemodynamic effects of inhaled nitric oxide, dobutamine and a combination of the two in patients with mild to moderate secondary pulmonary hypertension. Author(s): Vizza CD, Rocca GD, Roma AD, Iacoboni C, Pierconti F, Venuta F, Rendina E, Schmid G, Pietropaoli P, Fedele F. Source: Critical Care (London, England). 2001 December; 5(6): 355-61. Epub 2001 October 09. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11737925

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Acute pulmonary edema caused by epoprostenol infusion in a child with scimitar syndrome and pulmonary hypertension. Author(s): von Schnakenburg C, Peuster M, Norozi K, Roebl M, Maibohm M, Wessel A, Fink C. Source: Pediatric Critical Care Medicine : a Journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2003 January; 4(1): 111-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12656556

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Advances in the treatment of secondary pulmonary hypertension. Author(s): Maloney JP. Source: Current Opinion in Pulmonary Medicine. 2003 March; 9(2): 139-43. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12574694

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Aeolus myth: chronic obstructive lung disease and nocturnal lumbosacral pain in association with lumbar spinal stenosis and pulmonary hypertension. Author(s): LaBan MM, Kucway EJ. Source: American Journal of Physical Medicine & Rehabilitation / Association of Academic Physiatrists. 2003 September; 82(9): 660-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12960906

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An assessment of the role of the inhibitory gamma subunit of the retinal cyclic GMP phosphodiesterase and its effect on the p42/p44 mitogen-activated protein kinase pathway in animal and cellular models of pulmonary hypertension. Author(s): Murray F, MacLean MR, Pyne NJ. Source: British Journal of Pharmacology. 2003 April; 138(7): 1313-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12711632

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An infant with pulmonary hypertension due to a congenital porto-caval shunt. Author(s): Ersch J, Banziger O, Braegger C, Arbenz U, Stallmach T. Source: European Journal of Pediatrics. 2002 December; 161(12): 660-2. Epub 2002 November 08. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12447666

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Angiogenesis and pulmonary hypertension: a unique process in a unique disease. Author(s): Tuder RM, Voelkel NF. Source: Antioxidants & Redox Signalling. 2002 October; 4(5): 833-43. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12470512

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Angiopoietin-1 and pulmonary hypertension: cause or cure? Author(s): Rudge JS, Thurston G, Yancopoulos GD. Source: Circulation Research. 2003 May 16; 92(9): 947-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12750304

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Angiotensin-converting enzyme DD genotype in patients with primary pulmonary hypertension: increased frequency and association with preserved haemodynamics. Author(s): Abraham WT, Raynolds MV, Badesch DB, Wynne KM, Groves BM, Roden RL, Robertson AD, Lowes BD, Zisman LS, Voelkel NF, Bristow MR, Perryman MB. Source: J Renin Angiotensin Aldosterone Syst. 2003 March; 4(1): 27-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12692750

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Anomalous left coronary artery from the main pulmonary trunk: physiologic and clinical importance of its association with patent ductus arteriosus and pulmonary hypertension. Author(s): Kilic A, Elshershari H, Ozkutlu S. Source: Turk J Pediatr. 2002 October-December; 44(4): 363-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12458819

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Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? Author(s): Morris CR, Morris SM Jr, Hagar W, Van Warmerdam J, Claster S, KepkaLenhart D, Machado L, Kuypers FA, Vichinsky EP. Source: American Journal of Respiratory and Critical Care Medicine. 2003 July 1; 168(1): 63-9. Epub 2003 March 05. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12626350

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Asphyxia aggravates systemic hypotension but not pulmonary hypertension in piglets with meconium aspiration. Author(s): Aaltonen M, Soukka H, Halkola L, Jalonen J, Holopainen IE, Kero P, Kaapa PO. Source: Pediatric Research. 2003 March; 53(3): 473-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12595597

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Assessment of the vasodilator response in primary pulmonary hypertension. Comparing prostacyclin and iloprost administered by either infusion or inhalation. Author(s): Opitz CF, Wensel R, Bettmann M, Schaffarczyk R, Linscheid M, Hetzer R, Ewert R. Source: European Heart Journal. 2003 February; 24(4): 356-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12581683

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Association between hyperhomocysteinemia and primary pulmonary hypertension. Author(s): Arroliga AC, Sandur S, Jacobsen DW, Tewari S, Mustafa M, Mascha EJ, Robinson K. Source: Respiratory Medicine. 2003 July; 97(7): 825-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12854633

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Atrial septostomy for severe primary pulmonary hypertension - report on two cases. Author(s): Kurzyna M, Dabrowski M, Torbicki A, Burakowski J, Kuca P, Fijalkowska A, Sikora J. Source: Kardiologia Polska. 2003 January; 58(1): 27-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14502299

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Autoantibodies against B23, a nucleolar phosphoprotein, occur in scleroderma and are associated with pulmonary hypertension. Author(s): Ulanet DB, Wigley FM, Gelber AC, Rosen A. Source: Arthritis and Rheumatism. 2003 February 15; 49(1): 85-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12579598

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Background diseases in 671 patients with moderate to severe pulmonary hypertension. Author(s): Yigla M, Dabbah S, Azzam ZS, Rubin AH, Reisner SA. Source: Isr Med Assoc J. 2000 September; 2(9): 684-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11062769

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Balloon atrial septostomy in end-stage pulmonary hypertension guided by a novel intracardiac echocardiographic transducer. Author(s): Moscucci M, Dairywala IT, Chetcuti S, Mathew B, Li P, Rubenfire M, Vannan MA. Source: Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions. 2001 April; 52(4): 530-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11285613

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Balloon pulmonary angioplasty for treatment of chronic thromboembolic pulmonary hypertension. Author(s): Feinstein JA, Goldhaber SZ, Lock JE, Ferndandes SM, Landzberg MJ. Source: Circulation. 2001 January 2; 103(1): 10-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11136677

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Before predicting survival in children with pulmonary hypertension and congenital heart disease. Author(s): Berger RM, Geiger R, Meijboom FJ. Source: Journal of the American College of Cardiology. 1998 May; 31(6): 1447-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9581753

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Beraprost sodium for pulmonary hypertension with congenital heart disease. Author(s): Suzuki H, Sato S, Tanabe S, Hayasaka K. Source: Pediatrics International : Official Journal of the Japan Pediatric Society. 2002 October; 44(5): 528-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12225555

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Beta-blocker therapy in an infant with pulmonary hypertension. Author(s): Buchhorn R, Hulpke-Wette M, Wessel A, Bursch J. Source: European Journal of Pediatrics. 1999 December; 158(12): 1007-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10592082

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Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension. Author(s): Rubens C, Ewert R, Halank M, Wensel R, Orzechowski HD, Schultheiss HP, Hoeffken G. Source: Chest. 2001 November; 120(5): 1562-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11713135

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Bilateral leg edema, obesity, pulmonary hypertension, and obstructive sleep apnea. Author(s): Blankfield RP, Hudgel DW, Tapolyai AA, Zyzanski SJ. Source: Archives of Internal Medicine. 2000 August 14-28; 160(15): 2357-62. Erratum In: Arch Intern Med 2000 September 25; 160(17): 2650. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10927734

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Bilateral leg edema, pulmonary hypertension, and obstructive sleep apnea: a crosssectional study. Author(s): Blankfield RP, Zyzanski SJ. Source: The Journal of Family Practice. 2002 June; 51(6): 561-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12100781

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Bilateral lung transplantation with intra- and postoperatively prolonged ECMO support in patients with pulmonary hypertension. Author(s): Pereszlenyi A, Lang G, Steltzer H, Hetz H, Kocher A, Neuhauser P, Wisser W, Klepetko W. Source: European Journal of Cardio-Thoracic Surgery : Official Journal of the European Association for Cardio-Thoracic Surgery. 2002 May; 21(5): 858-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12062275

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Biochemical reaction products of nitric oxide as quantitative markers of primary pulmonary hypertension. Author(s): Kaneko FT, Arroliga AC, Dweik RA, Comhair SA, Laskowski D, Oppedisano R, Thomassen MJ, Erzurum SC. Source: American Journal of Respiratory and Critical Care Medicine. 1998 September; 158(3): 917-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9731026

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BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. Author(s): Humbert M, Deng Z, Simonneau G, Barst RJ, Sitbon O, Wolf M, Cuervo N, Moore KJ, Hodge SE, Knowles JA, Morse JH. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 September; 20(3): 518-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12358323

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BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Author(s): Machado RD, Pauciulo MW, Thomson JR, Lane KB, Morgan NV, Wheeler L, Phillips JA 3rd, Newman J, Williams D, Galie N, Manes A, McNeil K, Yacoub M, Mikhail G, Rogers P, Corris P, Humbert M, Donnai D, Martensson G, Tranebjaerg L, Loyd JE, Trembath RC, Nichols WC. Source: American Journal of Human Genetics. 2001 January; 68(1): 92-102. Epub 2000 December 12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11115378

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Bone morphogenetic protein receptor 2 mutations in pulmonary hypertension. Author(s): Morse JH. Source: Chest. 2002 March; 121(3 Suppl): 50S-53S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11893684

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Bone morphogenetic proteins, genetics and the pathophysiology of primary pulmonary hypertension. Author(s): De Caestecker M, Meyrick B. Source: Respiratory Research. 2001; 2(4): 193-7. Epub 2001 June 11. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11686884

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Bordetella pertussis infection causing pulmonary hypertension. Author(s): Casano P, Odena MP, Cambra FJ, Martin JM, Palomeque A. Source: Archives of Disease in Childhood. 2002 June; 86(6): 453. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12023188

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Bosentan for pulmonary hypertension. Author(s): Dietrich CG, Geier A, Lammert F. Source: The New England Journal of Medicine. 2002 July 25; 347(4): 292-4; Author Reply 292-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12141332

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Bosentan for pulmonary hypertension. Author(s): Pereira BN, Salvi S. Source: The New England Journal of Medicine. 2002 July 25; 347(4): 292-4; Author Reply 292-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12140310

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Bosentan treatment in patients with primary pulmonary hypertension receiving nonparenteral prostanoids. Author(s): Hoeper MM, Taha N, Bekjarova A, Gatzke R, Spiekerkoetter E. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2003 August; 22(2): 330-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12952269

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Bronchopulmonary shunts in patients with chronic thromboembolic pulmonary hypertension: evaluation with helical CT and MR imaging. Author(s): Ley S, Kreitner KF, Morgenstern I, Thelen M, Kauczor HU. Source: Ajr. American Journal of Roentgenology. 2002 November; 179(5): 1209-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12388501

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Cardiology patient page. Pulmonary hypertension. Author(s): Benisty JI. Source: Circulation. 2002 December 10; 106(24): E192-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12473565

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Cardio-pulmonary interactions at high altitude. Pulmonary hypertension as a common denominator. Author(s): Maggiorini M. Source: Advances in Experimental Medicine and Biology. 2003; 543: 177-89. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14713122

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Cardiopulmonary resuscitation in pulmonary hypertension. Author(s): Sandroni C, Maggiore SM, Proietti R. Source: American Journal of Respiratory and Critical Care Medicine. 2003 February 15; 167(4): 664-5; Author Reply 665. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12588717

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Cellular pathophysiology and therapy of pulmonary hypertension. Author(s): Olschewski H, Rose F, Grunig E, Ghofrani HA, Walmrath D, Schulz R, Schermuly R, Grimminger F, Seeger W. Source: The Journal of Laboratory and Clinical Medicine. 2001 December; 138(6): 367-77. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11753283

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Characterization of high-altitude pulmonary hypertension in the Kyrgyz: association with angiotensin-converting enzyme genotype. Author(s): Aldashev AA, Sarybaev AS, Sydykov AS, Kalmyrzaev BB, Kim EV, Mamanova LB, Maripov R, Kojonazarov BK, Mirrakhimov MM, Wilkins MR, Morrell NW. Source: American Journal of Respiratory and Critical Care Medicine. 2002 November 15; 166(10): 1396-402. Epub 2002 August 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12406857

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Chronic advanced pulmonary hypertension. Author(s): Takeda N, Kitahara K, Sumiyoshi T. Source: Intern Med. 2002 August; 41(8): 675. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12211543

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Chronic thromboembolic pulmonary hypertension. Author(s): Williamson TL, Kim NH, Rubin LJ. Source: Progress in Cardiovascular Diseases. 2002 November-December; 45(3): 203-12. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12525996

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Chronic thromboembolic pulmonary hypertension. Author(s): Fedullo PF, Auger WR, Kerr KM, Rubin LJ. Source: The New England Journal of Medicine. 2001 November 15; 345(20): 1465-72. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11794196

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Ciliochoroidal effusion and pulmonary hypertension in a patient with human immunodeficiency virus infection. Author(s): Dawson DG, Johnson MW. Source: Retina (Philadelphia, Pa.). 2001; 21(6): 672-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11756897

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Circulating monocytes from patients with primary pulmonary hypertension are hyporesponsive. Author(s): Raychaudhuri B, Bonfield TL, Malur A, Hague K, Kavuru MS, Arroliga AC, Thomassen MJ. Source: Clinical Immunology (Orlando, Fla.). 2002 August; 104(2): 191-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12165280

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Clinical and therapeutical follow-up of HIV-associated pulmonary hypertension: prospective study of 10 patients. Author(s): Recusani F, Di Matteo A, Gambarin F, D'Armini A, Klersy C, Campana C. Source: Aids (London, England). 2003 April; 17 Suppl 1: S88-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12870536

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Clinical manifestation of HIV-related pulmonary hypertension. Author(s): Petrosillo N, Pellicelli AM, Boumis E, Ippolito G. Source: Annals of the New York Academy of Sciences. 2001 November; 946: 223-35. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11762989

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Comparison of acute hemodynamic effects of aerosolized and intravenous iloprost in secondary pulmonary hypertension in children with congenital heart disease. Author(s): Hallioglu O, Dilber E, Celiker A. Source: The American Journal of Cardiology. 2003 October 15; 92(8): 1007-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14556887

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Comparison of survival in patients with pulmonary hypertension associated with fenfluramine to patients with primary pulmonary hypertension. Author(s): Rich S, Shillington A, McLaughlin V. Source: The American Journal of Cardiology. 2003 December 1; 92(11): 1366-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14636926

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Concurrent transcatheter closure of an apical muscular ventricular septal defect and a patent ductus arteriosus in a child with severe hyperkinetic pulmonary hypertension. Author(s): Joseph G, Muthunayagam JV, Mandalay A. Source: Pediatric Cardiology. 2003 January-February; 24(1): 47-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12574978

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Continuous positive airway pressure normalizes pulmonary artery pressures in subjects with obstructive sleep apnea and pulmonary hypertension. Author(s): Blankfield RP. Source: American Journal of Respiratory and Critical Care Medicine. 2003 January 1; 167(1): 94; Author Reply 94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12502485

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Current and emerging therapy for primary pulmonary hypertension. Author(s): Pass SE, Dusing ML. Source: The Annals of Pharmacotherapy. 2002 September; 36(9): 1414-23. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12196062

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Current management of primary pulmonary hypertension. Author(s): De Backer TL, Smedema JP, Carlier SG. Source: Biodrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy. 2001; 15(12): 801-17. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11784212

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Current management of primary pulmonary hypertension. Author(s): Klings ES, Farber HW. Source: Drugs. 2001; 61(13): 1945-56. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11708765

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Cyclooxygenase-2 acts as an endogenous brake on endothelin-1 release by human pulmonary artery smooth muscle cells: implications for pulmonary hypertension. Author(s): Wort SJ, Woods M, Warner TD, Evans TW, Mitchell JA. Source: Molecular Pharmacology. 2002 November; 62(5): 1147-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12391278

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Daytime pulmonary hypertension in patients with obstructive sleep apnea: the effect of continuous positive airway pressure on pulmonary hemodynamics. Author(s): Alchanatis M, Tourkohoriti G, Kakouros S, Kosmas E, Podaras S, Jordanoglou JB. Source: Respiration; International Review of Thoracic Diseases. 2001; 68(6): 566-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11786710

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Decreased sialic acid content of plasma von Willebrand factor in precapillary pulmonary hypertension. Author(s): Lopes AA, Ferraz de Souza B, Maeda NY. Source: Thrombosis and Haemostasis. 2000 May; 83(5): 683-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10823262

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Decreased surfactant proteins in lambs with pulmonary hypertension secondary to increased blood flow. Author(s): Gutierrez JA, Parry AJ, McMullan DM, Chapin CJ, Fineman JR. Source: American Journal of Physiology. Lung Cellular and Molecular Physiology. 2001 November; 281(5): L1264-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11597919

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Delayed-onset sensorineural hearing loss in a 3-year-old survivor of persistent pulmonary hypertension of the newborn. Author(s): Hutchin ME, Gilmer C, Yarbrough WG. Source: Archives of Otolaryngology--Head & Neck Surgery. 2000 August; 126(8): 1014-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10922237

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Deletion polymorphisms in the angiotensin converting enzyme gene are associated with pulmonary hypertension evoked by exercise challenge in patients with chronic obstructive pulmonary disease. Author(s): Kanazawa H, Okamoto T, Hirata K, Yoshikawa J. Source: American Journal of Respiratory and Critical Care Medicine. 2000 October; 162(4 Pt 1): 1235-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11029323

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Detectable serum cardiac troponin T as a marker of poor prognosis among patients with chronic precapillary pulmonary hypertension. Author(s): Torbicki A, Kurzyna M, Kuca P, Fijalkowska A, Sikora J, Florczyk M, Pruszczyk P, Burakowski J, Wawrzynska L. Source: Circulation. 2003 August 19; 108(7): 844-8. Epub 2003 Aug 04. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12900346

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Detection of Chlamydia pneumoniae in unexplained pulmonary hypertension. Author(s): Theegarten D, Anhenn O, Aretz S, Maass M, Mogilevski G. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 January; 19(1): 192-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11843318

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Determination of prostacyclin in plasma through a bioluminescent immunoassay for 6-keto-prostaglandin F1alpha: implication of dosage in patients with primary pulmonary hypertension. Author(s): Desai UA, Deo SK, Hyland KV, Poon M, Daunert S. Source: Analytical Chemistry. 2002 August 1; 74(15): 3892-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12175181

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Development of a noninvasive ultrasound color M-mode means of estimating pulmonary vascular resistance in pediatric pulmonary hypertension: mathematical analysis, in vitro validation, and preliminary clinical studies. Author(s): Shandas R, Weinberg C, Ivy DD, Nicol E, DeGroff CG, Hertzberg J, ValdesCruz L. Source: Circulation. 2001 August 21; 104(8): 908-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11514378

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Diagnosis and evaluation of pulmonary hypertension. Author(s): Budev MM, Arroliga AC, Jennings CA. Source: Cleve Clin J Med. 2003 April; 70 Suppl 1: S9-17. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12716138

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Diagnosis and management of primary pulmonary hypertension. Author(s): Krishnan U. Source: Indian J Pediatr. 2000 March; 67(3 Suppl): S41-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11129920

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Diagnosis and management of primary pulmonary hypertension. Author(s): Krishnan U. Source: Indian J Pediatr. 2000 July; 67(7): 523-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10957838

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Diagnosis and treatment of pulmonary hypertension. Author(s): Nauser TD, Stites SW. Source: American Family Physician. 2001 May 1; 63(9): 1789-98. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11352291

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Diagnosis and treatment of severe pediatric pulmonary hypertension. Author(s): Ivy D. Source: Cardiology in Review. 2001 July-August; 9(4): 227-37. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11405903

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Differential vasoactive response to endothelin receptor antagonists and prostacyclin in patients with severe pulmonary hypertension. Author(s): Apostolopoulou SC, Kourgiannidis G, Manginas A, Kyriakides ZS, Webb DJ, Rammos S, Kremastinos DT, Cokkinos DV. Source: Clinical Science (London, England : 1979). 2002 August; 103 Suppl 48: 298S-301S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12193108

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Diffusion capacity and haemodynamics in primary and chronic thromboembolic pulmonary hypertension. Author(s): Steenhuis LH, Groen HJ, Koeter GH, van der Mark TW. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2000 August; 16(2): 276-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10968503

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Disrupted pulmonary vascular development and pulmonary hypertension in transgenic mice overexpressing transforming growth factor-alpha. Author(s): Le Cras TD, Hardie WD, Fagan K, Whitsett JA, Korfhagen TR. Source: American Journal of Physiology. Lung Cellular and Molecular Physiology. 2003 November; 285(5): L1046-54. Epub 2003 August 01. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12896876

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Distribution of obstructive intimal lesions and their cellular phenotypes in chronic pulmonary hypertension. A morphometric and immunohistochemical study. Author(s): Yi ES, Kim H, Ahn H, Strother J, Morris T, Masliah E, Hansen LA, Park K, Friedman PJ. Source: American Journal of Respiratory and Critical Care Medicine. 2000 October; 162(4 Pt 1): 1577-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11029379

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Does inhaled nitric oxide improve survival in operated congenital disease with severe pulmonary hypertension? Author(s): Sharma R, Raizada N, Choudhary SK, Bhan A, Kumar P, Juneja R, Kothari SS, Saxena A, Venugopal P. Source: Indian Heart J. 2001 January-February; 53(1): 48-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11456141

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Doppler-derived mitral and pulmonary venous flow variables are predictors of pulmonary hypertension in dilated cardiomyopathy. Author(s): Dini FL, Nuti R, Barsotti L, Baldini U, Dell'Anna R, Micheli G. Source: Echocardiography (Mount Kisco, N.Y.). 2002 August; 19(6): 457-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12356340

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Echocardiographic assessment of overt or latent unexplained pulmonary hypertension. Author(s): Bossone E, Chessa M, Butera G, Carbone GL, Bodini BD, Mazza E, Ballotta A. Source: The Canadian Journal of Cardiology. 2003 April; 19(5): 544-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12717490

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Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Author(s): Arcasoy SM, Christie JD, Ferrari VA, Sutton MS, Zisman DA, Blumenthal NP, Pochettino A, Kotloff RM. Source: American Journal of Respiratory and Critical Care Medicine. 2003 March 1; 167(5): 735-40. Epub 2002 December 12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12480614

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Effect of nitroglycerin inhalation on patients with pulmonary hypertension undergoing mitral valve replacement surgery. Author(s): Yurtseven N, Karaca P, Kaplan M, Ozkul V, Tuygun AK, Aksoy T, Canik S, Kopman E. Source: Anesthesiology. 2003 October; 99(4): 855-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14508317

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Effect of orally active prostacyclin analogue on survival in patients with chronic thromboembolic pulmonary hypertension without major vessel obstruction. Author(s): Ono F, Nagaya N, Okumura H, Shimizu Y, Kyotani S, Nakanishi N, Miyatake K. Source: Chest. 2003 May; 123(5): 1583-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12740277

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Effects and problems of continuous infusion of epoprostenol for patients with primary pulmonary hypertension. Author(s): Takahashi T, Sakuma M, Ikeda J, Nawata J, Demachi J, Kitamukai O, Shirato K. Source: Intern Med. 2002 October; 41(10): 784-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12412996

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Effects of cilazapril on endothelial function and pulmonary hypertension in patients with congestive heart failure. Author(s): Tavli T, Gocer H. Source: Japanese Heart Journal. 2002 November; 43(6): 667-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12558130

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Effects of epoprostenol on right ventricular hypertrophy and dilatation in pulmonary hypertension. Author(s): Roeleveld RJ, Vonk-Noordegraaf A, Marcus JT, Bronzwaer JG, Marques KM, Postmus PE, Boonstra A. Source: Chest. 2004 February; 125(2): 572-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14769740

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Effects of inhaled salbutamol in primary pulmonary hypertension. Author(s): Spiekerkoetter E, Fabel H, Hoeper MM. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 September; 20(3): 524-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12358324

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Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension. Author(s): McLaughlin VV, Gaine SP, Barst RJ, Oudiz RJ, Bourge RC, Frost A, Robbins IM, Tapson VF, McGoon MD, Badesch DB, Sigman J, Roscigno R, Blackburn SD, Arneson C, Rubin LJ, Rich S; Treprostinil Study Group. Source: Journal of Cardiovascular Pharmacology. 2003 February; 41(2): 293-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12548091

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Emergent pulmonary thromboendarterectomy with percutaneous cardiopulmonary support system for chronic thromboembolic pulmonary hypertension. Author(s): Kitamura T, Morota T, Takamoto S. Source: European Journal of Cardio-Thoracic Surgery : Official Journal of the European Association for Cardio-Thoracic Surgery. 2003 October; 24(4): 656-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14500096

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Emerging therapies for pulmonary hypertension: striving for efficacy and safety. Author(s): Kao PN, Faul JL. Source: Journal of the American College of Cardiology. 2003 June 18; 41(12): 2126-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12821235

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Endothelial dysfunction associated with chronic intravascular coagulation in secondary pulmonary hypertension. Author(s): Lopes AA, Caramuru LH, Maeda NY. Source: Clinical and Applied Thrombosis/Hemostasis : Official Journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2002 October; 8(4): 353-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12516685

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Endothelial dysfunction in pulmonary hypertension. Author(s): Budhiraja R, Tuder RM, Hassoun PM. Source: Circulation. 2004 January 20; 109(2): 159-65. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14734504

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Endothelin-1 and functional tissue factor: a possible relationship with severity in primary pulmonary hypertension. Author(s): Collados MT, Velazquez B, Borbolla JR, Sandoval J, Masso F, Montano LF, Guarner V. Source: Heart and Vessels. 2003 March; 18(1): 12-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12644876

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Epoprostenol therapy as a bridge to pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension. Author(s): Kerr KM, Rubin LJ. Source: Chest. 2003 February; 123(2): 319-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12576339

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Epoprostenol therapy for primary pulmonary hypertension after rejection of a single donor lung. Author(s): Roeleveld RJ, Vonk Noordegraaf A, van der Bij W, Postmus PE, Boonstra A. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2003 January; 21(1): 192-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12570128

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Evaluation and management of pulmonary hypertension in systemic sclerosis. Author(s): Preston IR, Hill NS. Source: Current Opinion in Rheumatology. 2003 November; 15(6): 761-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14569207

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Evaluation of pulmonary hypertension in heart transplant candidates. Author(s): Natale ME, Pina IL. Source: Current Opinion in Cardiology. 2003 March; 18(2): 136-40. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12652220

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Expression of heme oxygenase-1 and endothelial nitric oxide synthase in the lung of newborns with congenital diaphragmatic hernia and persistent pulmonary hypertension. Author(s): Solari V, Piotrowska AP, Puri P. Source: Journal of Pediatric Surgery. 2003 May; 38(5): 808-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12720199

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Expression of human herpesvirus 8 in primary pulmonary hypertension. Author(s): Cool CD, Rai PR, Yeager ME, Hernandez-Saavedra D, Serls AE, Bull TM, Geraci MW, Brown KK, Routes JM, Tuder RM, Voelkel NF. Source: The New England Journal of Medicine. 2003 September 18; 349(12): 1113-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13679525

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Factor V Leiden and post thromboembolic pulmonary hypertension. Author(s): Naudziunas A, Miliauskas S. Source: Medicina (Kaunas, Lithuania). 2003; 39(12): 1171-4. English, Lithuanian. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14704505

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Factor V Leiden is not common in patients diagnosed with primary pulmonary hypertension. Author(s): Elliott CG, Leppert MF, Alexander GJ, Ward K, Nelson L, Pietra GG. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1998 November; 12(5): 1177-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9864017

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Failure of resting echocardiography and cardiac catheterization to identify pulmonary hypertension in two patients with type I Gaucher disease. Author(s): Sirrs S, Irving J, McCauley G, Gin K, Munt B, Pastores G, Mistry P. Source: Journal of Inherited Metabolic Disease. 2002 May; 25(2): 131-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12118528

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False-positive diagnosis of pulmonary hypertension by Doppler echocardiography. Author(s): Vachiery JL, Brimioulle S, Crasset V, Naeije R. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1998 December; 12(6): 1476-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9877511

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Familial persistent pulmonary hypertension of the newborn resulting from misalignment of the pulmonary vessels (congenital alveolar capillary dysplasia). Author(s): Vassal HB, Malone M, Petros AJ, Winter RM. Source: Journal of Medical Genetics. 1998 January; 35(1): 58-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9475097

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Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Author(s): Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ, Hodge SE, Knowles JA. Source: American Journal of Human Genetics. 2000 September; 67(3): 737-44. Epub 2000 July 20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10903931

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Familial primary pulmonary hypertension and associated ocular findings. Author(s): Saran BR, Brucker AJ, Bandello F, Verougstraete C. Source: Retina (Philadelphia, Pa.). 2001; 21(1): 34-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11217927

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Familial primary pulmonary hypertension locus mapped to chromosome 2q31-q32. Author(s): Morse JH, Jones AC, Barst RJ, Hodge SE, Wilhelmsen KC, Nygaard TG. Source: Chest. 1998 July; 114(1 Suppl): 57S-58S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9676630

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Familial primary pulmonary hypertension. Author(s): Shanmugasundaram S. Source: Indian Heart J. 2002 March-April; 54(2): 193-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12086385

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Fatal primary pulmonary hypertension in a 30-yr-old female with APECED syndrome. Author(s): Korniszewski L, Kurzyna M, Stolarski B, Torbicki A, Smerdel A, Ploski R. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2003 October; 22(4): 709-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14582926

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Fatal pulmonary hypertension associated with an atypical case of HunchinsonGilford progeria. Author(s): Shiraishi I, Hayashi S, Hirai E, Onouchi Z, Hamaoka K. Source: Pediatric Cardiology. 2001 November-December; 22(6): 530-3. Epub 2001 December 04. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11894164

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Fatal pulmonary hypertension associated with pertussis in infants: does extracorporeal membrane oxygenation have a role? Author(s): Halasa NB, Barr FE, Johnson JE, Edwards KM. Source: Pediatrics. 2003 December; 112(6 Pt 1): 1274-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14654596

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Fatal pulmonary hypertension associated with short-term use of fenfluramine and phentermine. Author(s): Mark EJ, Patalas ED, Chang HT, Evans RJ, Kessler SC. Source: The New England Journal of Medicine. 1997 August 28; 337(9): 602-6. Erratum In: N Engl J Med 1997 November 13; 337(20): 1483. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9271482

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Fine mapping of PPH1, a gene for familial primary pulmonary hypertension, to a 3cM region on chromosome 2q33. Author(s): Deng Z, Haghighi F, Helleby L, Vanterpool K, Horn EM, Barst RJ, Hodge SE, Morse JH, Knowles JA. Source: American Journal of Respiratory and Critical Care Medicine. 2000 March; 161(3 Pt 1): 1055-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10712363

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Fine specificity of anti-fibrillin-1 autoantibodies in primary pulmonary hypertension syndrome. Author(s): Morse JH, Antohi S, Kasturi K, Saito S, Fotino M, Humbert M, Simonneau G, Basst RJ, Bona CA. Source: Scandinavian Journal of Immunology. 2000 June; 51(6): 607-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10849372

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Frequency and prognostic significance of pericardial effusion in primary pulmonary hypertension. PPH Study Group. Primary pulmonary hypertension. Author(s): Hinderliter AL, Willis PW 4th, Long W, Clarke WR, Ralph D, Caldwell EJ, Williams W, Ettinger NA, Hill NS, Summer WR, de Biosblanc B, Koch G, Li S, Clayton LM, Jobsis MM, Crow JW. Source: The American Journal of Cardiology. 1999 August 15; 84(4): 481-4, A10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10468096

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Frequency and severity of tricuspid regurgitation determined by Doppler echocardiography in primary pulmonary hypertension. Author(s): Hinderliter AL, Willis PW 4th, Long WA, Clarke WR, Ralph D, Caldwell EJ, Williams W, Ettinger NA, Hill NS, Summer WR, de Boisblanc B, Koch G, Li S, Clayton LM, Jobsis MM, Crow JW; PPH Study Group. Source: The American Journal of Cardiology. 2003 April 15; 91(8): 1033-7, A9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12686360

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Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Author(s): Launay JM, Herve P, Peoc'h K, Tournois C, Callebert J, Nebigil CG, Etienne N, Drouet L, Humbert M, Simonneau G, Maroteaux L. Source: Nature Medicine. 2002 October; 8(10): 1129-35. Epub 2002 September 16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12244304

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Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Author(s): Rudarakanchana N, Flanagan JA, Chen H, Upton PD, Machado R, Patel D, Trembath RC, Morrell NW. Source: Human Molecular Genetics. 2002 June 15; 11(13): 1517-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12045205

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Functional heterogeneity of bone morphogenetic protein receptor-II mutants found in patients with primary pulmonary hypertension. Author(s): Nishihara A, Watabe T, Imamura T, Miyazono K. Source: Molecular Biology of the Cell. 2002 September; 13(9): 3055-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12221115

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Gadolinium chloride inhibits pulmonary macrophage influx and prevents O(2)induced pulmonary hypertension in the neonatal rat. Author(s): Jankov RP, Luo X, Belcastro R, Copland I, Frndova H, Lye SJ, Hoidal JR, Post M, Tanswell AK. Source: Pediatric Research. 2001 August; 50(2): 172-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11477200

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Gas exchange detection of exercise-induced right-to-left shunt in patients with primary pulmonary hypertension. Author(s): Sun XG, Hansen JE, Oudiz RJ, Wasserman K. Source: Circulation. 2002 January 1; 105(1): 54-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11772876

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Gas exchange responses to continuous incremental cycle ergometry exercise in primary pulmonary hypertension in humans. Author(s): Riley MS, Porszasz J, Engelen MP, Brundage BH, Wasserman K. Source: European Journal of Applied Physiology. 2000 September; 83(1): 63-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11072775

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Gene expression patterns in the lungs of patients with primary pulmonary hypertension: a gene microarray analysis. Author(s): Geraci MW, Moore M, Gesell T, Yeager ME, Alger L, Golpon H, Gao B, Loyd JE, Tuder RM, Voelkel NF. Source: Circulation Research. 2001 March 30; 88(6): 555-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11282888

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Gene expression profiles in pulmonary hypertension. Author(s): Geraci MW, Hoshikawa Y, Yeager M, Golpon H, Gesell T, Tuder RM, Voelkel NF. Source: Chest. 2002 March; 121(3 Suppl): 104S-105S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11893725

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Gene for familial primary pulmonary hypertension identified. Author(s): SoRelle R. Source: Circulation. 2000 August 8; 102(6): E9010-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10950623

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Gene for primary pulmonary hypertension identified. Author(s): McCarthy M. Source: Lancet. 2000 August 5; 356(9228): 489. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10981899

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Gene mutation linked to primary pulmonary hypertension. Author(s): Cockey CD. Source: Awhonn Lifelines / Association of Women's Health, Obstetric and Neonatal Nurses. 2000 October-November; 4(5): 17-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11898153

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Gene polymorphisms of endothelial nitric oxide synthase enzyme associated with pulmonary hypertension in patients with COPD. Author(s): Yildiz P, Oflaz H, Cine N, Erginel-Unaltuna N, Erzengin F, Yilmaz V. Source: Respiratory Medicine. 2003 December; 97(12): 1282-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14682408

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Gene transfer and metabolic modulators as new therapies for pulmonary hypertension. Increasing expression and activity of potassium channels in rat and human models. Author(s): Michelakis ED, Dyck JR, McMurtry MS, Wang S, Wu XC, Moudgil R, Hashimoto K, Puttagunta L, Archer SL. Source: Advances in Experimental Medicine and Biology. 2001; 502: 401-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11950153

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Gene transfer of human prostacyclin synthase ameliorates monocrotaline-induced pulmonary hypertension in rats. Author(s): Nagaya N, Yokoyama C, Kyotani S, Shimonishi M, Morishita R, Uematsu M, Nishikimi T, Nakanishi N, Ogihara T, Yamagishi M, Miyatake K, Kaneda Y, Tanabe T. Source: Circulation. 2000 October 17; 102(16): 2005-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11034952

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Genetic and molecular mechanisms of pulmonary hypertension. Author(s): Morrell NW, Wilkins MR. Source: Clinical Medicine (London, England). 2001 March-April; 1(2): 138-45. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11333460

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Genetic clues to the cause of primary pulmonary hypertension. Author(s): Loscalzo J. Source: The New England Journal of Medicine. 2001 August 2; 345(5): 367-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11484696

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Genetics and immunogenetic aspects of primary pulmonary hypertension. Author(s): Barst RJ, Loyd JE. Source: Chest. 1998 September; 114(3 Suppl): 231S-236S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9741574

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Genetics and pulmonary hypertension. Author(s): Loyd JE. Source: Chest. 2002 December; 122(6 Suppl): 284S-286S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12475800

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Genetics of primary pulmonary hypertension. Author(s): Thomas AQ, Gaddipati R, Newman JH, Loyd JE. Source: Clinics in Chest Medicine. 2001 September; 22(3): 477-91, Ix. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11590842

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Genetics of pulmonary hypertension: from bench to bedside. Author(s): Humbert M, Trembath RC. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 September; 20(3): 741-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12358355

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Genomic approaches to research in pulmonary hypertension. Author(s): Geraci MW, Gao B, Hoshikawa Y, Yeager ME, Tuder RM, Voelkel NF. Source: Respiratory Research. 2001; 2(4): 210-5. Epub 2001 May 01. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11686886

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Graded balloon atrial septostomy in severe pulmonary hypertension. Author(s): Tandon R. Source: Indian Heart J. 2002 May-June; 54(3): 326; Author Reply 326. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12216938

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Graded balloon atrial septostomy in severe pulmonary hypertension. Author(s): Kothari SS, Yusuf A, Juneja R, Yadav R, Naik N. Source: Indian Heart J. 2002 March-April; 54(2): 164-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12086379

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Haemodynamic evaluation of pulmonary hypertension. Author(s): Chemla D, Castelain V, Herve P, Lecarpentier Y, Brimioulle S. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 November; 20(5): 1314-31. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12449189

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Heart-lung transplantation for severe pulmonary hypertension with severe heart failure: presentation of four cases. Author(s): Wang SS, Chou NK, Hsu RB, Chen YS, Ko WJ, Yu HY, Chu SH, Lee YC, Liau CS, Lee YT. Source: Transplantation Proceedings. 2003 February; 35(1): 450-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12591483

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Heart-lung transplantation is the method of choice in the treatment of patients with end-stage pulmonary hypertension. Author(s): Franke UF, Wahlers T, Wittwer T, Franke T, Niedermeyer J, Harringer W, Haverich A. Source: Transplantation Proceedings. 2002 September; 34(6): 2181-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12270357

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Hemodynamic and hormonal effects of beraprost sodium, an orally active prostacyclin analogue, in patients with secondary precapillary pulmonary hypertension. Author(s): Ono F, Nagaya N, Kyotani S, Oya H, Nakanishi N, Miyatake K. Source: Circulation Journal : Official Journal of the Japanese Circulation Society. 2003 May; 67(5): 375-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12736472

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Hemodynamic effects of aerosolized iloprost in pulmonary hypertension at rest and during exercise. Author(s): Blumberg FC, Riegger GA, Pfeifer M. Source: Chest. 2002 May; 121(5): 1566-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12006445

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Hemodynamic effects of inhaled nitric oxide using pulse delivery and continuous delivery systems in pulmonary hypertension. Author(s): Kitamukai O, Sakuma M, Takahashi T, Nawata J, Ikeda J, Shirato K. Source: Intern Med. 2002 June; 41(6): 429-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12135173

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Hemodynamic monitoring during sexual intercourse and physical exercise in a patient with chronic heart failure and pulmonary hypertension. Author(s): Cremers B, Kjellstrom B, Sudkamp M, Bohm M. Source: The American Journal of Medicine. 2002 April 1; 112(5): 428-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11904125

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Hemodynamic response to sildenafil, nitric oxide, and iloprost in primary pulmonary hypertension. Author(s): Leuchte HH, Schwaiblmair M, Baumgartner RA, Neurohr CF, Kolbe T, Behr J. Source: Chest. 2004 February; 125(2): 580-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14769741

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Hemolytic anemia-associated pulmonary hypertension of sickle cell disease and the nitric oxide/arginine pathway. Author(s): Jison ML, Gladwin MT. Source: American Journal of Respiratory and Critical Care Medicine. 2003 July 1; 168(1): 3-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12826592

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Heterotaxy syndrome with severe pulmonary hypertension in an adult. Author(s): Brandenburg VM, Krueger S, Haage P, Mertens P, Riehl J. Source: Southern Medical Journal. 2002 May; 95(5): 536-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12005012

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HHV-8 in pulmonary hypertension. Author(s): Henke-Gendo C, Schulz TF, Hoeper MM. Source: The New England Journal of Medicine. 2004 January 8; 350(2): 194-5; Author Reply 194-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14711924

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High levels of nitric oxide in individuals with pulmonary hypertension receiving epoprostenol therapy. Author(s): Ozkan M, Dweik RA, Laskowski D, Arroliga AC, Erzurum SC. Source: Lung. 2001; 179(4): 233-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11891614

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HIV-associated pulmonary hypertension. Author(s): Farber HW. Source: Aids Clin Care. 2001 June; 13(6): 53-5, 59. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11710309

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HIV-associated pulmonary hypertension: diagnosis and treatment. Author(s): Burkart KM, Farber HW. Source: Adv Cardiol. 2003; 40: 197-207. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14533555

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How common is severe pulmonary hypertension after pediatric cardiac surgery? Author(s): Lindberg L, Olsson AK, Jogi P, Jonmarker C. Source: The Journal of Thoracic and Cardiovascular Surgery. 2002 June; 123(6): 1155-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12063463

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Hybrid cell-gene therapy for pulmonary hypertension based on phagocytosing action of endothelial progenitor cells. Author(s): Nagaya N, Kangawa K, Kanda M, Uematsu M, Horio T, Fukuyama N, Hino J, Harada-Shiba M, Okumura H, Tabata Y, Mochizuki N, Chiba Y, Nishioka K, Miyatake K, Asahara T, Hara H, Mori H. Source: Circulation. 2003 August 19; 108(7): 889-95. Epub 2003 June 30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12835224

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Hyperplasia of pulmonary artery smooth muscle cells is causally related to overexpression of the serotonin transporter in primary pulmonary hypertension. Author(s): Eddahibi S, Humbert M, Fadel E, Raffestin B, Darmon M, Capron F, Simonneau G, Dartevelle P, Hamon M, Adnot S. Source: Chest. 2002 March; 121(3 Suppl): 97S-98S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11893722

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Hyperthyroidism and pulmonary hypertension. Author(s): Marvisi M, Brianti M, Marani G, Del Borello R, Bortesi ML, Guariglia A. Source: Respiratory Medicine. 2002 April; 96(4): 215-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11999999

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Hypothyroidism and primary pulmonary hypertension. Author(s): Kashyap AS, Kashyap S. Source: Circulation. 2001 November 13; 104(20): E103. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11705834

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Hypoxia and altered platelet behavior influence von Willebrand factor multimeric composition in secondary pulmonary hypertension. Author(s): Caramuru LH, Soares Rde P, Maeda NY, Lopes AA. Source: Clinical and Applied Thrombosis/Hemostasis : Official Journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2003 July; 9(3): 251-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14507115

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Iloprost improves hemodynamics in patients with severe chronic cardiac failure and secondary pulmonary hypertension. Author(s): Sablotzki A, Czeslick E, Schubert S, Friedrich I, Muhling J, Dehne MG, Grond S, Hentschel T. Source: Canadian Journal of Anaesthesia = Journal Canadien D'anesthesie. 2002 December; 49(10): 1076-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12477682

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Images in congenital heart disease. Reversal of shunting in pulmonary hypertension after treatment with oral Sildenafil. Author(s): Karatza AA, Bush A, Magee AG. Source: Cardiology in the Young. 2002 December; 12(6): 561-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12636006

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Increase in thrombomodulin concentrations after pulmonary thromboendarterectomy in chronic thromboembolic pulmonary hypertension. Author(s): Sakamaki F, Kyotani S, Nagaya N, Sato N, Oya H, Nakanishi N. Source: Chest. 2003 October; 124(4): 1305-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14555559

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Increased superoxide generation is associated with pulmonary hypertension in fetal lambs: a role for NADPH oxidase. Author(s): Brennan LA, Steinhorn RH, Wedgwood S, Mata-Greenwood E, Roark EA, Russell JA, Black SM. Source: Circulation Research. 2003 April 4; 92(6): 683-91. Epub 2003 February 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12609968

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Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway. Author(s): Sullivan CC, Du L, Chu D, Cho AJ, Kido M, Wolf PL, Jamieson SW, Thistlethwaite PA. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 October 14; 100(21): 12331-6. Epub 2003 September 25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14512515

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Infection-induced pulmonary hypertension crisis after Rastelli procedure. Author(s): Katoh Y, Nakajima Y, Yamagishi M, Mizobe T. Source: Paediatric Anaesthesia. 2003 June; 13(5): 461-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12791125

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Influence of inhaled iloprost on transpulmonary gradient of big endothelin in patients with pulmonary hypertension. Author(s): Wilkens H, Bauer M, Forestier N, Konig J, Eichler A, Schneider S, Schafers HJ, Sybrecht GW. Source: Circulation. 2003 March 25; 107(11): 1509-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12654608

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Inhaled epoprostenol (prostacyclin) and pulmonary hypertension before cardiac surgery. Author(s): Hache M, Denault A, Belisle S, Robitaille D, Couture P, Sheridan P, Pellerin M, Babin D, Noel N, Guertin MC, Martineau R, Dupuis J. Source: The Journal of Thoracic and Cardiovascular Surgery. 2003 March; 125(3): 642-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12658208

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Inhaled ethyl nitrite gas for persistent pulmonary hypertension in infants. Author(s): Abman SH, Kinsella JP. Source: Lancet. 2002 December 21-28; 360(9350): 2076-7; Author Reply 2077. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12504430

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Inhaled iloprost in patients with chronic thromboembolic pulmonary hypertension: effects before and after pulmonary thromboendarterectomy. Author(s): Kramm T, Eberle B, Krummenauer F, Guth S, Oelert H, Mayer E. Source: The Annals of Thoracic Surgery. 2003 September; 76(3): 711-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12963183

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Inhaled nitric oxide for perioperative management of an adult patient with atrial septal defect and severe pulmonary hypertension. Author(s): Kim JH, Ham BM, Kim YL, Ahn H, Noh CI. Source: Journal of Cardiothoracic and Vascular Anesthesia. 2002 December; 16(6): 746-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12486659

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Inhaled nitric oxide for persistent pulmonary hypertension in a neonate with pulmonary atresia and intact ventricular septum after radiofrequency valvulotomy, balloon valvuloplasty and Blalock-Taussig shunt. Author(s): Lee ML, Chiu IS. Source: International Journal of Cardiology. 2003 February; 87(2-3): 273-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12559550

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Inhaled nitric oxide in persistent pulmonary hypertension of the newborn: four-year experience in a single medical center. Author(s): Su BH, Lin TW, Lin HC, Tsai FJ, Peng CT. Source: Acta Paediatr Taiwan. 2002 September-October; 43(5): 259-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12607481

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Inhaled prostacyclin for the treatment of pulmonary hypertension after cardiac surgery. Author(s): Lowson SM, Doctor A, Walsh BK, Doorley PA. Source: Critical Care Medicine. 2002 December; 30(12): 2762-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12483070

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Insights into the genetic and molecular basis of primary pulmonary hypertension. Author(s): Trembath RC, Harrison R. Source: Pediatric Research. 2003 June; 53(6): 883-8. Epub 2003 March 05. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12621102

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Intermittent epoprostenol infusions in systemic lupus erythematosus associated pulmonary hypertension--a series of three cases. Author(s): Kong KO, Badsha H, Thumboo J, Chng HH. Source: Ann Acad Med Singapore. 2003 January; 32(1): 118-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12625109

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Intraoperative inhalation of the long-acting prostacyclin analog iloprost for pulmonary hypertension. Author(s): Langer F, Wilhelm W, Tscholl D, Schramm R, Lausberg H, Wendler O, Schafers HJ. Source: The Journal of Thoracic and Cardiovascular Surgery. 2003 September; 126(3): 874-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14502175

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Intraoperative management of severe pulmonary hypertension during cardiac surgery with inhaled iloprost. Author(s): Rex S, Busch T, Vettelschoss M, de Rossi L, Rossaint R, Buhre W. Source: Anesthesiology. 2003 September; 99(3): 745-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12960562

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Intravascular ultrasound of the elastic pulmonary arteries: a new approach for the evaluation of primary pulmonary hypertension. Author(s): Rodes-Cabau J, Domingo E, Roman A, Majo J, Lara B, Padilla F, Anivarro I, Angel J, Tardif JC, Soler-Soler J. Source: Heart (British Cardiac Society). 2003 March; 89(3): 311-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12591838

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Pulmonary Hypertension

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Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn? Author(s): Hartigan D. Source: Archives of Disease in Childhood. 2003 January; 88(1): 84. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12495975

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Janus face of vascular endothelial growth factor: the obligatory survival factor for lung vascular endothelium controls precapillary artery remodeling in severe pulmonary hypertension. Author(s): Voelkel NF, Cool C, Taraceviene-Stewart L, Geraci MW, Yeager M, Bull T, Kasper M, Tuder RM. Source: Critical Care Medicine. 2002 May; 30(5 Suppl): S251-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12004244

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khree-dimensional contrast-enhanced magnetic resonance angiography in a patient with chronic thromboembolic pulmonary hypertension before and after thromboendarterectomy. Author(s): Kreitner KF, Mayer E, Voigtlaender T, Thelen M, Oelert H. Source: Circulation. 1999 March 2; 99(8): 1101. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10051306

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KRN2391: dual action on rat pulmonary artery and no loss of potency in pulmonary hypertension. Author(s): Wanstall JC, Gambino A, Thomas BJ. Source: Clinical and Experimental Pharmacology & Physiology. 2000 April; 27(4): 28894. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10779127

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Lack of association between angiotensin converting enzyme (ACE) genotype, serum ACE activity, and haemodynamics in patients with primary pulmonary hypertension. Author(s): Hoeper MM, Tacacs A, Stellmacher U, Lichtinghagen R. Source: Heart (British Cardiac Society). 2003 April; 89(4): 445-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12639879

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Left ventricular dysfunction, pulmonary hypertension, obesity, and sleep apnea. Author(s): Blankfield RP, Tapolyai AA, Zyzanski SJ. Source: Sleep & Breathing = Schlaf & Atmung. 2001 June; 5(2): 57-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11868142

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93

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Lessons to be learned: a case study approach a case study of the temporal onset of pulmonary hypertension with pre-existent cirrhotic portal hypertension. Author(s): D'Souza R, MacFadyen RJ, Kerr F, Peacock A, Steven MM. Source: J R Soc Health. 2001 December; 121(4): 257-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11811097

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Linkage analysis in a large family with primary pulmonary hypertension: genetic heterogeneity and a second primary pulmonary hypertension locus on 2q31-32. Author(s): Janssen B, Rindermann M, Barth U, Miltenberger-Miltenyi G, Mereles D, Abushi A, Seeger W, Kubler W, Bartram CR, Grunig E. Source: Chest. 2002 March; 121(3 Suppl): 54S-56S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11893685

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Linking a serotonin transporter polymorphism to vascular smooth muscle proliferation in patients with primary pulmonary hypertension. Author(s): Rabinovitch M. Source: The Journal of Clinical Investigation. 2001 October; 108(8): 1109-11. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11602617

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Living-donor lobar lung transplantation for primary pulmonary hypertension in an adult. Author(s): Date H, Nagahiro I, Aoe M, Matsubara H, Kusano K, Goto K, Shimizu N. Source: The Journal of Thoracic and Cardiovascular Surgery. 2001 October; 122(4): 817-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11581620

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Living-donor single-lobe lung transplantation for primary pulmonary hypertension in a child. Author(s): Date H, Sano Y, Aoe M, Matsubara H, Kusano K, Goto K, Tedoriya T, Shimizu N. Source: The Journal of Thoracic and Cardiovascular Surgery. 2002 June; 123(6): 1211-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12063472

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Long term inhalation of iloprost in a child with primary pulmonary hypertension: an alternative to continuous infusion. Author(s): Beghetti M, Berner M, Rimensberger PC. Source: Heart (British Cardiac Society). 2001 September; 86(3): E10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11514501

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Pulmonary Hypertension

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Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. Author(s): Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Herve P, Rainisio M, Simonneau G. Source: Journal of the American College of Cardiology. 2002 August 21; 40(4): 780-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12204511

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Long-term treatment of pulmonary hypertension with aerosolized iloprost. Author(s): Saba T, Peacock AJ. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2001 July; 18(1): 247. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11510800

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Long-term treatment with sildenafil in a thalassemic patient with pulmonary hypertension. Author(s): Littera R, La Nasa G, Derchi G, Cappellini MD, Chang CY, Contu L. Source: Blood. 2002 August 15; 100(4): 1516-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12184280

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Low-dose nitric oxide therapy for persistent pulmonary hypertension: 1-year followup. Author(s): Clark RH, Huckaby JL, Kueser TJ, Walker MW, Southgate WM, Perez JA, Roy BJ, Keszler M; Clinical Inhaled Nitric Oxide Research Group. Source: Journal of Perinatology : Official Journal of the California Perinatal Association. 2003 June; 23(4): 300-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12774137

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Low-dose vasopressin infusion can be an alternative in treating patients with refractory septic shock combined with chronic pulmonary hypertension--a case report. Author(s): Wang HJ, Wong CS, Chiang CY, Yeh CC, Cherng CH, Ho ST, Wu CT. Source: Acta Anaesthesiol Sin. 2003 June; 41(2): 77-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12934421

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Low-dose, single-fraction, whole-lung radiotherapy for pulmonary hypertension associated with myelofibrosis with myeloid metaplasia. Author(s): Steensma DP, Hook CC, Stafford SL, Tefferi A. Source: British Journal of Haematology. 2002 September; 118(3): 813-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12181050

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Lung and heart-lung transplant practice patterns in pulmonary hypertension centers. Author(s): Pielsticker EJ, Martinez FJ, Rubenfire M. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2001 December; 20(12): 1297-304. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11744413

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Lung cGMP release subsequent to NO inhalation in pulmonary hypertension: responders versus nonresponders. Author(s): Ghofrani HA, Wiedemann R, Rose F, Weissmann N, Schermuly RT, Quanz K, Grimminger F, Seeger W, Olschewski H. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 April; 19(4): 664-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11998996

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Lung impairment following cardiac surgery in patients with pulmonary hypertension. Author(s): Ishikawa S, Ohtaki A, Takahashi T, Ohki S, Hasegawa Y, Yamagishi T, Oshima K, Hamada Y, Sakata K, Morishita Y. Source: The Journal of Cardiovascular Surgery. 2002 February; 43(1): 7-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11803320

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Lung overexpression of angiostatin aggravates pulmonary hypertension in chronically hypoxic mice. Author(s): Pascaud MA, Griscelli F, Raoul W, Marcos E, Opolon P, Raffestin B, Perricaudet M, Adnot S, Eddahibi S. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 October; 29(4): 449-57. Epub 2003 April 24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12714372

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Lung transplantation for primary and secondary pulmonary hypertension. Author(s): Conte JV, Borja MJ, Patel CB, Yang SC, Jhaveri RM, Orens JB. Source: The Annals of Thoracic Surgery. 2001 November; 72(5): 1673-9; Discussion 167980. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11722064

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Lung transplantation for primary pulmonary hypertension. Author(s): Trulock EP. Source: Clinics in Chest Medicine. 2001 September; 22(3): 583-93. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11590850

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Malignant infantile osteopetrosis and primary pulmonary hypertension: a new combination? Author(s): Kasow KA, Bonfim C, Asch J, Margolis DA, Jenkins J, Tamburro RF, Handgretinger R, Horwitz EM. Source: Pediatric Blood & Cancer. 2004 February; 42(2): 190-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14752886

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Management of pregnancy in women with pulmonary hypertension secondary to SLE and anti-phospholipid syndrome. Author(s): McMillan E, Martin WL, Waugh J, Rushton I, Lewis M, Clutton-Brock T, Townend JN, Kilby MD, Gordon C. Source: Lupus. 2002; 11(6): 392-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12139379

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Management of pulmonary hypertension resulting from interstitial lung disease. Author(s): Shapiro S. Source: Current Opinion in Pulmonary Medicine. 2003 September; 9(5): 426-30. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12904715

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Management of pulmonary hypertension: physiological and pharmacological considerations for anesthesiologists. Author(s): Fischer LG, Van Aken H, Burkle H. Source: Anesthesia and Analgesia. 2003 June; 96(6): 1603-16. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12760982

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Massive fetomaternal hemorrhage with persistent pulmonary hypertension in a neonate. Author(s): Parveen V, Patole SK, Whitehall JS. Source: Indian Pediatrics. 2002 April; 39(4): 385-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11976471

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Massive pulmonary artery thrombosis, pulmonary hypertension and untreated atrial septal defect. Author(s): Ishizaka N, Kage N, Iida H, Mutoh S, Hirata Y, Komuro I, Miyairi T, Kitamura T, Morota T, Takamoto S, Nagai R. Source: Cardiology. 2002; 97(1): 53-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11893832

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Mechanisms of pulmonary hypertension in Bordetella pertussis. Author(s): Peters MJ, Pierce CM, Klein NJ. Source: Archives of Disease in Childhood. 2003 January; 88(1): 92-3; Author Reply 92-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12495987

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Molecular and cellular basis of pulmonary vascular remodeling in pulmonary hypertension. Author(s): Jeffery TK, Morrell NW. Source: Progress in Cardiovascular Diseases. 2002 November-December; 45(3): 173-202. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12525995

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Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. Author(s): Harrison RE, Flanagan JA, Sankelo M, Abdalla SA, Rowell J, Machado RD, Elliott CG, Robbins IM, Olschewski H, McLaughlin V, Gruenig E, Kermeen F, Laitinen T, Morrell NW, Trembath RC, Halme M, Raisanen-Sokolowski A. Source: Journal of Medical Genetics. 2003 December; 40(12): 865-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14684682

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Multiple pulmonary emboli with pulmonary hypertension caused by effort thrombosis and effective balloon venoplasty of the subclavian vein. Author(s): Isaka N, Yamada N, Araki S, Onishi K, Motoyasu M, Okinaka T, Ito M, Nakano T. Source: Japanese Circulation Journal. 2001 October; 65(10): 920-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11665800

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Mutations of bone morphogenetic protein receptor type II are not found in patients with pulmonary hypertension and underlying connective tissue diseases. Author(s): Tew MB, Arnett FC, Reveille JD, Tan FK. Source: Arthritis and Rheumatism. 2002 October; 46(10): 2829-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12384956

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Neonatal pulmonary hypertension--urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. Author(s): Pearson DL, Dawling S, Walsh WF, Haines JL, Christman BW, Bazyk A, Scott N, Summar ML. Source: The New England Journal of Medicine. 2001 June 14; 344(24): 1832-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11407344

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Neurodevelopmental and medical outcomes of persistent pulmonary hypertension in term newborns treated with nitric oxide. Author(s): Lipkin PH, Davidson D, Spivak L, Straube R, Rhines J, Chang CT. Source: The Journal of Pediatrics. 2002 March; 140(3): 306-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11953727

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New and experimental therapies for pulmonary hypertension. Author(s): Channick RN, Rubin LJ. Source: Clinics in Chest Medicine. 2001 September; 22(3): 539-45. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11590847

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New combined treatments avoided transplantation in a child with severe pulmonary hypertension. Author(s): Beghetti M, Nicod L, Barazzone-Argiroffo C, Rimensberger PC. Source: Heart (British Cardiac Society). 2004 February; 90(2): 154. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14729784

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New insights into the pathogenesis and treatment of primary pulmonary hypertension. Author(s): Rudarakanchana N, Trembath RC, Morrell NW. Source: Thorax. 2001 November; 56(11): 888-90. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11641516

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Nocturnal hypoxemia is common in primary pulmonary hypertension. Author(s): Rafanan AL, Golish JA, Dinner DS, Hague LK, Arroliga AC. Source: Chest. 2001 September; 120(3): 894-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11555526

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Nocturnal periodic breathing in primary pulmonary hypertension. Author(s): Schulz R, Baseler G, Ghofrani HA, Grimminger F, Olschewski H, Seeger W. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 April; 19(4): 658-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11998995

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Noninvasive delivery of inhaled nitric oxide therapy for late pulmonary hypertension in newborn infants with congenital diaphragmatic hernia. Author(s): Kinsella JP, Parker TA, Ivy DD, Abman SH. Source: The Journal of Pediatrics. 2003 April; 142(4): 397-401. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12712057

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Nonobstructive ASD creation to qualify patients for the Fontan operation: effects on pulmonary hypertension due to restrictive left atrioventricular valve and interatrial communication. Author(s): Ishiwata T, Kondo C, Nakanishi T, Nakazawa M, Imai Y, Momma K. Source: Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions. 2002 August; 56(4): 528-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12124968

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Novel nonsense mutation of the BMPR-II gene in a Japanese patient with familial primary pulmonary hypertension. Author(s): Uehara R, Suzuki H, Kurokawa N, Urashima T, Fujiwara M, Matoba M, Eto Y. Source: Pediatrics International : Official Journal of the Japan Pediatric Society. 2002 August; 44(4): 433-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12139571

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Octreotide-induced hypoxemia and pulmonary hypertension in premature neonates. Author(s): Arevalo RP, Bullabh P, Krauss AN, Auld PA, Spigland N. Source: Journal of Pediatric Surgery. 2003 February; 38(2): 251-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12596116

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Oral beraprost sodium improves exercise capacity and ventilatory efficiency in patients with primary or thromboembolic pulmonary hypertension. Author(s): Nagaya N, Shimizu Y, Satoh T, Oya H, Uematsu M, Kyotani S, Sakamaki F, Sato N, Nakanishi N, Miyatake K. Source: Heart (British Cardiac Society). 2002 April; 87(4): 340-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11907007

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Orthodeoxia without platypnea from interatrial defect associated with persistent left superior vena cava in the absence of pulmonary hypertension. Author(s): Maniscalco M, Dialetto G, Tufano G, Romano A, Sofia M. Source: Respiration; International Review of Thoracic Diseases. 2003 March-April; 70(2): 207-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12740520

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Outcome of liver transplantation for patients with pulmonary hypertension. Author(s): Starkel P, Vera A, Gunson B, Mutimer D. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2002 April; 8(4): 382-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11965583

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Outcome of neonates with persistent pulmonary hypertension of the newborn treated with inhaled nitric oxide. Author(s): Chotigeat U, Khorana M, Kanjanapatakul W. Source: J Med Assoc Thai. 2002 July; 85(7): 800-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12296412

100 Pulmonary Hypertension

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Overdosing with prostacyclin in primary pulmonary hypertension. Author(s): Wasserman K, Oudiz R. Source: Journal of the American College of Cardiology. 2000 June; 35(7): 1995-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10841256

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Overestimation of pulmonary artery occlusion pressure in pulmonary hypertension due to partial occlusion. Author(s): Leatherman JW, Shapiro RS. Source: Critical Care Medicine. 2003 January; 31(1): 93-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12545000

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Oxidative stress in patients with primary pulmonary hypertension. Author(s): Irodova NL, Lankin VZ, Konovalova GK, Kochetov AG, Chazova IE. Source: Bulletin of Experimental Biology and Medicine. 2002 June; 133(6): 580-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12447471

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Oxygen desaturation on the six-minute walk test and mortality in untreated primary pulmonary hypertension. Author(s): Paciocco G, Martinez FJ, Bossone E, Pielsticker E, Gillespie B, Rubenfire M. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2001 April; 17(4): 647-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11401059

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Oxygen therapy improves cardiac index and pulmonary vascular resistance in patients with pulmonary hypertension. Author(s): Roberts DH, Lepore JJ, Maroo A, Semigran MJ, Ginns LC. Source: Chest. 2001 November; 120(5): 1547-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11713133

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Plasma plasmin-alpha2-plasmin inhibitor complex levels are increased in systemic sclerosis patients with pulmonary hypertension. Author(s): Jinnin M, Ihn H, Yamane K, Asano Y, Yazawa N, Tamaki K. Source: Rheumatology (Oxford, England). 2003 February; 42(2): 240-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12595617

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Potts shunt in patients with pulmonary hypertension. Author(s): Blanc J, Vouhe P, Bonnet D. Source: The New England Journal of Medicine. 2004 February 5; 350(6): 623. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14762197

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Prostacyclin therapy before pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension. Author(s): Nagaya N, Sasaki N, Ando M, Ogino H, Sakamaki F, Kyotani S, Nakanishi N. Source: Chest. 2003 February; 123(2): 338-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12576349

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Pulmonary function in primary pulmonary hypertension. Author(s): Sun XG, Hansen JE, Oudiz RJ, Wasserman K. Source: Journal of the American College of Cardiology. 2003 March 19; 41(6): 1028-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12651053

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Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. Author(s): Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, Brown B, Coles WA, Nichols JS, Ernst I, Hunter LA, Blackwelder WC, Schechter AN, Rodgers GP, Castro O, Ognibene FP. Source: The New England Journal of Medicine. 2004 February 26; 350(9): 886-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14985486

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Pulmonary hypertension due to spontaneous premature ductal constriction in fetal life: association with right bundle branch block. Author(s): Benettoni A, Rustico MA. Source: Cardiology in the Young. 2002 December; 12(6): 581-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12636008

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Pulmonary hypertension in patients with COPD: NO treatment? Author(s): Pepke-Zaba J, Morrell NW. Source: Thorax. 2003 April; 58(4): 283-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12668784

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Pulmonary hypertension in sickle cell disease. Author(s): Vichinsky EP. Source: The New England Journal of Medicine. 2004 February 26; 350(9): 857-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14985481

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Pulmonary hypertension. Author(s): Nicod LP. Source: Swiss Medical Weekly : Official Journal of the Swiss Society of Infectious Diseases, the Swiss Society of Internal Medicine, the Swiss Society of Pneumology. 2003 February 22; 133(7-8): 103-10. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12644956

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Pulmonary vasodilator response to adrenomedullin in patients with pulmonary hypertension. Author(s): Nagaya N, Miyatake K, Kyotani S, Nishikimi T, Nakanishi N, Kangawa K. Source: Hypertens Res. 2003 February; 26 Suppl: S141-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12630825

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Quantifying pulmonary hypertension in ventilated infants with bronchiolitis: a pilot study. Author(s): Fitzgerald D, Davis GM, Rohlicek C, Gottesman R. Source: Journal of Paediatrics and Child Health. 2001 February; 37(1): 64-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11168873

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Quantitative analysis of lung perfusion in patients with primary pulmonary hypertension. Author(s): Fukuchi K, Hayashida K, Nakanishi N, Inubushi M, Kyotani S, Nagaya N, Ishida Y. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 2002 June; 43(6): 757-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12050319

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Quantitative assessment of right ventricular volumes in severe chronic thromboembolic pulmonary hypertension using transthoracic three-dimensional echocardiography: changes due to pulmonary thromboendarterectomy. Author(s): Menzel T, Kramm T, Bruckner A, Mohr-Kahaly S, Mayer E, Meyer J. Source: European Journal of Echocardiography : the Journal of the Working Group on Echocardiography of the European Society of Cardiology. 2002 March; 3(1): 67-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12067537

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Quantitative relationship between severity of pulmonary hypertension and LV diastolic function has been established. Author(s): Barasch E, Moustapha A, Kaushik V, Diaz S, Kang SH. Source: Journal of the American College of Cardiology. 2003 March 19; 41(6): 1066; Author Reply 1066-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12651061

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Questions remain regarding patients with aortic stenosis and severe pulmonary hypertension. Author(s): Rahimtoola SH. Source: Journal of the American College of Cardiology. 2003 May 21; 41(10): 1847-8; Author Reply 1848. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12767677

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Residual pulmonary vasoreactivity to inhaled nitric oxide in patients with severe obstructive pulmonary hypertension and Eisenmenger syndrome. Author(s): Budts W, Van Pelt N, Gillyns H, Gewillig M, Van De Werf F, Janssens S. Source: Heart (British Cardiac Society). 2001 November; 86(5): 553-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11602551

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Respiratory variation in superior vena cava flow in patients with chronic obstructive pulmonary disease: estimation of pulmonary hypertension using Doppler flow index. Author(s): Kunichika N, Miyahara N, Harada M, Tanimoto M. Source: Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography. 2002 October; 15(10 Pt 2): 1165-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12411900

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Response of the right ventricle to acute pulmonary vasodilation predicts the outcome in patients with advanced heart failure and pulmonary hypertension. Author(s): Gavazzi A, Ghio S, Scelsi L, Campana C, Klersy C, Serio A, Raineri C, Tavazzi L. Source: American Heart Journal. 2003 February; 145(2): 310-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12595849

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Reversal of nocturnal periodic breathing in primary pulmonary hypertension after lung transplantation. Author(s): Schulz R, Fegbeutel C, Olschewski H, Rose F, Schafers HJ, Seeger W. Source: Chest. 2004 January; 125(1): 344-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14718466

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Reversal of pulmonary hypertension after ligation of a brachiocephalic arteriovenous fistula. Author(s): Clarkson MR, Giblin L, Brown A, Little D, Donohoe J. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2002 September; 40(3): E8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12200825

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Reversible pulmonary hypertension and thalidomide therapy for multiple myeloma. Author(s): Younis TH, Alam A, Paplham P, Spangenthal E, McCarthy P. Source: British Journal of Haematology. 2003 April; 121(1): 191-2. Erratum In: Br J Haematol. 2003 November; 123(3): 563. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12670354

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Reversible pulmonary hypertension in heart transplant candidates--pretransplant evaluation and outcome after orthotopic heart transplantation. Author(s): Klotz S, Deng MC, Hanafy D, Schmid C, Stypmann J, Schmidt C, Hammel D, Scheld HH. Source: European Journal of Heart Failure : Journal of the Working Group on Heart Failure of the European Society of Cardiology. 2003 October; 5(5): 645-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14607204

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Right atrial size and tricuspid regurgitation severity predict mortality or transplantation in primary pulmonary hypertension. Author(s): Bustamante-Labarta M, Perrone S, De La Fuente RL, Stutzbach P, De La Hoz RP, Torino A, Favaloro R. Source: Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography. 2002 October; 15(10 Pt 2): 1160-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12411899

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Role of adrenomedullin in congenital heart disease associated with pulmonary hypertension. Author(s): Lu H, Chen S, Wang H, Cheng P. Source: J Huazhong Univ Sci Technolog Med Sci. 2003; 23(3): 275-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14526432

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Role of K+ channels in pulmonary hypertension. Author(s): Mandegar M, Yuan JX. Source: Vascular Pharmacology. 2002 January; 38(1): 25-33. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12378819

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Scleroderma patients with combined pulmonary hypertension and interstitial lung disease. Author(s): Chang B, Wigley FM, White B, Wise RA. Source: The Journal of Rheumatology. 2003 November; 30(11): 2398-405. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14677184

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Severe neutrophilia in an infant with persistent pulmonary hypertension of the newborn. Author(s): Engmann C, Donn SM. Source: American Journal of Perinatology. 2003 October; 20(7): 347-51. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14655090

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Severe pulmonary hypertension in a patient with hypertrophic cardiomyopathy: response to alcohol septal ablation. Author(s): Brilakis ES, Nishimura RA. Source: Heart (British Cardiac Society). 2003 July; 89(7): 790. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12807862

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Severe pulmonary hypertension: a frequent complication of stem cell transplantation for malignant infantile osteopetrosis. Author(s): Steward CG, Pellier I, Mahajan A, Ashworth MT, Stuart AG, Fasth A, Lang D, Fischer A, Friedrich W, Schulz AS; The Working Party on Inborn Errors of the European Blood and Marrow Transplantation Group. Source: British Journal of Haematology. 2004 January; 124(1): 63-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14675409

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Severe retinopathy of prematurity (ROP) in a premature baby treated with sildenafil acetate (Viagra) for pulmonary hypertension. Author(s): Marsh CS, Marden B, Newsom R. Source: The British Journal of Ophthalmology. 2004 February; 88(2): 306-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14736800

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Signaling molecules in nonfamilial pulmonary hypertension. Author(s): Du L, Sullivan CC, Chu D, Cho AJ, Kido M, Wolf PL, Yuan JX, Deutsch R, Jamieson SW, Thistlethwaite PA. Source: The New England Journal of Medicine. 2003 February 6; 348(6): 500-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12571257

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Sildenafil as a treatment for pulmonary hypertension. Author(s): Carroll WD, Dhillon R. Source: Archives of Disease in Childhood. 2003 September; 88(9): 827-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12937112

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Sildenafil improved pulmonary hypertension and peripheral blood flow in a patient with scleroderma-associated lung fibrosis and the raynaud phenomenon. Author(s): Rosenkranz S, Diet F, Karasch T, Weihrauch J, Wassermann K, Erdmann E. Source: Annals of Internal Medicine. 2003 November 18; 139(10): 871-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14623635

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Sildenafil in pulmonary hypertension. Author(s): Nanivadekar A. Source: Indian Heart J. 2003 May-June; 55(3): 285; Author Reply 285. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14560947

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Sildenafil treatment of primary pulmonary hypertension. Author(s): Laupland KB, Helmersen D, Zygun DA, Viner SM. Source: Can Respir J. 2003 January-February; 10(1): 48-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12624621

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The alteration of the pulmonary artery flow spectrum with pulmonary hypertension. Author(s): Guogan W, Baiping C, Hanying L, Rusheng C. Source: Chinese Medical Sciences Journal = Chung-Kuo I Hsueh K'o Hsueh Tsa Chih / Chinese Academy of Medical Sciences. 1999 December; 14(4): 220-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12894895

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The endothelin system in pulmonary hypertension. Author(s): Michel RP, Langleben D, Dupuis J. Source: Canadian Journal of Physiology and Pharmacology. 2003 June; 81(6): 542-54. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12839266

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The nineteenth pregnancy in a patient with cor pulmonale and severe pulmonary hypertension: a management challenge. Author(s): Al-Mobeireek AF, Almutawa J, Alsatli RA. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2003 July; 82(7): 676-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12790853

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The pathogenesis of HIV-associated pulmonary hypertension. Author(s): Klings ES, Farber HW. Source: Adv Cardiol. 2003; 40: 71-82. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14533547

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The role of magnesium sulphate in the treatment of persistent pulmonary hypertension of the newborn. Author(s): Saidy KM, Itto BA. Source: Saudi Med J. 2003 July; 24(7): 801-2. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12883626

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Thrombopoietin inside the pulmonary vessels in patients with and without pulmonary hypertension. Author(s): Haznedaroglu IC, Atalar E, Ozturk MA, Ozer N, Ovunc K, Aksoyek S, Kes S, Kirazli S, Ozmen F. Source: Platelets. 2002 November; 13(7): 395-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12487786

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Tianeptine, plasma serotonin, and pulmonary hypertension. Author(s): Lechin F, Lechin AE, van der Dijs B. Source: Lancet. 2003 January 4; 361(9351): 87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12517512

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Treatment of primary pulmonary hypertension. Author(s): Handa S. Source: Intern Med. 2002 October; 41(10): 757-8. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12412989

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Treatment of pulmonary hypertension: a promising new age. Author(s): Park MH, Scott RL, Uber PA, Mehra MR. Source: Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions. 2002 November; 57(3): 395-403. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12410520

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Treatment of severe pulmonary hypertension with inhaled iloprost. Author(s): Leuchte HH, Baumgartner RA, Behr J. Source: Annals of Internal Medicine. 2003 August 19; 139(4): 306. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12965995

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Understanding primary pulmonary hypertension. Author(s): Berkowitz DS, Coyne NG. Source: Critical Care Nursing Quarterly. 2003 January-March; 26(1): 28-34. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12669944

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Unexplained pulmonary hypertension in chronic myeloproliferative disorders. Author(s): Dingli D, Utz JP, Krowka MJ, Oberg AL, Tefferi A. Source: Chest. 2001 September; 120(3): 801-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11555513

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Unexplained pulmonary hypertension is associated with systolic arterial hypertension in patients undergoing routine Doppler echocardiography. Author(s): Finkelhor RS, Yang SX, Bosich G, Bahler RC. Source: Chest. 2003 March; 123(3): 711-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12628867

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Unexplained severe pulmonary hypertension in the elderly: report on 14 patients. Author(s): Yigla M, Kramer MR, Bendayan D, Reisner SA, Solomonov A. Source: Isr Med Assoc J. 2004 February; 6(2): 78-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14986462

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Unilateral pulmonary thromboendarterectomy for iatrogenic pulmonary hypertension in a ten-year-old child. Author(s): Zacharias J, Clark SC, Hamilton JR, Dark JH, Hasan A. Source: The Journal of Thoracic and Cardiovascular Surgery. 2003 October; 126(4): 12101. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14566280

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Use of inhaled iloprost in a case of pulmonary hypertension during pediatric congenital heart surgery. Author(s): Muller M, Scholz S, Kwapisz M, Akinturk H, Thul J, Hempelmann G. Source: Anesthesiology. 2003 September; 99(3): 743-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12960561

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Usefulness of endothelin-1 concentration in capillary blood in patients with mitral stenosis as a predictor of regression of pulmonary hypertension after mitral valve replacement or valvuloplasty. Author(s): Snopek G, Pogorzelska H, Rywik TM, Browarek A, Janas J, Korewicki J. Source: The American Journal of Cardiology. 2002 July 15; 90(2): 188-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12106858

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Usefulness of transcutaneous Doppler jugular venous echo to predict pulmonary hypertension in COPD patients. Author(s): Burgess MI, Bright-Thomas R. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 February; 19(2): 382-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11866021

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Usefulness of transcutaneous Doppler jugular venous echo to predict pulmonary hypertension in COPD patients. Author(s): Matsuyama W, Ohkubo R, Michizono K, Abe M, Nakamura Y, Kawabata M, Osame M. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2001 June; 17(6): 1128-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11491154

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Uveal effusion and angle-closure glaucoma in primary pulmonary hypertension. Author(s): Krohn J, Bjune C. Source: American Journal of Ophthalmology. 2003 May; 135(5): 705-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12719080

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Value of a Doppler-derived index combining systolic and diastolic time intervals in predicting outcome in primary pulmonary hypertension. Author(s): Yeo TC, Dujardin KS, Tei C, Mahoney DW, McGoon MD, Seward JB. Source: The American Journal of Cardiology. 1998 May 1; 81(9): 1157-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9605059

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Value of contrast-enhanced MR angiography and helical CT angiography in chronic thromboembolic pulmonary hypertension. Author(s): Ley S, Kauczor HU, Heussel CP, Kramm T, Mayer E, Thelen M, Kreitner KF. Source: European Radiology. 2003 October; 13(10): 2365-71. Epub 2003 April 24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12712256

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Vanishing pulmonary hypertension in mixed connective tissue disease. Author(s): Lahaye IE, Rogiers PE, Nagler JM, Chappel R. Source: Clinical Rheumatology. 1999; 18(1): 45-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10088949

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Vascular smooth muscle cell phenotypes in primary pulmonary hypertension. Author(s): Mitani Y, Ueda M, Komatsu R, Maruyama K, Nagai R, Matsumura M, Sakurai M. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2001 February; 17(2): 316-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11334137

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Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. Author(s): Petkov V, Mosgoeller W, Ziesche R, Raderer M, Stiebellehner L, Vonbank K, Funk GC, Hamilton G, Novotny C, Burian B, Block LH. Source: The Journal of Clinical Investigation. 2003 May; 111(9): 1339-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12727925

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Vasodilator therapy for primary pulmonary hypertension in children. Author(s): Barst RJ, Maislin G, Fishman AP. Source: Circulation. 1999 March 9; 99(9): 1197-208. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10069788

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Vasodilators in the treatment of primary pulmonary hypertension. Author(s): Weir EK, Schremmer B. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1998 August; 12(2): 263-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9727771

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Vasoresponsiveness of sarcoidosis-associated pulmonary hypertension. Author(s): Preston IR, Klinger JR, Landzberg MJ, Houtchens J, Nelson D, Hill NS. Source: Chest. 2001 September; 120(3): 866-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11555522

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Ventilatory inefficiency for carbon dioxide during exercise in patients with pulmonary hypertension. Author(s): Reybrouck T, Mertens L, Schulze-Neick I, Austenat I, Eyskens B, Dumoulin M, Gewillig M. Source: Clinical Physiology (Oxford, England). 1998 July; 18(4): 337-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9715760

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von Recklinghausen disease complicated by pulmonary hypertension. Author(s): Aoki Y, Kodama M, Mezaki T, Ogawa R, Sato M, Okabe M, Aizawa Y. Source: Chest. 2001 May; 119(5): 1606-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11348977

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Weaning strategy with inhaled nitric oxide treatment in persistent pulmonary hypertension of the newborn. Author(s): Aly H, Sahni R, Wung JT. Source: Archives of Disease in Childhood. Fetal and Neonatal Edition. 1997 March; 76(2): F118-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9135291

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CHAPTER 2. NUTRITION AND PULMONARY HYPERTENSION Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and pulmonary hypertension.

Finding Nutrition Studies on Pulmonary Hypertension 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 “pulmonary hypertension” (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.

112 Pulmonary Hypertension

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

Acute effect of intrapulmonary enalaprilat in ten patients with severe pulmonary hypertension due to toxic oil syndrome. Author(s): Cardiology Service, Hospital 12 de Octubre, Madrid, Spain. Source: Gomez Pajuelo, C Gomez Sanchez, M A Alonso Gutierrez, M Lombera Romero, F Gabriel Sanchez, R Fernandez Cruz, A Saenz de la Calzada, C Cor-Vasa. 1990; 32(3): 225-30 0010-8650

•

Acute effects of nebulised epoprostenol in pulmonary hypertension due to systemic sclerosis. Author(s): Department of Respiratory Medicine, Royal Sunderland Hospital, U.K. [email protected] Source: Parameswaran, K Purcell, I Farrer, M Holland, C Taylor, I K Keaney, N P RespirMed. 1999 February; 93(2): 75-8 0954-6111

•

Aerosolized vasodilators in pulmonary hypertension. Author(s): Department of Internal Medicine II, Justus Liebig University of Giessen, Klinikstrasse 36, D-35392 Giessen, Germany. [email protected] Source: Gessler, T Schmehl, T Olschewski, H Grimminger, F Seeger, W J-Aerosol-Med. 2002 Summer; 15(2): 117-22 0894-2684

•

Atrial septostomy for pulmonary hypertension. Author(s): Cardiopulmonary Department, Ignacio Chavez National Institute of Cardiology, Mexico City, Mexico. [email protected] Source: Sandoval, J Rothman, A Pulido, T Clin-Chest-Med. 2001 September; 22(3): 547-60 0272-5231

•

Bacterial lipopolysaccharide induction of the prostaglandin G/H synthase 2 gene causes thromboxane-dependent pulmonary hypertension in rabbits. Author(s): Section on Infectious Diseases, Department of Medicine, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157-1042, USA. Source: Delong, P O'Sullivan, M G Huggins, E Hubbard, C L McCall, C Am-J-RespirCell-Mol-Biol. 1999 March; 20(3): 493-9 1044-1549

•

Combination of inhaled nitric oxide and intravenous prostacyclin for successful treatment of severe pulmonary hypertension in a patient with acute respiratory distress syndrome. Author(s): Department of Anesthesiology, University Hospital Aachen, Germany. Ralf [email protected] Source: Kuhlen, R Walbert, E Frankel, P Thaden, S Behrendt, W Rossaint, R IntensiveCare-Med. 1999 July; 25(7): 752-4 0342-4642

•

Complex vascular lesions at autopsy in a patient with phentermine-fenfluramine use and rapidly progressing pulmonary hypertension. Author(s): Department of Pathology, University of California, San Diego, La Jolla, CA 92093-0624, USA. Source: Strother, J Fedullo, P Yi, E S Masliah, E Arch-Pathol-Lab-Med. 1999 June; 123(6): 539-40 0003-9985

•

Continuous intravenous epoprostenol in pulmonary hypertension: the Israel experience. Author(s): Pulmonary Institute, Rabin Medical Center (Beilinson Campus), Petah Tiqva, Israel.

Nutrition 113

Source: Bendayan, Daniele Fink, Gershon Aravot, Dan Ygla, Mordechai Bendov, Issahar Bliden, Leonard Nir, Amiran Kramer, Mordechai R Isr-Med-Assoc-J. 2002 April; 4(4): 255-8 1565-1088 •

Dynamic pulmonary arterial hypertension: a new form of pulmonary hypertension in patients with impaired pulmonary diffusing capacity due to toxic oil syndrome. Author(s): Cardiology Service, Hospital 1/2 de Octubre, Madrid, Spain. Source: Gomez Sanchez, M A Diaz de Atauri, M J Alonso Gutierrez, M Martin Escribano, P Saenz de la Calzada, C Gomez Pajuelo, C Izquierdo Martinez, M Ramis Pedromingo, M Cor-Vasa. 1990; 32(3): 211-7 0010-8650

•

Effect of aerosolized prostacyclin and inhaled nitric oxide on experimental hypoxic pulmonary hypertension. Author(s): Klinik fur Anasthesie, Medizinische Einrichtungen der RheinischWestfalischen Technischen Hochschule Aachen, Pauwelsstrasse 30, 52 074 Aachen, Germany. [email protected] Source: Max, M Kuhlen, R Dembinski, R Rossaint, R Intensive-Care-Med. 1999 October; 25(10): 1147-54 0342-4642

•

Effect of prolonged inhibition of angiotensin converting enzyme by captopril on some hemodynamic parameters of pulmonary circulation in patients with secondary pulmonary hypertension. Source: Dubiel, J P Zmudka, K Brzostek, T Horzela, T Acta-Med-Pol. 1989; 30(1-2): 23-30 0001-608X

•

Effect of prostaglandin E1 on pulmonary hypertension after protamine injection during cardiac surgery. Author(s): Department of Anaesthesiology, Osaka University Medical School, Suita, Japan. [email protected] Source: Abe, K Sakakibara, T Miyamoto, Y Ohnishi, K Eur-J-Clin-Pharmacol. 1998 March; 54(1): 21-5 0031-6970

•

Effects of captopril combined with oxygen therapy at rest and on exercise in patients with chronic bronchitis and pulmonary hypertension. Author(s): Department of Medecine, Hopital A. Michallon, Joseph Fourier University, Grenoble, France. Source: Pison, C M Wolf, J E Levy, P A Dubois, F Brambilla, C G Paramelle, B Respiration. 1991; 58(1): 9-14 0025-7931

•

Epoprostenol therapy for primary pulmonary hypertension. Author(s): Marquette University College of Nursing, Milwaukee, Wis., USA. Source: Cheever, K H Kitzes, B Genthner, D Crit-Care-Nurse. 1999 August; 19(4): 20-7 0279-5442

•

Epoprostenol-induced pulmonary vasodilatation in patients with pulmonary hypertension measured by electrical impedance tomography. Author(s): Department of Pulmonary Medicine, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. [email protected] Source: Smit, H J Vonk Noordegraaf, A Roeleveld, R J Bronzwaer, J G F Postmus, P E de Vries, P M J M Boonstra, A Physiol-Meas. 2002 February; 23(1): 237-43 0967-3334

•

How to manage primary pulmonary hypertension. Giving hope to patients with a life-threatening illness. Author(s): Division of Cardiology, Northwestern University Medical School, Chicago, USA. [email protected]

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Source: Ricciardi, M J Rubenfire, M Postgrad-Med. 1999 March; 105(3): 45-8, 51-6 00325481 •

Inhaled iloprost for severe pulmonary hypertension. Author(s): Department of Internal Medicine II, University Clinic, Giessen, Germany. Source: Olschewski, Horst Simonneau, Gerald Galie, Nazzareno Higenbottam, Timothy Naeije, Robert Rubin, Lewis J Nikkho, Sylvia Speich, Rudolf Hoeper, Marius M Behr, Jurgen Winkler, Jorg Sitbon, Olivier Popov, Wladimir Ghofrani, H Ardeschir Manes, Alessandra Kiely, David G Ewert, Ralph Meyer, Andreas Corris, Paul A Delcroix, Marion Gomez Sanchez, Miguel Siedentop, Harald Seeger, Werner N-Engl-J-Med. 2002 August 1; 347(5): 322-9 1533-4406

•

Inhaled prostacyclin: from pulmonary hypertension to splanchnic hypoperfusion. Author(s): Istituto di Anestesiologia e Rianimazione, Universita' di Bari, Policlinico, Italy. Source: Brienza, N Intensive-Care-Med. 1998 November; 24(11): 1228-30 0342-4642

•

Intravenous epoprostenol: a new therapy for primary pulmonary hypertension. Author(s): Fairview-University Medical Center, St Paul, Minn, USA. Source: Sabo J, A Nord C, P Crit-Care-Nurse. 2000 December; 20(6): 31-40 0279-5442

•

Liver transplantation in patients with severe portopulmonary hypertension treated with preoperative chronic intravenous epoprostenol. Author(s): Division of Transplant Surgery, Johns Hopkins University School of Medicine, 600 North Wolfe St., Baltimore, MD, USA. [email protected] Source: Tan, H P Markowitz, J S Montgomery, R A Merritt, W T Klein, A S Thuluvath, P J Poordad, F F Maley, W R Winters, B Akinci, S B Gaine, S P Liver-Transpl. 2001 August; 7(8): 745-9 1527-6465

•

Long-term prostacyclin reduces pulmonary vascular resistance in severe primary pulmonary hypertension. Author(s): Columbia-Presbyterian Medical Center, Babies Hospital, Division of Pediatric Cardiology, New York, New York 10032, USA. Source: Barst, R J Clin-Exp-Rheumatol. 1998 May-June; 16(3): 253-4 0392-856X

•

Long-term therapy for pulmonary hypertension in children. Author(s): St. Louis Children's Hospital, MO 63110, USA. [email protected] Source: Dent, C L Perez Fontan, J J Curr-Opin-Pediatr. 1999 June; 11(3): 218-22 1040-8703

•

Lung transplantation for pulmonary hypertension: patient selection and maintenance therapy while awaiting transplantation. Author(s): Section of Cardiology, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612-3824, USA. Source: Rich, S McLaughlin, V V Semin-Thorac-Cardiovasc-Surg. 1998 April; 10(2): 135-8 1043-0679

•

Medical therapy of pulmonary hypertension. An overview of treatment and goals. Author(s): Department of Pediatrics, Columbia University College of Physicians and Surgeons, Division of Pediatric Cardiology, Pulmonary Hypertension Center, New York Presbyterian Hospital, New York, New York, USA. Source: Barst, R J Clin-Chest-Med. 2001 September; 22(3): 509-15, ix 0272-5231

•

Modulation of angiotensin II receptor expression during development and regression of hypoxic pulmonary hypertension. Author(s): INSERM U127, Institut Federatif de Recherche Circulation, Hopital Lariboisiere, Universite Denis Diderot, Paris, France. [email protected]

Nutrition 115

Source: Chassagne, C Eddahibi, S Adamy, C Rideau, D Marotte, F Dubois Rande, J L Adnot, S Samuel, J L Teiger, E Am-J-Respir-Cell-Mol-Biol. 2000 Mar; 22(3): 323-32 10441549 •

Progressive splenomegaly after epoprostenol therapy in portopulmonary hypertension. Author(s): Department of Anesthesiology, Mayo Foundation, Rochester, MN 55905, USA. Source: Findlay, J Y Plevak, D J Krowka, M J Sack, E M Porayko, M K Liver-TransplSurg. 1999 September; 5(5): 362-5 1074-3022

•

Prostacyclin analogs as the brakes for pulmonary artery smooth muscle cell proliferation: is it sufficient to treat severe pulmonary hypertension? Author(s): Division of Cardiopulmonary Pathology, Department of Pathology, The Johns Hopkins University School of Medicine, 720 Rutland Ave., Baltimore, MD 21205, USA. [email protected] Source: Tuder, Rubin M Zaiman, Ari L Am-J-Respir-Cell-Mol-Biol. 2002 February; 26(2): 171-4 1044-1549

•

Prostacyclin and right ventricular function in patients with pulmonary hypertension associated with ARDS. Author(s): Institute for Anaesthesiology, Heinrich-Heine-University, Dusseldorf, FRG. Source: Radermacher, P Santak, B Wust, H J Tarnow, J Falke, K J Intensive-Care-Med. 1990; 16(4): 227-32 0342-4642

•

Prostacyclin for pulmonary hypertension. Author(s): Division of Physiological Medicine, St George's Hospital Medical School, Cranmer Terrace, London, UK, SW17 0RE. Source: Paramothayan, N S Lasserson, T J Wells, A U Walters, E H Cochrane-DatabaseSyst-Revolume 2002; (3): CD002994 1469-493X

•

Prostacycline (Flolan). Intravenous nursing responsibilities in the care of the patient with primary pulmonary hypertension. Author(s): Intravenous Nurses Society, Cambridge, MA, USA. Source: Benvenuto, D B J-Intraven-Nurs. 1999 Sep-October; 22(5): 267-72 0896-5846

•

Prostacyclins in pulmonary hypertension treatment. Author(s): Clinic of Thoracic Surgery, National Tuberculosis and Respiratory Diseases Institute, Bratislava, Slovakia. [email protected] Source: Pereszlenyi, A Jr Harustiak, S Klepetko, W Bratisl-Lek-Listy. 2002; 103(4-5): 17984 0006-9248

•

Prostaglandins for the control of pulmonary hypertension in the postoperative cardiac surgery patient: nursing implications. Source: Kelleher, R M Rose, A A Ordway, L Crit-Care-Nurs-Clin-North-Am. 1991 December; 3(4): 741-8 0899-5885

•

Protamine-induced pulmonary hypertension in heparinized monkeys and pigs is inhibited by the thromboxane receptor antagonist SQ 30,741. Author(s): Department of Pharmacology, Squibb Institute for Medical Research, Princeton, NJ 08543-4000. Source: Schumacher, W A Heran, C L Ogletree, M L Eicosanoids. 1990; 3(2): 87-93 09349820

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•

Pulmonary capillary hemangiomatosis associated with primary pulmonary hypertension: report of 2 new cases and review of 35 cases from the literature. Author(s): Service of Internal Medicine, Hospital Mutua de Terrassa, University of Barcelona, Catalonia, Spain. [email protected] Source: Almagro, P Julia, J Sanjaume, M Gonzalez, G Casalots, J Heredia, J L Martinez, J Garau, J Medicine-(Baltimore). 2002 November; 81(6): 417-24 0025-7974

•

Pulmonary hypertension associated with connective tissue disease. Author(s): Pulmonary Hypertension Center, University of Colorado Health Sciences Center, Denver, CO, USA. Source: Fagan, K A Badesch, D B Prog-Cardiovasc-Dis. 2002 Nov-December; 45(3): 22534 0033-0620

•

Pulmonary veno-occlusive disease, antiphospholipid antibody and pulmonary hypertension in an adolescent. Author(s): University Witten-Herdecke, Department of Pediadric Cardiology and Pulmonology, Datteln, Germany. Source: Hussein, A Trowitzsch, E Brockmann, M Klin-Padiatr. 1999 Mar-April; 211(2): 92-5 0300-8630

•

Recovery from circulatory shock in severe primary pulmonary hypertension (PPH) with aerosolization of iloprost. Author(s): Department of Internal Medicine II, Justus-Liebig-University, Giessen, Germany. [email protected] Source: Olschewski, H Ghofrani, H A Walmrath, D Temmesfeld Wollbruck, B Grimminger, F Seeger, W Intensive-Care-Med. 1998 June; 24(6): 631-4 0342-4642

•

Recurrent portopulmonary hypertension after liver transplantation: management with epoprostenol and resolution after retransplantation. Author(s): Divisions of Pulmonary and Critical Care Medicine, Department of Medicine, University of Miami School of Medicine, Miami, FL, USA. [email protected] Source: Kett, D H Acosta, R C Campos, M A Rodriguez, M J Quartin, A A Schein, R M Liver-Transpl. 2001 July; 7(7): 645-8 1527-6465

•

Successful treatment with immunosuppression, anticoagulation and vasodilator therapy of pulmonary hypertension in SLE associated with secondary antiphospholipid syndrome. Author(s): Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong. Source: Tam, L S Li, E K Lupus. 1998; 7(7): 495-7 0961-2033

•

Suppressive effect of pulmonary hypertension and leukocyte activation by inhaled prostaglandin E1 in rats with monocrotaline-induced pulmonary hypertension. Author(s): Department of Cardiology and Pneumology, Dokkyo University School of Medicine, Tochigi Prefecture, Japan. Source: Kato, Shiro Sugimura, Hiroyuki Kishiro, Izumi Machida, Masaru Suzuki, Hidehiko Kaneko, Noboru Exp-Lung-Res. 2002 June; 28(4): 265-73 0190-2148

•

The effect of amlodipine on exercise-induced pulmonary hypertension and right heart function in patients with chronic obstructive pulmonary disease. Author(s): Klinik Wehrawald, BfA Schwarzenbacher Strasse 3 79682 Todtmoos, Germany. [email protected] Source: Franz, I W Van Der Meyden, J Schaupp, S Tonnesmann, U Z-Kardiol. 2002 October; 91(10): 833-9 0300-5860

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•

The role of magnesium in lung diseases: asthma, allergy and pulmonary hypertension. Author(s): New York Medical College, Valhalla. Source: Mathew, R Altura, B M Magnes-Trace-Elem. 1991-92; 10(2-4): 220-8 1015-3845

•

Urodilatin, a natriuretic peptide stimulating particulate guanylate cyclase, and the phosphodiesterase 5 inhibitor dipyridamole attenuate experimental pulmonary hypertension: synergism upon coapplication. Author(s): Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany. [email protected] Source: Schermuly, R T Weissmann, N Enke, B Ghofrani, H A Forssmann, W G Grimminger, F Seeger, W Walmrath, D Am-J-Respir-Cell-Mol-Biol. 2001 August; 25(2): 219-25 1044-1549

Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •

healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0

•

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

•

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

•

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

•

The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/

•

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

•

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

•

Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/

Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats

•

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

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

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•

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

•

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

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

•

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

•

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

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CHAPTER 3. HYPERTENSION

DISSERTATIONS

ON

PULMONARY

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

Dissertations on Pulmonary Hypertension 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 pulmonary hypertension. 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: •

Elastin and Elastase in the Pathogenesis of Pulmonary Hypertension in the Rat Monocrotaline Model by Todorovich-Hunter, Livia; PhD from University of Toronto (Canada), 1989 http://wwwlib.umi.com/dissertations/fullcit/NL54570

•

Pulmonary Disease in Scleroderma: Combined Interstitial Lung Disease and Pulmonary Hypertension and Predictors of Pulmonary Hypertension by Chang, Betty; PhD from The Johns Hopkins University, 2003, 72 pages http://wwwlib.umi.com/dissertations/fullcit/3068129

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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.

121

CHAPTER 4. CLINICAL HYPERTENSION

TRIALS

AND

PULMONARY

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

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

A Transition Study From Flolan(r) to Remodulin(r) in Patients with Pulmonary Arterial Hypertension Condition(s): Pulmonary Arterial Hypertension; Pulmonary Hypertension Study Status: This study is currently recruiting patients. Sponsor(s): United Therapeutics Purpose - Excerpt: This trial is a study of Remodulin in patients with pulmonary arterial hypertension who have been transitioned from Flolan therapy. The study consists of Screening, Baseline and Treatment Phases. Patients meeting all inclusion/exclusion criteria during the Screening Phase will enter the Baseline Phase, during which baseline exercise capacity, vital signs, and clinical signs and symptoms of the disease will be assessed. After confirmation of all inclusion/exclusion criteria, patients will be assigned to study drug (Remodulin or placebo) and will enter the Treatment Phase. The Treatment Phase begins with a Dose Transition Period, during which patients will begin receiving subcutaneous study drug at a low dose determined by the patient's current dose of Flolan. The study drug dose will be increased gradually while the Flolan dose is decreased gradually over a period of up to 14 days. The dose changes will continue until Flolan therapy has been discontinued and the patient is stable on study drug. Patients who are transitioned off Flolan, who are stable on study drug will be discharged from the clinic, and will continue to receive study drug on an outpatient basis. The patient will return to the clinic at Weeks 4 and 8 for assessments. Patients will remain on study

8

These are listed at www.ClinicalTrials.gov.

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drug for 8 weeks from the first dose of study drug. At Week 8, final assessments will be conducted and the patient will be dismissed from the study. Patients who successfully complete Week 8 assessments may be offered Remodulin therapy or other therapy, at the investigator's discretion. Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00058929 •

Development of a Hospital-Based Home Program for the Use of Inhaled Nitric Oxide in the Chronic Management of Severe Cardiopulmonary Diseases Condition(s): Pulmonary Hypertension; Lung Disease; Sickle Cell Disease; Cardiac transplant; Lung transplant Study Status: This study is currently recruiting patients. Sponsor(s): INO Therapeutics Purpose - Excerpt: The purpose of this program is to evaluate the logistic issues and patient requirements for chronic pulsed INOmax delivery in ambulatory, home-care patients. To understand patient needs, patients with a variety of underlying diseases will be included. Safety of chronic therapy will be monitored by serial measurements of methemoglobin, platelet function assay and reported adverse events. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00041574

•

Inhaled Nitric Oxide and Transfusion Therapy for Patients with Sickle Cell Anemia and Secondary Pulmonary Hypertension Condition(s): Sickle Cell Anemia; Pulmonary Hypertension Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: This study will test whether inhaling nitric oxide gas mixed with room air can improve pulmonary hypertension (high blood pressure in the lungs) in patients with sickle cell anemia. It is estimated that 20 to 30 percent of patients with sickle cell anemia have moderate to severe pulmonary hypertension, a disease complication associated with higher rates of illness and death. Patients with sickle cell disease 18 years of age or older may be eligible to participate in one or more parts of this three-stage study. Candidates will be screened with a medical history, physical examination, electrocardiogram, echocardiogram and blood tests. Those enrolled will undergo the following tests and procedures: Stage 1: Patients will be tested to determine the cause of pulmonary hypertension. They will have an echocardiogram (ultrasound study of the heart); a test for asthma, with measurement of arterial blood oxygen levels; oxygen breathing study with measurement of arterial blood oxygen levels; chest X-ray; computed tomography (CT) scans of the lung with and without contrast material; magnetic resonance imaging (MRI) of the heart; 6-minute walk to measure the distance covered in that time at a comfortable pace; night-hawks oxygen measurement while

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sleeping; blood tests for HIV, hepatitis virus, lupus and arthritis and pregnancy; pulmonary ventilation/perfusion scan with evaluation of shunt fraction to the brain and kidney; and exercise studies will be performed to determine oxygen and carbon dioxide consumption and production and to measure the anaerobic threshold. Stage 2: Patients who proceed with stage 2 will have a detailed MRI evaluation of the heart and will be admitted to the Clinical Center intensive care unit for the following procedure: A small intravenous (IV) catheter (plastic tube) is placed in the patient arm and a longer tube, called a central line, in a deeper neck or leg vein. A long thin tube is then inserted through the vein into the heart and the lung artery to measure all blood pressures in the heart and lungs directly. Following baseline measurements the following medications will be delivered for two hours each, separated by a 30 minute wash-out period. The patients is then given oxygen to breathe for 2 hours, followed by infusion of prostacyclin, a blood pressure-lowering drug, for 2 hours; and finally inhaled nitric oxide for 2 hours. A small blood sample (3 tablespoons) of blood is drawn during the nitric oxide administration. Stage 3: For patients who complete stage II or III and do not respond to NO gas as determined by a decrease in mean or systolic pulmonary artery pressure of greater than 10% from baseline or a 10% increase in 6 minute walk distance, or are unable to receive it due to technical, regulatory (no free standing home structure for storage of NO gas, etc.) or personal lifestyle issues (some patient do not want to carry two tanks of gas - oxygen and NO - or have difficulty learning how to use the NO gas system), we will offer regular exchange transfusions and home oxygen for three months with a goal of maintaining hemoglobin levels of 8-10 and hemoglobin S levels of less than 40%. The monitoring of patients receiving exchange transfusions will be the same as for the patients receiving NO gas: Measurements will include pulmonary artery pressure measured by repeat right heart catheterization, other hemodynamic parameters, exercise tolerance by 6-minute walk, plasma adhesion molecule levels, neutrophil and monocyte mRNA gene profiles, and circulating erythroid progenitor cell a/a hemoglobin message and protein levels. This portion of the study is to be undertaken as an outpatient. Clinical follow-up will involve bi-weekly clinic visits with the principal investigator, associate investigators, or study nurse. At these clinic visits venous blood will be obtained for hemoglobin electrophoresis (including hemoglobin F and A2), CBC, ESR, C-reactive protein and standard chemistries. Research blood, for plasma and erythrocyte reactive nitrogen species and plasma adhesion molecule levels, will be collected with total blood drawn per day not to exceed 30 mL. Protocol nurse or principal investigator will record total weekly symptoms, emergency room visits, hospital admissions, and narcotic use. Echocardiograms and 6-minute walk will be repeated at two-week intervals. 32 mL of blood will be drawn prior to the exchange transfusion and a 4 and 8 weeks for neutrophil and monocyte mRNA expression chip profiling. Patients who develop any complication of their disease (i.e. vaso-occlusive crisis, acute chest syndrome, let ulcers, priapism, avascular necrosis of the femoral hip, asthma, etc.) will be strongly encouraged to directly come to the Clinical Center's 10D ICU for evaluation and direct admission by the 10D ICU physician on-call. If they are very ill they will be instructed to either call and ambulance or go to the nearest emergency room. If they are relatively stable, patients will be instructed to call the 10D ICU and speak with the physician on-call. We will follow patients according to the NO protocol with right heart catheterization at 3 months of therapy and serial echocardiograms. The effects of exchange transfusion will be statistically analyzed separately but in a similar fashion as delineated for NO treatment. All patients will complete Stage I and II of the study prior to entering into Exchange Transfusion therapy. Patients with greater than a 10% increase in six-minute walk distance or a 10% reduction in mean or systolic pulmonary artery pressures, who want to continue Exchange Transfusion therapy will have the option of continuing therapy. In these

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cases, blood draws and clinical follow-up will be reduced to bi-monthly intervals and when clinically indicated. The Clinical Center will continue to pay for these clinic visits and urgent care at the Clinical Center. The Transfusion Therapy and the Clinical Center care will continue until the study has terminated (anticipated three year study duration). Our physicians and social workers will work with patients to help them obtain appropriate insurance to cover Exchange Transfusion therapy. However, it is possible that circumstances may arise that prevent the patient from continuing this therapy after the study is terminated. Alternative Therapies Patients who have enrolled in the NO or transfusion treatment arm of the study who do not respond to the treatment (defined by a 10% reduction in mean or systolic pulmonary artery pressure measured by right heart catheterization or a 10% increase in 6-minute walk distance) will be eligible to receive the alternative therapy (NO or transfusion) or other FDA approved medications. These medications may include oxygen, prostacyclin (flolan or remodulin), L-arginine, bosentan or sidenafil. We will limit the number of patients who are treated with medication other than NO or exchange transfusion to 10 subjects. Such patients will be managed at the NIH, in collaboration with their primary medical providers, according to accepted current standards of care using only FDA approved medication. The effect of such treatments on estimated pulmonary artery pressures, measured by echocardiogram, and on 6-minute walk distance will be assessed at regular intervals (every 1-3 months while on protocol) and all adverse events reported to the IRB and DSMB as defined by the current protocol. Patients maintained on alternative therapies will not have research bloods drawn, all laboratory testing will be obtained only for clinical indications. Such patients may be managed on this protocol until the protocol is terminated, the medication used becomes FDA approved specifically for use in sickle cell disease, the patient wishes to end participation, or the patient wishes to enroll in another study for treatment of pulmonary hypertension. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00023296 •

Natrecor in Pulmonary Hypertension Condition(s): Pulmonary Hypertension; Cancer; Lung Disease; Cardiothoracic Surgery Study Status: This study is currently recruiting patients. Sponsor(s): M.D. Anderson Cancer Center Purpose - Excerpt: The primary objective of this study is to establish that Nesiritide (Natrecor) is effective in reducing pulmonary hypertension (PHTN) acutely as measured by a 20% reduction in the mean pulmonary arterial (PA) pressure. The secondary objectives will include: improvement in pulmonary vascular resistance (PVR), patient symptoms, exercise tolerance, frequency of toxicity, and surgeon's willingness to proceed with operation. Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00075179

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Phase III Randomized Study of UT-15 in Patients with Primary Pulmonary Hypertension Condition(s): Pulmonary Hypertension Study Status: This study is currently recruiting patients. Sponsor(s): FDA Office of Orphan Products Development; United Therapeutics Purpose - Excerpt: Objectives: I. Determine the safety and efficacy of UT-15 in patients with severe symptomatic primary pulmonary hypertension. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004497

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Pulmonary Hypertension--Mechanisms and Family Registry Condition(s): Lung Diseases; Hypertension, Pulmonary Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To establish a registry of primary pulmonary hypertension (PPH), a lethal disease which causes progressive obstruction of small pulmonary arteries and to investigate basic mechanisms of the disease. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005357

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Secondary Pulmonary Hypertension in Adults with Sickle Cell Anemia Condition(s): Pulmonary Hypertension; Sickle Cell Anemia Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: The purpose of this study is to determine how often people with sickle cell anemia develop pulmonary hypertension-a serious disease in which blood pressure in the artery to the lungs is elevated. Men and women 18 years of age and older with sickle cell anemia may be eligible for this study. Participants will undergo an evaluation at Howard University's Comprehensive Sickle Cell Center in Washington, D.C. or at the National Institutes of Health in Bethesda, Maryland. It will include the following: -medical history -physical examination -blood collection (no more than 50 ml., or about 1/3 cup) to confirm the diagnosis of sickle cell anemia, sickle cell trait or beta-thalassemia (Some blood will be stored for future research testing on sickle cell anemia.) -echocardiogram (ultrasound test of the heart) to check the pumping action of the heart and the rate at which blood travels through the tricuspid valve. Following this evaluation, a study nurse will contact participants twice a month for 2 months and then once every 3 months for the next 3 years for a telephone interview. The interview will include questions about general health and recent health-related events, such as hospitalizations or emergency room visits. Study Type: Observational Contact(s): see Web site below

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Web Site: http://clinicaltrials.gov/ct/show/NCT00011648 •

Risk Factors for Pulmonary Hypertension of the Newborn Condition(s): Persistent Fetal Circulation Syndrome; Lung Diseases Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To conduct a multicenter case-control study of persistent pulmonary hypertension of the newborn (PPHN) in relation to maternal exposure to smoking and non-steroidal anti-inflammatory drugs (NSAIDs). Also, to assess other potential antenatal risk factors and collect and store buccal cell specimens for future analyses. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005497

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Safety and Efficacy of Sitaxsentan in the Treatment of Pulmonary Arterial Hypertension Condition(s): Pulmonary Hypertension Study Status: This study is no longer recruiting patients. Sponsor(s): ICOS-Texas Biotechnology; ICOS; Texas Biotechnology Corporation Purpose - Excerpt: This is a clinical research study designed to evaluate an investigational new medication called sitaxsentan for the treatment of pulmonary arterial hypertension (patients with NYHA functional class II, III or IV). The purpose of this study is to evaluate the safety and effectiveness of two different doses of sitaxsentan, compared to placebo (inactive treatment) for the treatment of pulmonary arterial hypertension. Patients who complete this trial may be eligible to take part in an extension trial (Protocol FPH01-X). Eligible patients who receive placebo in the 12-week study cross over to receive sitaxsentan for the extension trial. Phase(s): Phase II; Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00034307

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Study of BSF 208075 evaluating exercise capacity in patients with pulmonary arterial hypertension Condition(s): Pulmonary Hypertension Study Status: This study is no longer recruiting patients. Sponsor(s): Myogen Purpose - Excerpt: The purpose of this study is to determine if treating patients suffering from moderate to severe pulmonary arterial hypertension with BSF 208075 will improve the patients' ability to exercise. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below

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Web Site: http://clinicaltrials.gov/ct/show/NCT00046319 •

Epidemiology of Persistent Pulmonary Hypertension of the Newborn - SCOR in Lung Biology and Diseases in Infants and Children Condition(s): Lung Diseases; Cardiovascular Diseases; Defect, Congenital Heart; Heart Diseases; Persistent Fetal Circulation Syndrome Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To conduct an epidemiologic study of persistent pulmonary hypertension of the newborn ( PPHN) infant. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005323

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Phase IV Study of Chronic Infusional Epoprostenol for Severe Primary Pulmonary Hypertension Condition(s): Hypertension, Pulmonary Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); Baylor College of Medicine Purpose - Excerpt: Objectives: I. Provide epoprostenol (Flolan, prostaglandin I2) by chronic infusion to patients with severe primary pulmonary hypertension for whom no alternative therapy is available. II. Obtain additional safety information on continuous infusion epoprostenol. III. Obtain additional information on economic resource health consumption. Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004754

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Study of the Effect of Four Methods of Cardiopulmonary Resuscitation Instruction on Psychosocial Response of Parents with Infants at Risk of Sudden Death Condition(s): Pulmonary Hypertension; Bronchopulmonary Dysplasia; Respiratory Distress Syndrome Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); University of California, Los Angeles Purpose - Excerpt: Objectives: I. Describe the psychosocial response of parents and caretakers who learn cardiopulmonary resuscitation (CPR) techniques for infants at high risk for respiratory or cardiac arrest. II. Compare the effect of 4 methods of CPR instruction on psychosocial response. III. Evaluate a psychological intervention based on social support theory designed to offset the potential adverse psychological outcomes of CPR instruction. IV. Evaluate a self-paced CPR learning module using the principles of adult learning theory. V. Document the level of CPR knowledge and skill retention over

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time. VI. Document the frequency of CPR and its outcome following a witnessed respiratory or cardiac arrest. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004805

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 “pulmonary hypertension” (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 5. PATENTS ON PULMONARY HYPERTENSION 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 “pulmonary hypertension” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on pulmonary hypertension, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Pulmonary Hypertension By performing a patent search focusing on pulmonary hypertension, 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 pulmonary hypertension: •

Cell-based gene therapy for the pulmonary system Inventor(s): Stewart; Duncan J. (3 Blythwood Crescent, Toronto, Ontario, CA) Assignee(s): None Reported Patent Number: 6,482,406 Date filed: September 24, 1999 Abstract: Cell-based gene transfer is effected by administering transfected cells containing an expressible transgene coding for an angiogenic factor or other therapeutic factor, into the pulmonary circulation of a patient, where the cells express and secrete expression products of the transgene to act locally at the site of expression of expression, and in some cases to be conveyed by the patient's circulation to other body organs. The process is especially useful in treatment of pulmonary hypertension by means of expressed angiogenic factors. Also provided is the use of angiogenic factors, delivered by other means than cell-based gene transfer, in treating pulmonary hypertension. Excerpt(s): This invention relates to medical treatments and composition and procedures useful therein. More specifically, it relates to cell-based gene transfer systems for administration to the pulmonary system of a mammalian patient. Cell-based gene transfer is a known, albeit relatively new and experimental, technique for conducting gene therapy on a patient. In this procedure, DNA sequences containing the genes which it is desired to introduce into the patient's body (the trans-genes) are prepared extracellularly, e.g. by using enzymatic cleavage and subsequent recombination of DNA with insert DNA sequences. Mammalian cells such as the patient's own cells are then cultured in vitro and treated so as to take up the transgene in an expressible form. The trans-genes may be foreign to the mammalian cell, additional copies of genes already present in the cell, to increase the amount of expression product of the gene or copies of normal genes which may be defective or missing in a particular patient. Then the cells containing the trans-gene are introduced into the patient, so that the gene may express the required gene products in the body, for therapeutic purposes. The take-up of the foreign gene by the cells in culture may be accomplished by genetic engineering techniques, e.g. by causing transfection of the cells with a virus containing the DNA of the gene to be transferred by lipofection, by electro-poration, or by other accepted means to obtain transfected cells, [such as the use of viral vectors]. This is sometimes followed by selective culturing of the cells which have successfully taken up the transgene in an expressible form, so that administration of the cells to the patient can be limited to the transfected cells expressing the trans-gene. In other cases, all of the cells subject to the take-up process are administered. This procedure has in the past required administration of the cells containing the trans-gene directly to the body organ requiring treatment with the expression product of the trans-gene. Thus, transfected cells in an appropriate medium have been directly injected into the liver or into the muscle requiring the treatment, or via the systemic arterial circulation to enter the organ requiring treatment. Web site: http://www.delphion.com/details?pn=US06482406__

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Compounds having cGMP-PDE inhibitory effect Inventor(s): Nishida; Hidemitsu (Tokyo, JP), Ohashi; Masayuki (Tokyo, JP), Shudo; Toshiyuki (Tokyo, JP) Assignee(s): Mochida Pharmaceutical Co., Ltd. (tokyo, Jp) Patent Number: 6,476,021 Date filed: May 26, 2000 Abstract: Novel fused tetracyclic heterocyclic compounds having a potent and highly selective effect of inhibiting cyclic GMP phosphodiesterase (cGMP-PDE) and a high safety; a process for producing the same; drugs characterized by containing at least one of these compounds as the active ingredient, in particular, preventives and/or remedies for pulmonary hypertension, ischemic heart diseases, erectile insufficiency, female sexual dysfunction or diseases against which cGMP-PDE inhibitory effects are efficacious and intermediates useful in producing the above compounds. Excerpt(s): This invention relates to novel condensed tetracyclic hetero-ring compounds having action in inhibiting strongly and highly selectively cyclic GMPphosphodiesterase (hereinafter abbreviated as cGMP-PDE), featuring high safety, processes for producing such compounds, pharmaceuticals containing at least one of such compounds as an active ingredient, in particular, agents for preventing and/or treating pulmonary hypertension, ischemic heart diseases, erectile dysfunction, female sexual dysfunction or diseases against which the cGMP-PDE inhibition is effective, and intermediates useful for the production of the condensed tetracyclic hetero-ring compounds. The identity of vascular endothelial cell derived relaxing factors has been found to be nitric oxide (hereinafter abbreviated as NO) which, like nitroglycerin used to treat angina pectoris, manifests its vascular relaxing action as mediated by the increase in cyclic GMP (hereinafter abbreviated as cGMP). Briefly, nitrites-like relaxing factors exist endogenously and counteract catecholamine and other endogenous vasoconstricting factors to adjust the tone of blood vessels and contribute to the retention of adequate blood flow. Therefore, the decrease in NO or cGMP is believed to enhance vasotonia and reduce the blood flow in tissue, eventually causing circulatory disorders or ischemic heart diseases. Increase in vasotonia resulting from damage to coronary endothelial cells which are in the class of NO producing cells is believed to induce insufficiency in the blood flow in myocardial tissue, thereby causing anginal attacks. This results from disorders in the NO-cGMP system working as an endogenous relaxing factor. The vasodilating action of nitrites depends on the diameter of blood vessels for the degree of relaxation and because of their active site specificity (i.e., thicker coronary arteries are relaxed more intensely), nitrites have so far been in common use. However, the nitrites have a disadvantage in that their action is transient and attenuated during prolonged use. In addition, it has been pointed out that among vasodilators, adenosine enhancers such as dipyridamole which dilate narrow portions of coronary arteries to increase the coronary blood flow increase the myocardial blood flow at normal sites rather than at the lesion, thereby aggravating the ischemia (this phenomenon is generally referred to as "steal") and, hence, showing side effects such as aggravation of angina pectoris and pectoralgia. While no effective therapeutics have been available for the various pathogenic conditions that manifest pulmonary hypertension, it has recently been reported that NO gas inhalation therapy has certain utility. Since NO gas relaxes blood vessels and lower the pulmonary arterial pressure through the increase in cGMP, it is anticipated that activation of the cGMP producing system dilates selectively pulmonary arteries in the pulmonary circulation, thereby contributing to the treatment of pulmonary hypertension. Calcium blockers and many

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other vasodilating drugs have so far been used in attempts to treat pulmonary hypertension, none have been commercialized since every one of them is more potent in lowering the systemic blood pressure than the pulmonary arterial pressure. An oxygen therapy has been verified to be effective in achieving improvements after its application. However, oxygen intoxication occurs as a serious side effect and the occurrence of pulmonary lesions such as pulmonary edema and fibrosis has been reported with patients who were on prolonged oxygen therapy at home. The NO gas inhalation therapy is not an exception and the NO gas used in this therapy is one of the air pollutants NO.sub.x and will easily generate NO.sub.2 in the presence of oxygen, thereby potentially causing adverse effects on the airway and lungs; hence, utmost care is required in applying the NO gas and many problems are involved in its prolonged use. On the other hand, suppressing the cGMP degradation system is believed another way to maintain the concentration of cGMP, thereby allowing for selective decrease in the pulmonary arterial pressure. Briefly, an inhibitor of phosphodiesterase (hereinafter abbreviated as PDE) which is an enzyme catalyzing specific hydrolyzation of cyclic GMP holds promise as a new therapeutic free from the aforementioned side effects. Web site: http://www.delphion.com/details?pn=US06476021__ •

Endogenous nitric oxide synthesis under conditions of low oxygen tension Inventor(s): de Tejada; Inigo Saenz (Madrid, ES) Assignee(s): Nitromed, Inc. (bedford, Ma) Patent Number: 6,436,997 Date filed: October 29, 1999 Abstract: The present invention provides methods of promoting synthesis of nitric oxide or endothelium-derived relaxing factor (EDRF) in hypoxic mammalian tissues by administering at least one N-hydroxyguanidine compound that is a substrate of nitric oxide synthase, and, optionally, one or more vasoactive agents and/or thromboxane A2 receptor antagonists. The present invention also provides methods of promoting vasorelaxation and treating sexual dysfunctions in patients by administering at least one N-hydroxyguanidine compound that is a substrate for nitric oxide synthase, and, optionally, at least one vasoactive agent and/or thromboxane A2 receptor antagonist. The present invention also provides methods for treating clinical conditions resulting from hypoxic conditions such as pulmonary disease, cardiovascular disorders, circulatory hypoxia, specific organ hypoxia, localized hypoxia, edema, central nervous system disorders, memory loss, or arterial disease. The present invention also provides methods for treating clinical conditions resulting from an abnormally high level of arginase activity, such as, heart disease, systemic hypertension, pulmonary hypertension, sexual dysfunction, autoimmune disease, chronic renal failure and cerebral vasospasm. The present invention also provides methods for treating clinical conditions associated with a deficient nitric oxide pathway by administering at least one N-hydroxyguanidine compound and, optionally, one or more vasoactive agents and/or thromboxane A2 receptor antagonists. The present invention also provides pharmaceutical compositions comprising at least one N-hydroxyguanidine compound, and, optionally, one or more vasoactive agents and/or thromboxane A2 receptor antagonists. Excerpt(s): The present invention describes novel methods to induce synthesis of endogenous nitric oxide or endothelium-derived relaxing factor, and methods for maintaining levels of nitric oxide under hypoxic conditions. One aspect of the invention

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relates to novel methods to induce vasodilation. The present invention also provides methods for treating or preventing sexual dysfunctions in males and females by administering at least one N-hydroxyguanidine compound, such as N-hydroxy-Larginine, and, optionally, one or more vasoactive agents and/or thromboxane A2 receptor antagonists. The present invention also provides methods for treating clinical conditions resulting from hypoxic conditions, such as, pulmonary diseases, cardiovascular disorders, circulatory hypoxia, specific organ hypoxia, localized hypoxia, edema, central nervous system disorders, memory loss and/or arterial disease. The present invention also provides methods for treating clinical conditions resulting from an abnormally high level of arginase activity, such as, heart diseases, systemic hypertension, pulmonary hypertension, sexual dysfunctions, autoimmune diseases, chronic renal failure and/or cerebral vasospasm. The present invention also provides methods for treating clinical conditions associated with a deficient nitric oxide pathway by administering at least one N-hydroxyguanidine compound, and, optionally, one or more vasoactive agents and/or thromboxane A2 receptor antagonists. The present invention also provides novel compositions comprising at least one Nhydroxyguanidine, and optionally, one or more vasoactive agents and/or thromboxane A2 receptor antagonists. The N-hydroxyguanidine compounds in the present invention are substrates for nitric oxide synthase. Nitric oxide is a small diatomic molecule with multiple biological actions, including inhibition of platelet adhesion and aggregation, and relaxation of vascular and non-vascular smooth muscles. Nitric oxide has also been reported to have antiinflammatory, anti-bacterial and anti-viral properties (Moncada et al, Pharmacol Rev. 43:109-142 (1991)). In the gaseous state nitric oxide exists as a lipophilic molecule in a neutral redox state (NO). Nitric oxide is a complex molecule since it is able to exist in multiple redox states under different physiological conditions. It can also formally exist in charged forms i.e., nitrosonium (NO.sup.+) or nitroxyl (NO.sup.-), or as the neutral species, nitric oxide (NO.cndot.). In biological tissues, nitric oxide has a very short half-life, estimated at less than one second. One of the potent actions of nitric oxide in mammals is to relax vascular and non-vascular tissue, and, as such, either nitric oxide or an adduct that delivers nitric oxide, is useful as a vasodilator. In the mammalian body, endogenous nitric oxide is produced through an enzymatic reaction in which nitric oxide synthases utilize L-arginine and molecular oxygen for the synthesis of nitric oxide and citrulline. One of the actions of nitric oxide is believed to be the activation of a soluble form of guanylate cyclase, a cellular enzyme, which catalyses the formation of 3',5'-cyclic guanosine monophosphate (cGMP). The cGMP is believed to act on other cellular targets to mediate the relaxation of vascular smooth muscle and provide the therapeutic effect of vasodilation. Another action of nitric oxide is believed to be the regulation of Na.sup.(+) -K.sup.(+) -ATPase. Web site: http://www.delphion.com/details?pn=US06436997__ •

Endothelin antagonistic peptide derivatives Inventor(s): Fujita; Kagari (Tokyo, JP), Fukami; Takehiro (Tokyo, JP), Hayama; Takashi (Tokyo, JP), Ihara; Masaki (Tokyo, JP), Ikemoto; Fumihiko (Tokyo, JP), Ishikawa; Kiyofumi (Tokyo, JP), Mase; Toshiaki (Tokyo, JP), Nagase; Toshio (Tokyo, JP), Niiyama; Kenji (Tokyo, JP), Yano; Mitsuo (Tokyo, JP) Assignee(s): Banyu Pharmaceutical Co., Ltd. (tokyo, Jp) Patent Number: 5,691,315 Date filed: June 26, 1995

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Abstract: The invention relates to compounds which are antagonists of endothelin, to processes for their preparation, and to their use as pharmaceuticals. The compounds of the invention are Useful in the treatment of hypertension, pulmonary hypertension, Reynaud's disease, myocardial infarction, angina pectoris, acute renal failure, cerebral infarction, cerebral vasospasm, arteriosclerosis, asthma, endotoxin shock, endotoxininduced multiple organ failure or disseminated intravascular coagulation, and/or cyclosporin-induced renal failure or hypertension. Excerpt(s): The present invention relates to novel compounds having antagonism against a physiologically highly active endogenous peptide, endothelin, processes for their preparation and their use as a drug. The compounds of the present invention have antagonism against endothelint and thereby providing a new therapeutic potential, particularly for the treatment of hypertensiont pulmonary hypertension, Raynaud's disease, myocardial infarction, angina pectoris, acute renal failure, cerebral infarction, cerebral vasospasm, arteriosclerosis, asthmat endotoxin shock, endotoxin-induced multiple organ failure or disseminated intravascular coagulation, and/or cyclosporininduced renal failure or hypertension. As reported, the endothelin levels are clearly elevated in the blood of patients with essential hypertension, acute myocardial infarction, pulmonary hypertension of Raynaud's disease or atherosclerosis, or in the washing fluids of the respiratory tract of patients with asthmaticus as compared with normal levels (Japan. J. Hypertension, 12, 79 (1989), J. Vascular Medicine Biology, 2, 207 (1990), J. Am. Med. Association, 264, 2868 (1990), and The Lancet, ii, 207 (1990) and ii, 747-748 (1989)). Web site: http://www.delphion.com/details?pn=US05691315__ •

Endothelin antagonists Inventor(s): Cody; Wayne Livingston (Saline, MI), DePue; Patricia (Canton, MI), Doherty; Annette Marian (Ann Arbor, MI), He; John Xiaoqiang (Ypsilanti, MI), Taylor; Michael Douglas (Ann Arbor, MI) Assignee(s): Warner-lambert Company (morris Plains, Nj) Patent Number: 5,773,414 Date filed: March 7, 1997 Abstract: Novel antagonists of endothelin are described, as well as methods for the preparation and pharmaceutical compositions of the same, which are useful in treating elevated levels of endothelin, acute and chronic renal failure, hypertension, myocardial infarction, metabolic, endocrinological, neurological disorders, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, preeclampsia, Raynaud's disease, percutaneous transluminal coronary angioplasty or restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, ischemic bowel disease, and diabetes. Excerpt(s): The present invention relates to novel antagonists of endothelin useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. More particularly, the novel compounds of the present invention are antagonists of endothelin useful in treating elevated levels of endothelin, acute and chronic renal failure, hypertension, myocardial infarction, metabolic, endocrinological, neurological disorders, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, preeclampsia, Raynaud's

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disease, percutaneous transluminal coronary angioplasty and restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, ischemic bowel disease, and diabetes. Endothelin-1 (ET-1), a potent vasoconstrictor, is a 21 amino acid bicyclic peptide that was first isolated from cultured porcine aortic endothelial cells. Endothelin-1, is one of a family of structurally similar bicyclic peptides which include; ET-2, ET-3, vasoactive intestinal contractor (VIC), and the sarafotoxins (SRTX's). The unique bicyclic structure and corresponding arrangement of the disulfide bridges of ET1, which are the same for the endothelins, VIC, and the sarafotoxins, has led to significant speculation as to the importance of the resulting induced secondary structure to receptor binding and functional activity. ET-1 analogues with incorrect disulfide pairings exhibit at least 100-fold less vasoconstrictor activity. The flexible C-terminal hexapeptide of ET-1 has been shown to be important for binding to the ET receptor and functional activity in selected tissues. Additionally, the C-terminal amino acid (Trp-21) has a critical role in binding and vasoconstrictor activity, since ET›1-20! exhibits approximately 1000-fold less functional activity. Endothelin is involved in many human disease states. Web site: http://www.delphion.com/details?pn=US05773414__ •

Endothelin antagonists with ether-linked groups Inventor(s): Cheng; Xue-Min (Ann Arbor, MI), Doherty; Annette Marian (Ann Arbor, MI), Patt; William Chester (Chelsea, MI), Repine; Joseph Thomas (Ann Arbor, MI) Assignee(s): Warner-lambert Company (morris Plains, Nj) Patent Number: 6,133,263 Date filed: August 3, 1998 Abstract: Novel nonpeptide endothelin antagonists with ether-linked groups are described, as well as methods for the preparation and pharmaceutical compositions of the same, which are useful in treating atherosclerosis, restenosis, Raynaud's phenomenon, mild or severe congestive heart failure, cerebral ischemia, cerebral infarction, embolic stroke, cerebral vasospasm, subarachnoid hemorrhage, hemorrhagic stroke, diabetes, gastric ulceration and mucosal damage, ischemnic bowel disease, Chrohn's disease, essential or malignant hypertension, pulmonary hypertension, pulmonary hypertension after bypass, acute respiratory distress syndrome, chronic obstructive pulmonary diseases, male penile erectile dysfunction, cancer, especially malignant hemangicendothelioma or prostate cancer, myocardial infarction or ischemia, acute or chronic renal failure, renal ischemia, radiocontrast-induced nepbrotoxicity, endotoxic, septic, hemorrhagic shock, angina, preeclampsia, asthma, arhythmias, benign prostatic hyperplasia, and elevated levels of endothelin. Excerpt(s): The present invention relates to novel antagonists of endothelin useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. More particularly, the compounds of the present invention are antagonists of endothelin useful in treating elevated levels of endothelin, angina, arrhythmias, asthma, atherosclerosis, benign prostatic hyperplasia, Buerger's Disease, cardiac arrest, cardiogenic shock, cerebral trauma, Chrohn's Disease, congenital heart disease, congestive heart failure (CHF) (mild), congestive heart failure (CHF) (severe), cerebral ischemia, cerebral infarction, cerebral vasospasm, cirrhosis, diabetes, dilated cardiomyopathy, drowning (anoxia), endotoxic shock, gastric mucosal damage, glaucoma, head injury, hemodialysis, hemorrhagic shock, hypertension (essential),

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hypertension (malignant), hypertension (pulmonary), hypertension (pulmonary, after bypass), hypoglycemia, inflammatory arthritides, ischemic bowel disease, ischemic disease, male penile erectile dysfunction, malignant hemangioendothelioma, myocardial infarction, myocardial ischemia, prenatal asphyxia, postoperative cardiac surgery, prostate cancer, preeclampsia, Raynaud's Phenomenon, renal failure (acute), renal failure (chronic), renal ischemia, restenosis, sepsis syndrome, subarachnoid hemorrhage (acute), surgical operations, status epilepticus, stroke (thromboembolic), stroke (hemorrhagic), Takayasu's arteritis, ulcerative colitis, uremia after hemodialysis, and uremia before hemodialysis. Endothelin-1 (ET-1), a potent vasoconstrictor, is a 21 amino acid bicyclic peptide that was first isolated from cultured porcine aortic endothelial cells. Endothelin-1, is one of a family of structurally similar bicyclic peptides which include: ET-2, ET-3, vasoactive intestinal contractor (VIC), and the sarafotoxins (SRTXs). The distribution of the two cloned receptor subtypes, termed ET.sub.A and ET.sub.B, have been studied extensively (Arai H., et al., Nature, 1990;348:730, Sakurai T., et al., Nature, 1990;348:732). The ET.sub.A, or vascular smooth muscle receptor, is widely distributed in cardiovascular tissues and in certain regions of the brain (Lin H. Y., et al., Proc. Natl. Acad. Sci., 1991;88:3185). The ET.sub.B receptor, originally cloned from rat lung, has been found in rat cerebellum and in endothelial cells. The human ET receptor subtypes have been cloned and expressed (Sakamoto A., et al., Biochem. Biphys. Res. Chem., 1991;178:656, Hosoda K., et al., FEBS Lett., 1991;287:23). The ET.sub.A receptor clearly mediates vasoconstriction and there have been a few reports implicating the ET.sub.B receptor in the initial vasodilatory response to ET (Takayanagi R., et al., FEBS Lett., 1991;282:103). However, recent data has shown that the ET.sub.B receptor can also mediate vasoconstriction in some tissue beds (Panek R. L., et al., Biochem. Biophys. Res. Commun., 1992;183(2):566). Web site: http://www.delphion.com/details?pn=US06133263__ •

In ovo use of L-arginine and salts thereof in the prevention and/or treatment of pulmonary hypertension syndrome in avians Inventor(s): Bottje; Walter G. (Fayetteville, AR), Wideman, Jr.; Robert F. (Fayetteville, AR) Assignee(s): The Board of Trustees of the University of Arkansas (little Rock, Ak) Patent Number: 6,127,421 Date filed: January 31, 1997 Abstract: A method of treating an avian egg, including the step of administering to an avian egg a sufficient amount of an L-arginine compound to prevent pulmonary hypertension syndrome in an avian to be hatched from the egg. Excerpt(s): The present invention relates to treatment of avians. In another aspect, the present invention relates to the use of L-arginine for the treatment of avians. In even another aspect, the present invention relates to the administration of L-arginine to avians in ovo for the treatment of or prevention of pulmonary hypertension syndrome, also commonly known as ascites in poultry. Pulmonary hypertension syndrome was reported as early as 1968, and is a condition characterized by mortality with the accumulation of fluid (ascites fluid) in the abdomen of the bird. Ascites fluid accumulation in the body cavity may also be caused by tumor growth in the abdominal cavity. Pulmonary hypertension syndrome is caused by a high resistance to blood flow through the lungs. This excessive resistance of blood flow through the lungs causes an adverse effect on the heart, and hence pulmonary hypertension syndrome. As used

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hereinafter, "ascites" and "pulmonary hypertension syndrome" will be used interchangeably with the understanding that this form of ascites in poultry is in no way related to tumor growth. Pulmonary hypertension syndrome poses a serious problem to young fast growing poultry all over the world. First associated with flocks raised at high altitude, it is now recognized that other factors, such as cold temperatures, rapid growth, respiratory distress, high salt intake, and poor ventilation, also encourage pulmonary hypertension syndrome. Death from pulmonary hypertension syndrome results due to an enlarged heart, specifically including dilation and hypertrophy of the right ventricle. Congestive heart failure develops leading to liver damage, and kidney lung and intestinal problems, and compression of the air sac with abdominal fluids. While traditionally, male birds were at greater risk than females because of their faster growth rate, the conditions of modern poultry farming have caused female birds to suffer almost equally. Web site: http://www.delphion.com/details?pn=US06127421__ •

Indole derivatives useful in therapy Inventor(s): Challenger; Stephen (Kent, GB), Dack; Kevin Neil (Kent, GB), Derrick; Andrew Michael (Kent, GB), Dickinson; Roger Peter (Kent, GB), Ellis; David (Kent, GB), Hajikarimian; Yousef (Kent, GB), James; Kim (Kent, GB), Rawson; David James (Kent, GB) Assignee(s): Pfizer Inc. (new York, Ny) Patent Number: 6,211,223 Date filed: April 18, 2000 Abstract: The invention provides S-(+)-3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4methylphenyl)sulfonylami no]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylic acid, which is substantially free from its (R)-(-)-enantiomer, and pharmaceutically acceptable derivatives thereof. The compounds are useful in the treatment of inter alia acute renal failure, restenosis and pulmonary hypertension. Excerpt(s): This invention relates to an indole derivative useful in the treatment of a variety of diseases including acute renal failure, restenosis, and pulmonary hypertension, and to pharmaceutical formulations containing the compound. International Patent Application WO 94/14434 discloses indole derivatives which are indicated as endothelin receptor antagonists. European Patent Application 617001 discloses a large number of phenoxyphenylacetic acid derivatives which are also indicated as endothelin receptor antagonists. Bergman et al, Tetrahedron, Vol. 31, N.degree. 17, 1975, pages 2063-2073, disclose a number of indole-3-acetic acids. Similar compounds are disclosed by Rusinova et al., Khim. Geterotsikl. Soedin., 1974, (2), 211213 (see also Chemical Abstracts, Vol. 81, N.degree. 7, Aug. 19, 1974, abstract N.degree. 37455a), and Yarovenko et al, J. Gen. Chem. USSR (English translation), Vol. 39, 1969, page 2039 (see also Beilstein, Registry Number 431619). Web site: http://www.delphion.com/details?pn=US06211223__

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Injection of fructose-1,6-diphosphate (FDP) prior to coronary artery bypass grafting surgery Inventor(s): Fox; Anthony W. (Rancho LaCosta, CA), Marangos; Paul J. (La Costa, CA), Riedel; Bernhard (Harefield, GB), Royston; David (Harefield, GB) Assignee(s): Cypros Pharmaceutical Corp. (carlsbad, Ca) Patent Number: 6,076,528 Date filed: April 15, 1998 Abstract: Fructose-1,6-diphosphate (FDP) is used to treat patients who are undergoing coronary artery bypass grafting (CABG) surgery. Before cardiopulmonary bypass begins, a liquid that contains FDP is intravenously infused in the patient, preferably for about 10 to 30 minutes, to allow the FDP to enter the heart and lung tissue while the heart is still beating. FDP can also be added to cardioplegia solution; in addition, FDP can be injected after bypass is terminated, but if post-bypass injection is used, steps should be taken to avoid excess lactic acid accumulation, which appears to increase the risk of atrial fibrillation. To prevent or control lactic acidosis, a buffering or alkalizing agent, such as sodium bicarbonate, or an agent which reduces lactic acid formation, such as dichloroacetate, can be used. In double-blinded trials, this use of FDP substantially reduced heart damage and improved overall outcomes, as shown by lower levels of creatine kinase in blood, improvements in pumping performance, reduced requirements for vasodilator and inotropic drugs, and shorter stays in intensive care units. Certain dosages also reduced the likelihood of atrial fibrillation; however, FDP at high dosages increased the likelihood of A-fib. FDP also helped reduce pulmonary vascular resistance (PVR); this is an important finding, since pulmonary hypertension following cardiopulmonary bypass is a very difficult and often intractable problem, and is a contributing factor in nearly all deaths following CPB surgery. Excerpt(s): This invention relates to a method of using a drug to treat patients who undergo a surgical operation called "coronary artery bypass grafting" (abbreviated herein as CABG). In this type of surgery, segments of coronary arteries are replaced after they have become clogged or blocked (occluded) by cholesterol or fat deposits, to an extent where they cannot be adequately reopened by less invasive techniques such as balloon angioplasty. When replacement or bypass of the artery segments becomes necessary, the chest is opened and the clogged segments of the arteries are bypassed, using blood vessel segments harvested from elsewhere in the patient's body, usually from a saphenous veins in the patient's legs and/or a mammary vein in the patient's chest. Since the original coronary artery segments are usually left in place (empty, and not carrying blood) on the surface of the heart, this procedure is often referred to as an artery bypass, rather than an artery replacement. As used herein, terms such as "artery bypass" and "artery replacement" refer solely to coronary arteries, and are used interchangeably, regardless of whether a native artery segment is left in place or removed from the heart. Web site: http://www.delphion.com/details?pn=US06076528__

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Method for measuring nitric oxide in nitrosyl (FeII)-hemoglobin and Snitrosohemoglobin Inventor(s): Stamler; Jonathan S. (Chapel Hill, NC) Assignee(s): Duke University Medical Center (durham, Nc) Patent Number: 5,891,735 Date filed: March 15, 1996 Abstract: Nitrosyl (FeII) hemoglobin can be detected in biological samples, using a method which involves injections of samples into a photolysis cell, prior to detection of chemiluminescence generated by the reaction between nitric oxide and ozone. This method is useful for monitoring the levels of nitric oxide bioactivity in both normal physiological states, and disease states, such as septic shock, atherosclerosis, thrombosis, hyperhomocysteinemia, pulmonary hypertension, malignancy, infections and central nervous system disorders. Excerpt(s): This application claims priority to U.S. Provisional Application Number 60/003,801 filed on Sept. 15, 1995. Endothelium-derived relaxing factor (EDRF), is a product of the normal endothelial cell, and has both vasodilatory and antiplatelet properties (Furchgott, R. F. et al., Nature, 288:373-376 (1980); Moncada, S. et al., Biochem. Pharmacol, 38:1709-1713 (1989); Azuma, H. et al., Brit. J. Pharmacol. 88:411-415 (1986) and Radomski, M. W. et al., Brit. J. Pharmacol. 92:639-642 (1987)). Pharmacologic studies suggest that disease states as varied as septic shock, hyper-homocysteinemia, atherosclerosis, and hypoxia-induced pulmonary hypertension may be associated with abnormal concentrations of EDRF in the vascular milieu (Westernberger, U. et al., Free Rad. Res. Comm. 11:167-168 (1990); Yamamoto, H. et al., J. Clin. Invest. 81:1752-1758 (1988); Dinh-Xuan, A. T. et al., Engl. J. Med. 324:1539-1547 (1991)). This bioactive substance is believed to be equivalent to nitric oxide, or a chemical congener or adduct thereof (Palmer, R. M. G. et al., Nature 327:524-525 (1987); Ignarro, L. J. et al., Proc. Natl. Acad. Sci. 84:9265-9269 (1987)). Among the species of importance as biological adducts of nitric oxide are S-nitrosothiols, which are adducts with the sulfhydryl groups of amino acids, peptides, and proteins. It has been demonstrated that nitric oxide and authentic EDRF react with free thiol groups of proteins under physiologic conditions in vitro, to form S-nitroso-proteins. These nitric oxide adducts have bioactivities which are comparable to nitric oxide, but exhibit half-lives on the order of hours, significantly longer than that of EDRF (Stamler, J. S. et al., Proc. Natl. Acad. Sci. 89:444-448 (1992)). Web site: http://www.delphion.com/details?pn=US05891735__

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Method for the treatment of atherosclerosis and vascular injury by prevention of vascular smooth muscle cell proliferation Inventor(s): Horwitz; Lawrence D. (9853 E. Ida Ave., Englewood, CO 80111) Assignee(s): None Reported Patent Number: 5,786,326 Date filed: February 6, 1997 Abstract: A method for the treatment of atherosclerosis and vascular injury using exochelins, and more particularly exochelins of Mycobacterium tuberculosis, to prevent vascular smooth muscle cell proliferation. Delivery of an effective amount of a desferriExochelins to a living organism such as an animal or a human by oral, intravenous or

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direct delivery to the site at which the effect is desired will protect blood vessels in a living organism from restenosis following angioplasty or vascular surgery and will prevent or slow the progression of atherosclerosis, systemic hypertension, radiation damage to the vasculature, stenosis or closure of bypass grafts to the coronary arteries or other blood vessels following a surgical procedure and various forms of pulmonary hypertension. Excerpt(s): Inappropriate vascular smooth muscle proliferation is an integral component of the pathophysiology of several clinically important forms of vascular disease. Proliferation and migration of vascular smooth muscle cells are an important mechanism of the genesis of the atherosclerotic plaques that cause heart attacks, strokes or peripheral vascular disease (N Eng J Med;314:488-500, 1986). Restenosis after treatment of atherosclerotic vascular lesions with percutaneous transluminal angioplasty is a common adverse clinical outcome of this procedure. Restenosis involves a proliferative response of vascular smooth muscle at the site of the injury (J Am Coll Cardiol;6:369-375, 1985). Finally vascular smooth muscle proliferation has been proposed as an important component in the genesis of other forms of vascular injury or obstruction including closure of surgical bypass tracts (J Vascular Research;29:405-409, 1992), irradiation injury to the vasculature (J Am Coll Cardiol;19:1106-1113, 1992), systemic hypertension (J Hypertension;12:163-172, 1994) and neonatal or primary pulmonary hypertension (J Clin Invest;96:273-281, 1995 and Circulation;42:1163-1184, 1970). In vitro cell culture preparations are often used to study vascular smooth muscle cell proliferation. Proliferation of cells in culture after exposure to serum containing growth factors or exposure to individual growth factors can be quantitated by measurement of radioactive thymidine uptake in the cells (Circulation;90:1908-1918, 1994). Compounds which inhibit growth of cultured vascular smooth muscle cells have the potential to prevent abnormal vascular smooth muscle proliferation in human diseases (Am J Physiol;269:H1641-H1647, 1995). There is evidence that iron may be an important requirement for development of atherosclerosis. Iron overload due to injections of iron-dextran augments the formation of arterial atherosclerotic lesions in hypercholesterolemic rabbits (Arterioscler Thromb Vasc Biol;15:1172-1180, 1995). Oxidation of low density lipoprotein cholesterol is an important step in the early stages of development of atherosclerosis and is iron dependent (J Clin Invest;95:2104-2110, 1995). This may reflect the ability of free iron to catalyze the formation of highly reactive oxygen free radicals (Biochem J;184:469-472, 1979). However, chelation of iron inhibits cell growth or cell cycle progression in other models, including lymphocytes and neuroblastoma cell growth, where mechanisms unrelated to oxidation of low density lipoprotein cholesterol may occur (Blood;86:2268-2280, 1995). Finally the iron chelator deferoxamine prevents proliferation of vascular smooth muscle cells in vitro and prevents intimal thickening in vivo in rabbits (Arterioscler Thromb;14:299-304, 1994). Deferoxamine also reduces intimal smooth muscle proliferation in experimental vein grafts (J Vascular Research;29:405-409, 1992). Web site: http://www.delphion.com/details?pn=US05786326__

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Method for treating peripheral vascular disease by administering benzindene prostaglandins by inhalation Inventor(s): Cloutier; Gilles (Chapel Hill, NC), Crow; James (Chapel Hill, NC), Loyd; James E. (Nashville, TN), Parker; Richard E. (Spring Hill, TN), Wade; Michael (Chapel Hill, NC) Assignee(s): United Therapeutics Corporation (silver Spring, Md) Patent Number: 6,521,212 Date filed: March 15, 2000 Abstract: A method of delivering benzindene prostaglandins to a patient by inhalation is discussed. A benzindene prostaglandin known as UT-15 has unexpectedly superior results when administered by inhalation compared to parenterally administered UT-15 in sheep with induced pulmonary hypertension. Excerpt(s): Benzindene prostaglandins are now known to be useful to treat a variety of conditions. U.S. Pat. No. 5,153,222 describes the use of a preferred class of benzindene prostaglandins in the treatment of pulmonary hypertension, including both primary and secondary pulmonary hypertension. In particular, this patent discusses the use of the compound 9-deoxy-2',9-alpha-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene)-1 3,14-dihydro-prostaglandin F1 (also known as UT-15). However, this patent does not specifically suggest the administration of such benzindene prostaglandins by inhalation or the surprising benefits that result from their delivery by inhalation. All blood is driven through the lungs via the pulmonary circulation in order, among other things, to replenish the oxygen which it dispenses in its passage around the rest of the body via the systemic circulation. The flow through both circulations is in normal circumstances equal, but the resistance offered to it in the pulmonary circulation is generally much less than that of the systemic circulation. When the resistance to pulmonary blood flow increases, the pressure in the circulation is greater for any particular flow. This is referred to as pulmonary hypertension. Generally, pulmonary hypertension is defined through observations of pressures above the normal range pertaining in the majority of people residing at the same altitude and engaged in similar activities. Web site: http://www.delphion.com/details?pn=US06521212__

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Method of inducing vasorelaxation to treat pulmonary hypertension Inventor(s): Lawson; Charles A. (Verona, NY), Pinsky; David J. (Riverdale, NY), Smerling; Arthur (New Rochelle, NY), Stern; David M. (Great Neck, NY) Assignee(s): The Trustees of Columbia University in the City of New York (new York, Ny) Patent Number: 5,728,705 Date filed: October 4, 1993 Abstract: This invention provides a method of selectively decreasing pulmonary vascular resistance in a subject by administering endobronchially a drug chosen from among cAMP analogs, cGMP analogs, phosphodiesterase inhibitors, nitric oxide precursors, nitric oxide donors, and nitric oxide analogs. Excerpt(s): Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this

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invention pertains. Full bibliographic citation for these references may be found at the end of this application, preceding the claims. Pulmonary hypertension is associated with significant morbidity and mortality, yet therapeutic options remain limited because agents which lower pulmonary vascular resistance (PVR) also lower systemic vascular resistance (SVR) (1). Nitric oxide (NO) gas has recently been shown to selectively lower PVR in pulmonary hypertension (2,3), but concerns remain involving its potential chromosomal effects (4), formation of toxic products from reaction with oxygen (4,5), logistic difficulties associated with delivery of a gas, and its short biological half-life, necessitating constant administration for continued effect (3,6). Initial observations dealing with the use of cAMP and cGMP compounds go back to models of heart transplantation, where it was demonstrated that these systems were dysfunctional in the blood vessels of a transplanted heart. Supplementation of either the cGMP or the cAMP pathways could enhance the function of blood vessels within the graft, promoting successful transplantation. Stimulators of cAMP pathway used in these experiments included Sp-cAMPs, 8-Br-cAMP, db-cAMP, and phosphodiesterase inhibitors (indolidan, rolipram), all of which helped graft preservation. An antagonist of this pathway (RpcAMPS) blocked the beneficial effects of 8-Br-cAMP. Web site: http://www.delphion.com/details?pn=US05728705__ •

Method of reducing pulmonary hypertension and atrial fibrillation after surgery using cardiopulmonary bypass Inventor(s): Fox; Anthony W. (Rancho LaCosta, CA), Marangos; Paul J. (La Costa, CA), Riedel; Bernhard (Harefield, GB), Royston; David (Harefield, GB) Assignee(s): Cypros Pharmaceutical Corp. (carlsbad, Ca) Patent Number: 6,011,017 Date filed: April 15, 1998 Abstract: A method is disclosed for using fructose-1,6-diphosphate (FDP) to reduce and prevent two very serious problems caused by surgery that requires cardiopulmonary bypass. Before bypass begins, a liquid that contains FDP is intravenously injected into the patient, preferably over a period such as about 10 to 30 minutes, to allow the FDP to permeate in significant quantity into the heart and lungs while the heart is still beating. FDP can be added to the cardioplegia solution that is pumped through the heart to stop the heartbeat, and/or during bypass. This treatment was found to reduce two very important and serious problems that have unavoidably plagued CPB surgery in the past, which are: (1) elevated levels of pulmonary vascular resistance (PVR), which includes pulmonary hypertension; and (2) high occurrence rates for atrial fibrillation. Prior to this discovery, there has never been any satisfactory treatment which could reduce the severity and occurrence rates for these two major problems. FDP also can be co-administered in this manner, along with (1) a buffering or alkalizing agent that counteracts acidosis, such as sodium bicarbonate or THAM, and/or (2) a drug that reduces the formation of lactic acid, such as dichloroacetate. Excerpt(s): This invention relates to a method of using a drug to reduce and prevent two very serious problems that often arise as a result of surgery involving cardiopulmonary bypass. (7) surgery to correct a congenital heart disease, which is done most commonly in children. It should be noted that children who suffer from congenital heart disease that is sufficiently severe to require CPB surgery also tend to suffer from high rates of pulmonary hypertension. All of these types of surgery are described in various wellknown medical texts, such as Gibbon's Surgery of the Chest (Sabiston and Spencer, eds.,

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Saunders Publ., Philadelphia, Pa.) and in various medical journals that are devoted to the subject of cardiac and/or thoracic surgery. Web site: http://www.delphion.com/details?pn=US06011017__ •

Method of treating pulmonary hypertension Inventor(s): Lehtonen; Lasse (Espoo, FI) Assignee(s): Orion Corporation (espoo, Fi) Patent Number: 6,462,045 Date filed: February 22, 2001 Abstract: Levosimendan, or (-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3pyridazinyl)phenyl]hydrazono] -propanedinitrile, which has been previously suggested for tho treatment of congestive heart failure is useful in the treatment of pulmonary hypertension. Excerpt(s): This application is a national stage filing of PCT International Application No. PCT/FI99/00540, filed on Jun. 18, 1999, which published in the English language. The present invention relates to the use of levosimendan, or (-)-[[4-(1,4,5,6-tetrahydro-4methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono] propanedinitrile (I), or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of pulmonary hypertension. The hemodynamic effects of levosimendan in man are described in Sundberg, S. et al., Am. J. Cardiol., 1995; 75: 1061-1066 and in Lilleberg, J. et al., J. Cardiovasc. Pharmacol., 26(Suppl.1), S63-S69, 1995. Pharmacokinetics of levosimendan in man after i.v. and oral dosing is described in Sandell, E.-P. et al., J. Cardiovasc. Pharmacol., 26(Suppl.1), S57-S62, 1995. The use of levosimendan in the treatment of myocardial ischemia is described in WO 93/21921. Clinical studies have confirmed the beneficial effects of levosimendan in heart failure patients. Web site: http://www.delphion.com/details?pn=US06462045__

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Method of using PKC inhibiting compounds to treat vascular disease Inventor(s): Dempsey; Edward C. (Denver, CO) Assignee(s): University Technology Corporation (boulder, Co) Patent Number: 6,228,843 Date filed: April 21, 2000 Abstract: A method for treating pulmonary and systemic vascular diseases associated with cardiac hypotrophy, dysfunction or failure that involves the administration of an effective amount of a PKC antagonist to a patient suffering from one of such diseases is disclosed. PKC antagonists are selected from bryostatin derivatives and more preferably from bryostatin-1. The disease states treatable in accordance with the present invention are characterized by alterations in vascular structure, vascular tone, myocardial hypotrophy, dysfunction or failure, idiopathic pulmonary hypertension and chronic hypoxic pulmonary hypertension. Particular formulations include bryostatin-1 in an effective amount to treat one or more of the above-referenced diseases.

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Excerpt(s): The present invention is directed to a method for treating pulmonary and systemic vascular diseases associated with cardiac hypertrophy, dysfunction, or failure, such method comprising administering effective amounts of a PKC antagonist to a patient suffering from one of such diseases. The methods may also be effective at directly treating airway and interstitial diseases of the lung that lead to the development of pulmonary hypertension. Other embodiments relate to particular formulations of bryostatin compounds formulated for particular diseases, as well as methods of using such compounds to treat patients having such diseases. Adult and neonatal pulmonary and systemic vascular disease is a common clinical problem. These vascular diseases include pulmonary and/or systemic hypertension, atherosclerosis, post-angioplasty restenosis, post-transplant vasculopathy, diabetic vasculopathy, peripheral vascular disease, vasculitis, and capillaritis. They are complicated by cardiac hypertrophy, dysfunction, or failure. These clinical problems characteristically include alterations in vascular structure, such as abnormalities in vessel wall thickness and/or vessel formation and/or obliteration, and alterations in vascular tone, such as abnormal contractile response to agonists. Myocardial hypertrophy, dysfunction, or failure are also often observed. These disease processes also cause important vascular cell responses in smooth muscle cells, adventitial fibroblasts, and endothelial cells that contribute to the disease process, including hypertrophy, proliferation, migration, matrix protein synthesis, permeability, and contraction. Inflammatory cell recruitment and activation is also though to be important in the pathogenesis of vascular disease. Among these diseases is chronic hypoxic pulmonary hypertension (PHTN), which results from structural remodeling and abnormalities of vascular tone (Reeves and Herget, 1984; Haworth, 1993). The alteration in vascular structure results from changes in cellular hypertrophy, proliferation, apoptosis, differentiation, migration, permeability and matrix protein synthesis (Meyrick and Reid, 1979; Rabinovich, et al., 1981; Jones, et al., 1984; Stenmark, et al., 1987). The pulmonary hypertensive process has been observed in several species, including adult mice (Hales, et al., 1983; Klinger, et al., 1993; Steudel, et al., 1998; Fagan, et al., 1999). Web site: http://www.delphion.com/details?pn=US06228843__ •

Methods of treating pulmonary hypertension Inventor(s): Gehlert; Donald Richard (Indianapolis, IN), Steinberg; Mitchell Irvin (Indianapolis, IN) Assignee(s): Eli Lilly and Company (indianapolis, In) Patent Number: 5,846,973 Date filed: May 23, 1997 Abstract: This invention provides methods of inhibiting pulmonary hypertensive disease which comprise administering to a mammal in need thereof a compound having activity as a tachykinin receptor antagonist. Excerpt(s): This application claims the benefit of United States Provisional Patent application Ser. No. 60/018,266, filed May 24, 1996. Tachykinins are a family of peptides which share a common amidated carboxy terminal sequence. Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early 1970's. Between 1983 and 1984 several groups reported the isolation of two novel mammalian tachykinins, now termed neurokinin A (also known as substance K, neuromedin L, and neurokinin.alpha.), and

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neurokinin B (also known as neuromedin K and neurokinin.beta.). See, J. E. Maggio, Peptides, 6 (Supplement 3):237-243 (1985) for a review of these discoveries. Web site: http://www.delphion.com/details?pn=US05846973__ •

Nitric oxide donor compounds and pharmaceutical compositions for pulmonary hypertension and other indications Inventor(s): Brilli; Richard J. (43150 Ashley Meadow Ct., Cincinnati, OH 45227), KrafteJacobs; Brian (2216 Heather Hill Blvd., Cincinnati, OH 45244), Salzman; Andrew L. (8280 Kugler Mill Rd., Cincinnati, OH 45243), Smith; Daniel J. (2988 Ridgeline Trail, Stow, OH 44224), Szabo; Csaba (3654 Stonebridge Dr., Apt. #E, Cincinnati, OH 45209) Assignee(s): None Reported Patent Number: 5,958,427 Date filed: November 8, 1996 Abstract: The invention is directed to nitric oxide (NO) donor compounds and to pharmaceutical compositions containing such nitric oxide (NO) donor compounds, for delivering NO to the apical surface of a mucosa, where the nitric oxide is released for passage across the epithelial monolayer of the mucous membrane. The NO donor compounds include polyalkyleneamine NO donors as well as tertiary and quaternary amino aliphatic NO donor compounds. The compounds and compositions of the invention are useful in any situation in which it is desirable to deliver NO across a mucosal surface. For example, the compounds and compositions of the invention are particularly useful in treating pulmonary hypertension, male impotence, and several other specific conditions. Excerpt(s): This invention relates to nitric oxide donor compounds and, more particularly, to such compounds and their pharmaceutical compositions for use in delivering nitric oxide to the apical surface of a mucosa, where the nitric oxide is released for passage across the epithelial monolayer of the mucous membrane. The invention also relates to the treatment of specific conditions and disorders in which the local delivery of nitric oxide has a salutory effect. Such conditions and disorders include, for example, pulmonary hypertension and impotence, which benefit from the invention's ability to cause local vasodilation without causing a similar vasodilation of the systemic vasculature. Pulmonary hypertension is a serious medical condition. Acute pulmonary hypertension, resulting from a deficiency of nitric oxide (NO) production in the pulmonary vasculature or from a non-NO related process, increases pulmonary capillary pressure, augments transvascular flux, and increases right ventricular afterload. Additionally, in the presence of right to left anatomic extrapulmonary shunts or intrapulmonary physiologic shunts, pulmonary hypertension may contribute to systemic desaturation. Chronic pulmonary hypertension also may induce remodeling of the pulmonary vasculature, inducing an irreversible smooth muscle hypertrophy. In addition to being quite serious, pulmonary hypertension is frequently encountered, resulting from a number of conditions, including for example, adult respiratory distress syndrome, neonatal respiratory distress syndrome, pneumonia, asthma, bronchiolitis, chronic obstructive pulmonary disease, restrictive lung disease, near drowning, cardiopulmonary arrest, cardiopulmonary bypass, emphysema, sepsis, infection, shock, congenital heart disease and congenital diaphragmatic hernia. Web site: http://www.delphion.com/details?pn=US05958427__

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Nonpeptide endothelin antagonists I Inventor(s): Berryman; Kent Alan (Ann Arbor, MI), Doherty; Annette Marian (Ann Arbor, MI), Edmunds; Jeremy John (Ypsilanti, MI), Patt; William Chester (Chelsea, MI), Plummer; Mark Stephen (Dexter, MI), Repine; Joseph Thomas (Ann Arbor, MI) Assignee(s): Warner-lambert Company (morris Plains, Nj) Patent Number: 5,691,373 Date filed: February 6, 1995 Abstract: Novel nonpeptide antagonists of endothelin I are described, as well as methods for the preparation and pharmaceutical compositions of the same, which are useful in treating elevated levels of endothelin, acute and chronic renal failure, hypertension, myocardial infarction, myocardial ischemia, cerebral vasospasm, cerebral ischemia, cerebral infarction, cirrhosis, septic shock, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, preeclampsia, atherosclerotic disorders including Raynaud's disease and restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, hemorrhagic shock, ischemic bowel disease, stroke, benign prosthatic hyperplasia (BPH), and diabetes. Excerpt(s): The present invention relates to novel antagonists of endothelin useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. More particularly, the compounds of the present invention are antagonists of endothelin useful in treating elevated levels of endothelin, acute and chronic renal failure, hypertension, myocardial infarction and myocardial ischemia, cerebral vasospasm, cirrhosis, septic shock, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, preeclampsia, atherosclerotic disorders including Raynaud's disease and restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, hemorrhagic shock, ischemic bowel disease, and diabetes. Also, the compounds will be useful in cerebral ischemia or cerebral infarction resulting from a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, head injury, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma. Several studies have been reported with both peptide and non-peptide ET antagonists showing efficacy in various models of subarachnoid hemorrhage (SAH). For example, BQ-123-prevents early cerebral vasospasm following SAH in various rat (Clozel M., et al., Life Sci, 1993;52:825) and rabbit (Lee K. S., et al., Cerebral Vasospasm 1993:217; and Neurosurgery 1994; 34:108) models. FR 139317 significantly inhibited the vascoconstriction of the basilar artery after 7 days in a canine two-hemorrhage model of SAH (Nirei H., et al., Life Sci. 1993;52:1869). BQ-485 also significantly inhibited the vascoconstriction of the basilar artery after 7 days in a canine two-hemorrhage model of SAH (Yano, et al., Biochem Biophys. Res Commun. 1993; 195:969). Ro 46-2005 (Clozel M., et al., Nature 1993;365:759) has been shown to prevent early cerebral vasospasm following SAH in the rat with no significant effect on systemic arterial blood pressure. Treatment with Ro 47-0203=Bosentan (Clozel et al., Circulation 1993;88(4) part 2:0907) to rabbits with SAH had a 36.+-.7% reduction of basilar artery cross-sectional area compared to sham rabbits. All of these studies show in vivo efficacy of endothelin antagonists in cerebral vasospasm resulting from SAH. Web site: http://www.delphion.com/details?pn=US05691373__

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Pyridocarbazole derivatives having cGMP-PDE inhibitory activity Inventor(s): Kikuchi; Akira (Tokyo, JP), Nishida; Hidemitsu (Tokyo, JP), Nishijima; Kazumi (Tokyo, JP), Notso; Tatsuto (Tokyo, JP), Ohashi; Masayuki (Tokyo, JP), Shudo; Toshiyuki (Tokyo, JP), Yanagibashi; Kazutoshi (Tokyo, JP) Assignee(s): Mochida Pharmaceutical Co., Ltd. (tokyo, Jp) Patent Number: 6,018,046 Date filed: January 29, 1998 Abstract: The invention relates to novel pyridocarbazole derivatives having highly selective action in inhibiting cyclic GMP-phosphodiesterase (hereinafter abbreviated as cGMP-PDE), processes for producing such derivatives, agents containing at least one of such derivatives as an active ingredient for preventing and/or treating pulmonary hypertension, ischemic heart diseases or diseases against which the cGMP-PDE inhibitory action is effective, and intermediates useful for the production of pyridocarbazole derivatives. Excerpt(s): This invention relates to novel pyridocarbazole derivatives having action in inhibiting highly selective cyclic GMP-phosphodiesterase (hereinafter abbreviated as cGMP-PDE), processes for producing such derivatives, pharmaceuticals containing at least one of such derivatives as an active ingredient, in particular, agents for preventing and/or treating pulmonary hypertension, ischemic heart diseases or diseases against which the cGMP-PDE inhibition is effective, and intermediates useful for the production of pyridocarbazole derivatives. The identity of vascular endothelial cell derived relaxing factors has been found to be nitric oxide (hereinafter abbreviated as NO) which, like nitroglycerin used to treat angina pectoris, manifests its vascular relaxing action as mediated by the increase in cyclic GMP (hereinafter abbreviated as cGMP). Briefly, nitrites-like relaxing factors exist endogenously and counteract catecholamine and other endogenous vasoconstricting factors to adjust the tone of blood vessels to thereby contribute to the retention of adequate blood flow. Therefore, the decrease in NO or cGMP is believed to enhance vasotonia and reduce the blood flow in tissue, eventually causing circulatory disorders or ischemic heart diseases. Increase in vasotonia resulting from damage to coronary endothelial cells which are in the class of NO producing cells is believed to induce insufficiency in the blood flow in myocardial tissue, thereby causing anginal attacks. This results from disorders in the NO-cGMP system working as an endogenous relaxing factor. The vasodilating action of nitrites depends on the diameter of blood vessels for the degree of relaxation and because of their active site specificity (i.e., thicker coronary arteries are relaxed more intensely), nitrites have so far been in common use. However, the nitrites have a disadvantage in that their action is transient and attenuated during prolonged use. In addition, it has been pointed out that among vasodilators, adenosine enhancers such as dipyridamole which dilate narrow portions of coronary arteries to increase the coronary blood flow increase the myocardial blood flow at normal sites rather than at the lesion, thereby aggravating the ischemia (this phenomenon is generally referred to as "steal") and, hence, showing side effects such as aggravation of angina pectoris and pectoralgia. Web site: http://www.delphion.com/details?pn=US06018046__

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Quinazolines as inhibitors of endothelin converting enzyme Inventor(s): Ahn; Kyunghye (Ann Arbor, MI), Cheng; Xue-Min (Ann Arbor, MI), Doherty; Annette Marian (Ann Arbor, MI), Elslager; Edward Faith (Ann Arbor, MI), Kornberg; Brian (Ann Arbor, MI), Lee; Chitase (Ann Arbor, MI), Leonard; Daniele (Ann Arbor, MI), Nikam; Sham (Ann Arbor, MI), Werbel; Leslie Morton (Ann Arbor, MI) Assignee(s): Warner-lambert Company (morris Plains, Nj) Patent Number: 5,773,444 Date filed: April 14, 1997 Abstract: Novel quinazoline inhibitors of endothelin converting enzyme are described, as well as methods for the preparation and pharmaceutical compositions of the same, which are useful in treating elevated levels of endothelin and in controlling hypertension, myocardial infarction and ischemia, metabolic, endocrinological, and neurological disorders, congestive heart failure, endotoxic and hemorrhagic shock, septic shock, subarachnoid hemorrhage, arrhythmias, asthma, acute and chronic renal failure, cyclosporin-A induced nephrotoxicity, angina, gastric mucosal damage, ischemic bowel disease, cancer, pulmonary hypertension, preeclampsia, atherosclerotic disorders including Raynaud's disease and restenosis, cerebral ischemia and vasospasm, and diabetes. Excerpt(s): The present invention relates to novel quinazoline inhibitors of endothelin converting enzyme useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. More particularly, the novel compounds of the present invention are inhibitors of endothelin converting enzyme useful in treating elevated levels of endothelin and in controlling hypertension, myocardial infarction and ischemia, metabolic, endocrinological, and neurological disorders, congestive heart failure, endotoxic and hemorrhagic shock, septic shock, subarachnoid hemorrhage, arrhythmias, asthma, acute and chronic renal failure, cyclosporin-A induced nephrotoxicity, angina, gastric mucosal damage, ischemic bowel disease, cancer, pulmonary hypertension, preeclampsia, atherosclerotic disorders including Raynaud's disease and restenosis, cerebral ischemia and vasospasm, and diabetes. Endothelin-1 (ET-1), a potent vasoconstrictor, is a 21 amino acid bicyclic peptide that was first isolated from cultured porcine aortic endothelial cells. Endothelin1, is one of a family of structurally similar bicyclic peptides which include; ET-2, ET-3, vasoactive intestinal contractor (VIC), and the sarafotoxins (SRTXs). The unique bicyclic structure and corresponding arrangement of the disulfide bridges of ET-1, which are the same for the endothelins, VIC, and the sarafotoxins, has led to significant speculation as to the importance of the resulting induced secondary structure to receptor binding and functional activity. ET-1 analogs with incorrect disulfide pairings exhibit at least 100fold less vasoconstrictor activity. Endothelin-1 is generated from a 203 amino acid peptide known as preproendothelin by an unknown dibasic endopeptidase. This enzyme cleaves the prepropeptide to a 38 (human) or 39 (porcine) amino acid peptide known as big endothelin or proendothelin. Big ET is then cleaved by an enzyme, known as endothelin converting enzyme or ECE, to afford the biologically active molecule ET-1. Big ET is only 1% as potent as ET-1 in inducing contractile activity in vascular strips but it is equally potent in vivo at raising blood pressure, presumably by rapid conversion to ET-1 (Kimura S, Kasuya Y, Sawamura T, et al., "Conversion of big endothelin-1 to 21residue endothelin-1 is essential for expression of full vasoconstrictor activity: Structureactivity relationship of big endothelin-1," J Cardiovasc Pharmacol 1989;13:S5). There have been numerous reports describing possible proteases in both the cytoplasm and

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membrane bound cellular fractions of endothelial cells (Ikegawa R, Matsumura Y, Takaoka M, et al., "Evidence for pepstatin-sensitive conversion of porcine big endothelin-1 to endothelin-1 by the endothelial cell extract," Biochem Biophys Res Commun 1990;167:860; Sawamura T, Kimura S, Shinmi O, et al., "Characterization of endothelin converting enzyme activities in soluble fraction of bovine cultured endothelial cells," Biochem Biophys Res Commun 1990;169:1138; Sawamura T, Shinmi O, Kishi N, et al., "Analysis of big endothelin-1 digestion by cathepsin D." Biochem Biophys Res Commun 1990;172:883; Shields P P, Gonzales T A, Charles D, et al., "Accumulation of pepstatin in cultured endothelial cells and its effect on endothelin processing," Biochem Biophys Res Commun 1991;177:1006; Matsumura Y, Ikegawa R, Tsukahara Y, et al., "Conversion of big endothelin-1 to endothelin-1 by two types of metalloproteinases derived from porcine aortic endothelial cells," FEBS Lett, 1990;272:166; Sawamura T, Kasuya Y, Matsushita S N, et al., "Phosphoramidon inhibits the intracellular conversion of big endothelin-1 to endothelin-1 in cultured endothelial cells," Biochem Biophys Res Commun 1991;174:779; Takada J, Okada K, Ikenaga T, et al., "Phosphoramidon-sensitive endothelin-converting enzyme in the cytosol of cultured bovine endothelial cells," Biochem Biophys Res Commun 1991;176:860; Ahn K, Beningo K, Olds G, Hupe D, "Endothelin-converting enzyme from bovine and human endothelial cells," J Vasc Res 1991;29:76, 2nd International symposium on endotheliumderived vasoactive factors). Many groups have chosen to isolate ECE from endothelial cells of various species, since endothelin is known to be synthesized and secreted by this cell type. It was initially reported that two types of protease activity were present in porcine or bovine endothelial cells that could cause conversion of big ET to ET in vitro (Ikegawa R, supra; Sawamura T, supra; Matsumura Y, supra; Takada J, supra; Ahn K, supra). However, it was subsequently found that the aspartic protease activity from porcine endothelial cells, thought to be predominantly cathepsin D, also caused further degradation of ET-1 and was therefore unlikely to be the true ECE (Sawamura T, supra). Moreover, human cathepsin D also causes rapid degradation of ET-1. In addition, there has been one study showing that the intracellular accumulation of pepstatin, an aspartic protease inhibitor, did not inhibit ET-1 production in cultured bovine aortic endothelial cells (Shields P P, supra). Stronger evidence that ECE is in fact a neutral metalloprotease has appeared (Matsumura Y, supra; Sawamura T, supra; Takada J, supra; Ahn K, supra) and, recently, rat and bovine ECE genes have been cloned and expressed, confirming that ECE is a phosphoramidon sensitive metalloprotease. (Shimada, K., Tanzawa, K., J. Biol. Chem. 1994, 269, 18275) (Dong, X., Emoto, N., Giaid, A., Slaughter, C., Kaw, S., deWit, D., Yanagisawa, M., Cell 1994, 78, 1-20). However, the nonspecific metalloproteinase inhibitor, phosphoramidon, has been shown to inhibit the intracellular conversion of big ET-1 to ET-1 in cultured vascular endothelial cells and smooth muscle cells (Sawamura T, supra). Web site: http://www.delphion.com/details?pn=US05773444__ •

Selective vasodilation by continuous adenosine infusion Inventor(s): Sollevi; Alf (Bromma, SE) Assignee(s): Item Development AB (stocksund, Se) Patent Number: 5,731,296 Date filed: March 15, 1993 Abstract: This invention is concerned with the use of adenosine as an agent for the treatment of human beings. More particularly, this invention is concerned with the

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administration of adenosine to human patients by continuous intravenous infusion for, inter alia, control of blood pressure, use as a selective vasodilator, decreasing pulmonary vascular resistance, treating acute pulmonary hypertension in conjunction with idiopathic respiratory distress syndrome, in diagnosing pulmonary hypertension in conjunction with cardiac septum defects, in percutaneous transluminal angioplasty (PTCA), in coronary thrombolysis (CTL) and in radionucleide scintography. Excerpt(s): This invention is concerned with the use of adenosine as an agent for the treatment of human beings. More particularly, this invention is concerned with the administration of adenosine to human patients by continuous intravenous infusion for, inter alia., control of blood pressure, use as a selective vasodilator, decreasing pulmonary vascular resistance, treating acute pulmonary hypertension, treating pulmonary hypertension in conjunction with idiopathic respiratory distress syndrome, and in diagnosing pulmonary hypertension in conjunction with cardiac septum defects. Adenosine is a naturally occurring nucleoside composed of the purine, adenine, and the sugar, D-ribose. Normal basal plasma levels of adenosine are from about 0.1 to about 0.2.mu.mol per liter. In addition, it is commonly present in the body in the form of adenosine monophosphate (AMP), adenosine diphosphate (ADP) and adenosine triphosphate (ATP). Adenosine has been reported to have a variety of biological effects, depending on whether the adenosine is endogenous or exogenously administered, including sedative and anti-epileptic effects on the central nervous system and inhibitory effects on respiration, cardio-vascular effects, including prolongation of atrioventricular conduction time and impulse formation in the sinus node, vasodilation, antiaggregatory effect, decreased release of free fatty acids, anti-secretory effect in the stomach, and anti-diuretic effect. As a general rule, however, adenosine and its biological effects have been largely of physiological interest. To the extent adenosine was of interest as a pharmaceutical product, that interest has centered primarily on its phosphate derivative, which now is known to be rapidly metabolized to yield adenosine and phosphate in the circulation. See Sollevi et al., Acta. Physiol. Scand. 120:171-6 (1984). However, phosphate may cause undesired side effects. For example, high levels of phosphate may cause arrhythmias secondary to chelation of magnesium and calcium. (See Dedrick, et al., Anesthesiology, 57:3A, 66 (1982)). Web site: http://www.delphion.com/details?pn=US05731296__ •

Treatments based on discovery that nitric oxide synthase is a paraquat diaphorase Inventor(s): Day; Brian J. (Englewood, CO), Griffith; Owen W. (Milwaukee, WI), Gross; Steven S. (New York, NY), Stamler; Jonathan S. (Chapel Hill, NC) Assignee(s): Cornell Research Foundation, Inc. (ithaca, Ny), Duke University (durham, Nc), National Jewish Medical and Research Center (denver, Co) Patent Number: 6,231,894 Date filed: October 21, 1999 Abstract: Paraquat has been found to accept electrons from nitric oxide synthase (NOS) whereupon the reduced paraquat generates toxic O.sub.2.sup.- and prevents NOS from giving electrons to arginine and thereby inhibits NO production. This is generalized for compounds with a redox potential greater than nitric oxide synthase. The compounds inhibit nitric oxide synthase and kill cells including NOS by generating O.sub.2.sup.and also by depriving the cells of the NO which they need. Applications include treating paraquat-induced injury and pathologically proliferating cells (tumors, restenosis benign prostatic hypertrophy, pulmonary hypertension, infective pathogens).

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Excerpt(s): The invention is directed to treating disorders in which reactive oxygen contributes to the pathology (e.g., paraquat-induced injury, stoke, adriamycin toxicity), to treating disorders characterized by pathologically proliferating cells containing a diaphorase, to inhibiting nitric oxide synthase, to constricting blood vessels, and for treating for NO depletion. Paraquat is a herbicide which damages the lungs, liver and kidneys, and produces toxicity by redox cycling with cellular diaphorases, thereby elevating intracellular levels of superoxide (O.sub.2.sup.-). Nitric oxide synthase (NOS) has been shown to participate in paraquat-induced lung injury. Current theory holds that nitric oxide (NO) generated by NOS reacts with O.sub.2.sup.- generated by paraquat to produce the toxic peroxynitrite. It has now been discovered that the "current theory" is incorrect and that rather NOS functions as a paraquat diaphorase. In other words, paraquat accepts electrons from nitric oxide synthase whereupon the reduced paraquat generates toxic O.sub.2.sup.- and prevents NOS from giving electrons to arginine and thereby inhibits NO production thereby resulting in NO depletion. This is generalized for compounds with a redox potential greater than nitric oxide synthase. The compounds cause generation of O.sub.2.sup.- and inhibit nitric oxide synthase and kill cells including NOS, by the combination of the increased O.sub.2.sup.- and of depriving the cells of the NO which they need. Web site: http://www.delphion.com/details?pn=US06231894__

Patent Applications on Pulmonary Hypertension 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 pulmonary hypertension: •

Acylated indanyl amines and their use as pharmaceuticals Inventor(s): Dharanipragada, Ramalinga M.; (Belle Meade, NJ), Safarova, Alena; (Tucson, AZ), Schonafinger, Karl; (Alzenau, DE), Strobel, Hartmut; (Liederbach, DE), Suzuki, Teri; (Tucson, AZ), Walser, Armin; (Tucson, AZ), Wohlfart, Paulus; (Bensheim, DE) Correspondence: Finnegan, Henderson, Farabow,; Garrett & Dunner, L.L.P.; 1300 I Street, N.W.; Washington; DC; 20005-3315; US Patent Application Number: 20030055093 Date filed: February 13, 2002 Abstract: The present invention relates to acylated indanyl amines according to the general formula (I) 1wherein R.sup.1-R.sup.4 have the meanings given in the description, A is CH.sub.2, CHOH or CH--(C.sub.1-C.sub.3-alkyl), B is CH.sub.2 or CH-(C.sub.1-C.sub.3-alkyl), and R.sup.5 is an aryl or heteroaryl group, possibly substituted by the substituents listed in the description. These compounds are useful in the upregulation of endothelial nitric oxide synthase (eNOS), and may therefore be useful for the manufacture of medicaments for the treatment of cardiovascular diseases, stable or unstable angina pectoris, coronary heart disease, Prinzmetal angina, acute coronary syndrome, heart failure, myocardial infarction, stroke, thrombosis, peripheral artery occlusive disease, endothelial dysfunction, atherosclerosis, restenosis, endothelial

10

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

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damage after PTCA, hypertension, essential hypertension, pulmonary hypertension, secondary hypertension, renovascular hypertension, chronic glomerulonephritis, erectile dysfunction, ventricular arrhythmia, diabetes or diabetes complications, nephropathy or retinopathy, angiogenesis, asthma bronchiale, chronic renal failure, cirrhosis of the liver, osteoporosis, restricted memory performance, a restricted ability to learn, or for the lowering of cardiovascular risk of postmenopausal women or after intake of contraceptives. Excerpt(s): Endothelial NO synthase (eNOS, NOS-III) belongs to a group of three isoenzymes which produce nitric oxide (NO) by oxidation of arginine. Endothelially released NO is of central importance in a number of key cardiovascular mechanisms. It has a vasodilating effect and inhibits the aggregation of platelets, the adhesion of leukocytes to the endothelium and the proliferation of intimal smooth muscle cells. Endothelial NO synthase is subject to physiological and pathophysiological regulation both at the transcriptional and at the post-transcriptional level. Enzyme already present in the endothelium may undergo calcium-dependent and calcium-independent activation through phosphorylation of specific amino acids, but also by direct interactions with specific proteins. Stimulators of this, usually transient, NO release are, extracellular arginine, 17.beta.-estrogen and the mechanical stimulus exerted on the luminal surface of the endothelium by the blood flow (shear stress). The latter additionally leads to regulation of eNOS at the transcriptional level. Thus, for example, Sessa et al. (Circ. Research 74 (1994) 349-353) were able by means of exercise training and the increase in shear stress associated therewith to obtain a marked increase in ecNOS. Whether regulation at the post-transcriptional level is relevant in vivo, is not unambiguously proved. Thus, for example, administration of a high arginine dose is followed by only a transient improvement in the endothelium-dependent vasorelaxation in patients with coronary heart disease. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Antithrombin for the prevention and therapy of vasculoproliferative disorders Inventor(s): Hoelschermann, Hans; (Pohlheim, DE), Roemisch, Juergen; (Vosendorf, AT), Stauss, Harald; (Dautphetal, DE) Correspondence: Finnegan, Henderson, Farabow,; Garrett & Dunner, L.L.P.; 1300 I Street, N.W.; Washington; DC; 20005-3315; US Patent Application Number: 20030134796 Date filed: December 4, 2002 Abstract: Antithrombin, in particular antithrombin III, is an agent or active ingredient suitable for the prevention and/or therapy of vasculoproliferative disorders such as, for example, transplant vasculopathy, restenosis, in-stent restenosis, and pulmonary hypertension. Excerpt(s): The present invention relates to the use of antithrombin (AT), and in particular the use of antithrombin III (AT III), for the prevention and/or therapy of vasculoproliferative disorders. The present invention additionally encompasses corresponding medicaments and processes for the production thereof. Vasculoproliferative disorders mean, for the purposes of the present invention, preferably transplant vasculopathy, restenosis, in-stent restenosis, and pulmonary hypertension. However, the present invention also encompasses the prevention and/or therapy of other disorders involving a proliferation of vessel walls that are harmful for

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the patient. Transplant vasculopathy (TVP) is a form of coronary heart disease which affects the entire coronary vascular bed in the transplanted heart. It can lead to rapid occlusions of vessels, and represents the commonest cause of death in the first postoperative year for patients who have undergone a heart transplant. Similar vessel changes are observed in the coronary vascular bed following balloon angioplasty and stent implantation, and in the pulmonary vascular bed in patients with pulmonary hypertension. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Catheter deployed partial occlusion devices and methods Inventor(s): Boucek, Mark M.; (Golden, CO) Correspondence: Alison B. Mohr; Parsons Behle & Latimer; 201 South Main Street, Suite 1800; Salt Lake City; UT; 84111-2218; US Patent Application Number: 20030032976 Date filed: May 21, 2002 Abstract: A device and method of use for a partial occlusion device (POD) for matter and liquid flow control. More specifically, a device relating to the partial occlusion of blood vessels to affect the flow of blood through the blood vessels is disclosed. The POD may be formed from a mesh material and includes one or more lumens. The POD may be particularly useful in treating Hypoplastic Left Heart Syndrome, by reducing pulmonary blood flow to decrease the risk of pulmonary hypertension. The POD may also be used to deliver therapeutic agents to a specific site. The POD can be retrieved after placement. Excerpt(s): This application is based on Provisional Application Serial No. 60/292,357, filed May 21, 2001, and priority is claimed thereto. The present inventions relate to matter and liquid flow control devices. More specifically, the present inventions relate to the partial occlusion of blood vessels to affect the flow of blood through the blood vessels. Some medical conditions require restriction of blood flow or controlled passage of an agent (for example a drug, a biochemical, or a gene therapy delivery device or virus) through a blood vessel. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Certain benzothiazine dioxide endothelin antagonists and processes for their preparation Inventor(s): Bunker, Amy Mae; (Middletown, CT), Cheng, Xue-Min; (Ann Arbor, MI), Doherty, Annette Marian; (Paris, FR), Edmunds, Jeremy John; (Ypsilanti, MI), Kanter, Gerald David; (West Bloomfield, MI), Lee, Chitase; (Ann Arbor, MI), Repine, Joseph Thomas; (Ann Arbor, MI), Skeean, Richard William; (Ann Arbor, MI) Correspondence: Warner-lambert Company; 2800 Plymouth Road; Ann Arbor; MI; 48105; US Patent Application Number: 20010036944 Date filed: March 27, 2001 Abstract: The instant invention is a series of benzothiazine dioxides, or a pharmaceutically acceptable salt thereof, which are potent endothelin A antagonists

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with profound in vitro activity, and improved syntheses for the Formula 1 1The compounds are useful in treating elevated levels of endothelin, essential renovascular malignant and pulmonary hypertension, cerebral infarction, cerebral ischemia, congestive heart failure, and subarachnoid hemorrhage. Excerpt(s): The present invention relates to improved syntheses of known and novel benzothiazine dioxide which are potent and selective endothelin antagonists. The processes of the instant invention are improved over those recited in U.S. Pat. No. 5,599,811 which is hereby incorporated by reference. The compounds of the instant invention exhibit very significant improvements over those described in U.S. Pat. No. 5,599,811. These improvements include: binding affinity to the ETA receptor, ETA selectivity, functional activity, long pharmacokinetic halflife, high bioavailability, in vivo activity in inhibiting the pressor effect caused by bET 1, oral activity with relatively long duration of action, and efficacy in acute hypoxic pulmonary hypertension in rats. The processes of the instant invention provide more facile syntheses with higher yields. They are short, clean, reproducible and no tedious chromatography is needed. Moreover, the processes are scaleable and therefore useful for large scale development. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Composition & methods for treatment and screening Inventor(s): Aguilar, Douglas; (Jersey City, NJ), Cong, Hui; (Cranbury, NJ), Lu, Hong; (Plainsboro, NJ), Miller, Shoreh; (Plainsboro, NJ), Nyce, Jonathan W.; (Titusville, NJ), Sandrasagra, Anthony; (South Brunswick, NJ), Shahabuddin, Syed; (Newtown, PA), Tang, Lei; (Princeton, NJ) Correspondence: Howrey Simon Arnold & White, Llp; Box 34; 301 Ravenswood AVE.; Menlo Park; CA; 94025; US Patent Application Number: 20040049022 Date filed: July 25, 2003 Abstract: This invention relates to single or multiple target anti-sense oligonucleotides (STA or MTA oligos) of low or no adenosine content for respiratory disease-relevant genes, composition thereof and method for manufacturing the composition. The compositions are effective in the prophylaxis and treatment of diseases and conditions associated with the up-regulated expression of one or more different combination of the genes, including airway inflammation, allergy(ies), asthma, impeded respiration, cystic fibrosis (CF), Chronic Obstructive Pulmonary Diseases (COPD), allergic rhinitis (AR), Acute Respiratory Distress Syndrome (ARDS), pulmonary hypertension, lung inflammation, bronchitis, airway obstruction, and bronchoconstriction, among others. This invention further relates to a method for screening candidate compounds useful for the prevention and/or treatment of respiratory diseases which binds to gene(s), EST(s), cDNA(s), mRNA(s), or their expresed product(s). Excerpt(s): This application is a continuation-in-part of PCT Application No. PCT/US02/13135 (EPI-0629), entitled COMPOSITIONS, FORMULATIONS & KIT WITH ANTI-SENSE OLIGONUCLEOTIDE & ANTI-INFLAMMATORY STEROID AND/OR UBIQUINONE FOR TREATMENT OF RESPIRATORY & LUNG DISEASE, and PCT/US02/13143 (EPI-0529), entitled COMPOSITION, FORMULATIONS & KITS FOR TREATMENT OF RESPIRATORY & LUNG DISEASE WITH ANTI-SENSE OLIGONUCLEOTIDES & A BRONCHODILATING AGENT, both filed Apr. 24, 2002, by Jonathan W. Nyce et al. The substitute Sequence Listing submitted on compact disc,

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created on Jun. 12, 2002 as file entitled, "EPI-00673 seqlist st25.txt" containing 827K bytes of data, is hereby incorporated by reference. This invention relates to single and multiple target anti-sense (STA or MTA) oligonucleotides (oligos) targeted to certain genes, compositions and formulations thereof, mRNAs and proteins, that are useful in the prophylaxis and treatment of various diseases and conditions associated with the gene(s) up-regulated expression, and for screening compounds active at the gene(s), mRNA(s), or gene product(s). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

COMPOSITION, FORMULATIONS & METHOD FOR PREVENTION & TREATMENT OF DISEASES AND CONDITIONS ASSOCIATED WITH BRONCHOCONSTRICTION, ALLERGY(IES) & INFLAMMATION Inventor(s): NYCE, JONATHAN W.; (PRINCETON, NJ) Correspondence: Viviana Amzel, PH.D.; Epigenesis Pharmaceuticals, INC.; 7 Clarke Drive; Cranbury; NJ; 05812; US Patent Application Number: 20030087845 Date filed: June 9, 1998 Abstract: A pharmaceutical composition effective for preventing and alleviating bronchoconstriction, allergy(ies) and/or inflammation comprises a surfactant and a nucleic acid comprising an oligonucleotide anti-sense to an adenosine A1, A2a, A2b or A3 receptor gene, mRNA, flanking regions or regions bridging the intro/exon borders, analogues which bind thymidine but have low adenosine content or exhibit lower or no adenosine receptor agonist activity, combinations thereof, physiologically acceptable salts thereof or mixtures thereof, and optionally a carrier and other agents such as therapeutic agents and formulation products known in the art. The composition is formulated for administration by a multiplicity of routes for the prevention or alleviation of diseases and conditions associated with breathing difficulties, impeded and obstructed airways, bronchoconstriction, allergy and/or inflammation. Among the appplications of this technology are the prevention and treatment of diseases and conditions such as asthma, kidney damage or failure, ARDS, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, pain, cystic fibrosis, pulmonary hypertension, pulmonary vasoconstriction, emphysema, chronic obstructive pulmonary disease (COPD), and cancers such as leukemias, lymphomas, carcinomas, and the like, e.g. colon cancer, breast cancer, lung cancer, pancreatic cancer, hepatocellular carcinoma, kidney cancer, melanoma, hepatic, lung, breast, and prostate metastases, etc., to counter the renal damage and failure associated with ischemic conditions and the administration of certain drugs and radio active diagnostic and therapeutic agents, as well as a joint therapy with the administration of adenosine and adenosine-like agents in the treatment of arrhythmias such as SVT and in cardiovascular function tests (stress tests). The present agent(s) is (are) also suitable for administration before, during and after other treatments, including radiation, chemotherapy, antibody therapy, phototherapy and cancer, and other types of surgery. Alternatively, the present agent may be effectively administered preventatively, prophylactically or therapeutically, and in conjunction with other therapies, or by itself for conditions without known therapies or as a substitute for therapies that have significant negative side effects. Excerpt(s): This invention relates to compositions and formulations of oligonucleotides and surfactants, which are highly effective for the prevention and treatment of diseases

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and conditions associated with difficult breathing, bronchoconstriction, impeded airways, allergy(ies) and inflammation of the lungs. Adenosine A.sub.1-mediated diseases and conditions, such as asthma and Acute Respiratory Distress Syndrome (ARDS), among others, are common diseases in industrialized countries, and in the United States alone account for extremely high health care costs. These diseases or conditions have recently been increasing at an alarming rate, both in terms of prevalence and mortality. Occupational asthma is predicted to be the preeminent occupational lung disease in the next decade. In many of these, the underlying causes remain poorly understood. Adenosine, a natural nucleoside, may constitute an important natural mediator of bronchial asthma and ARDS. The potential role of adenosine in these diseases or conditions is supported by experimental findings that, for example and in contrast to normal individuals, asthmatics respond to aerosolized adenosine with marked bronchoconstriction. Similarly, asthmatic rabbits produced using the dust mite allergic rabbit model of human asthma also were shown to respond to aerosolized adenosine with marked bronchoconstriction, while non-asthmatic rabbits showed no response. Recent work using this model system has suggested that adenosine-mediated bronchoconstriction in asthma is mediated through the stimulation of the adenosine A.sub.1 receptor. Other experimental data suggest the possibility that adenosine receptors may also be involved in allergic and inflammatory responses. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Compounds with the biological activity of vasoactive intestinal peptide for the treatment of pulmonary and arteriolar hypertension Inventor(s): Block, Lutz-Henning; (Emmendingen, DE) Correspondence: Jenkens & Gilchrist, PC; 1445 Ross Avenue; Suite 3200; Dallas; TX; 75202; US Patent Application Number: 20040063631 Date filed: October 3, 2003 Abstract: The present invention relates to peptides which are highly biologically and pharmacologically active as therapeutic drug for the treatment of diseases related to hypertension, especially in medical interventions involving dilatation and remodelling of arterial blood vessels, either in the pulmonary or in the systemic circulation. The peptides which can be used according to the invention for the treatment of said diseases comprises at least one specific highly conservative amino acid residue sequence which seem to play an important role in connection with pulmonary and arteriolar hypertension events. It could be shown that the known naturally occurring peptides "vasoactive intestinal peptide (VIP)" and pituitary adenylate cyclaseactivating polypeptide (PACAP)", having these specific sequences are potent drugs which can be successfully used for treatment of primary pulmonary hypertension (PPH), secondary pulmonary hypertension (SPH), and hypertension of the systemic circulation. Furthermore, the present invention discloses pharmaceutical compositions useful for treatment of PPH, SPH, and hypertension of the systemic circulation within said methods. Excerpt(s): The present invention relates to peptides which are highly biologically and pharmacologically active as therapeutic drug for the treatment of diseases related to hypertension, especially in medical interventions involving dilatation and remodeling of arterial blood vessels, either in the pulmonary or in the systemic circulation. The peptides which can be used according to the invention for the treatment of said diseases

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comprise at least one specific highly conservative amino acid residue sequence which seem to play an important role in connection with pulmonary and arteriolar hypertension events. It could be shown that especially the known naturally occurring peptides "vasoactive intestinal peptide (VIP)" and "pituitary adenylate cyclase-activating polypeptide (PACAP)", having these specific sequences are potent drugs which can be successfully used for treatment of primary pulmonary hypertension (PPH), secondary pulmonary hypertension (SPH), and hypertension of the systemic circulation. Furthermore, the present invention discloses pharmaceutical compositions useful for treatment of PPH, SPH, and hypertension of the systemic circulation within said methods. Primary pulmonary hypertension (PPH) is a fatal disease causing progressive right heart failure within three years after diagnosis. Recently, various pathophysiological changes associated with this disorder, including vasoconstriction, vascular remodelling (i.e. proliferation of both media and intima of the pulmonary resistance vessels), and in situ thrombosis have been characterized (e.g.: D'Alonzo, G. E., Barst, R. J., Ayres, S. M. et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann.Intern.Med. 115, 343349. 1-9-1991; Palevsky, H. I., Schloo, B. L., Pietra, G. G. et al. Primary pulmonary hypertension. Vascular structure, morphometry, and responsiveness to vasodilator agents. Circulation 80, 1207-1221. 1989; Rubin, L. J. Primary pulmonary hypertension. N.Engl.J.Med. 336, 111-117. 9-1-1997; Wagenvoort, C. A. and Wagenvoort, N. Primary pulmonary hypertension: a pathological study of the lung vessel in 156 clinically diagnosed cases. Circulation 42, 1163-1184. 1970; Wood, P. Pulmonary hypertension with special reference to the vasoconstrictive factor. Br.heart J. 20, 557-570. 1958). Impairment of vascular and endothelial homeostasis is evidenced from a reduced synthesis of prostacyclin (PGI.sub.2), increased thromboxane production, decreased formation of nitric oxide and increased synthesis of endothelin-1 (Giaid, A. and Saleh, D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N.Engl.J.Med 333, 214-221. 1995; Xue, C. and Johns, R. A. Endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension [letter]. N.Engl.J.Med. 333, 1642-1644. 14-12-1995). The intracellular free calcium concentration of VSMC of pulmonary arteries in PPH has been reported to be elevated. The therapy of pulmonary hypertension is unsatisfactory. Current therapy involves calcium cannel blockers and prostacyclins. Although the vasodilation in numerous tissues, heart and lung tissue included, there is no clinical evidence up to now that VIP or PACAP are effective in the treatment of pulmonary hypertension in humans. The invention describes for the first time the clinical relevance of VIP, PACAP and compounds having the biological activity of VIP or PACAP for the treatment of primary pulmonary hypertension (PPH), secondary pulmonary hypertension (SPH), and arteriolar hypertension associated with PPH. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Indole derivatives useful as endothelin receptor antagonists Inventor(s): Dack, Kevin Neil; (Sandwich, GB), Dickinson, Roger Peter; (Sandwich, GB), James, Kim; (Sandwich, GB), Rawson, David James; (Sandwich, GB) Correspondence: Gregg C. Benson; Pfizer Inc; Patent Department, MS 4519, Eastern Point Road; Groton; CT; 06340; US Patent Application Number: 20010014677 Date filed: January 9, 2001

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Abstract: 1Compounds of formula (I), and their pharmaceutically acceptable derivatives, wherein R.sup.1 and R.sup.2 are optional substituents and independently represent C.sub.1-6 alkyl, C.sub.2-6 alkenyl, optionally substituted by CO.sub.2H or CO.sub.2(C.sub.1-6 alkyl), C.sub.2-6 alkynyl, halogen, C.sub.1-3 perfluoroalkyl, (CH.sub.2).sub.mAr.sup.1, (CH.sub.2).sub.mHet.sup.1, (CH.sub.2).sub.mCONR.sup.7R.sup.8, (CH.sub.2).sub.mCO.sub.2R.sup.8, O(CH.sub.2).sub.qCO.sub.2R.sup.8, (CH.sub.2).sub.mCOR.sup.8, (CH.sub.2).sub.mOR.sup.8, O(CH.sub.2).sub.pOR.sup.8, (CH.sub.2).sub.mNR.sup.7R.sup.8, CO.sub.2(CH.sub.2).sub.qNR.sup.7R.sup.8, (CH.sub.2).sub.mCN, S(O).sub.nNR.sup.8, SO.sub.2NR.sup.7R.sup.8, CONH(CH.sub.2).sub.mAr.sup.1 or CONH(CH.sub.2).sub.mHet.sup.1; R.sup.3 represents H, C.sub.1-6 alkyl, (CH.sub.2).sub.pNR.sup.9R.sup.10, SO.sub.2R.sup.10, SO.sub.2NR.sup.9R.sup.10, (CH.sub.2).sub.mCO.sub.2R.sup.10, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl (CH.sub.2).sub.mCONR.sup.9R.sup.10, (CH.sub.2).sub.mCO.sub.2R.sup.10, (CH.sub.2).sub.pCN, (CH.sub.2).sub.pR.sup.10 or (CH.sub.2).sub.pOR.sup.10; R.sup.4 represents H or C.sub.1-6 alkyl; R.sup.5 represents H or OH; R.sup.6 represents phenyl optionally fused to a heterocyclic ring, the group as a whole being optionally substituted; R.sup.7-10 are fully defined herein and may independently represent Ar.sup.2 or Het.sup.2; Z represents CO.sub.2H, CONH(tetrazol-5-yl), CONHSO.sub.2O(C.sub.1-4 alkyl), CO.sub.2Ar.sup.3, CO.sub.2(C.sub.1-6 alkyl), tetrazol-5-yl, CONHSO.sub.2Ar.sup.3, CONHSO.sub.2(CH.sub.2).sub.qAr.sup.3 or CONHSO.sub.2(C.sub.1-4 alkyl); Ar.sup.1-3 independently represent phenyl, naphthyl, or an aromatic heterocycle, which groups are optionally fused and optionally substituted; and Het.sup.1 and Het.sup.2 independently represent a non-aromatic heterocycle which is optionally substituted; are useful in the treatment of restenosis, renal failure and pulmonary hypertension. Excerpt(s): This invention relates to indole derivatives useful in the treatment of a variety of diseases including restenosis, renal failure and pulmonary hypertension. and to pharmaceutical formulations containing such compounds. International Patent Application WO 94/14434 discloses indole derivatives which are indicated as endothelin receptor antagonists. European Patent Application 617001 discloses a large number of phenoxvphenylacetic acid derivatives which are also indicated as endothelin receptor antagonists. Bergman et al. Tetrahedron. Vol 31. No. 17.1975. pages 2063-2073, disclose a number of indole-3-acetic acids. Similar compounds arc disclosed by Rusinova et al. Khim Geterotsikl Soedin. 1974, (2), 211-213 (see also Chemical Abstracts. Vol 81, No. 7.19 August 1974, abstract No. 37455a). and Yarovenko et al. J Gen Chem USSR (English translation), Vol 39, 1969, page 2039 (see also Beilstein. Registry Number 431619). These compounds are not indicated in any kind of therapy, and proviso (i) below relates to them. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Isoform-selective inhibitors phosphodiesterases

and

activators

of

PDE3

cyclic

nucleotide

Inventor(s): Movsesian, Matthew A.; (Salt Lake City, UT) Correspondence: Richard A. Nakashima; Blakely, Sokoloff, Taylor & Zafman Llp; Seventh Floor; 12400 Wilshire Boulevard; Los Angeles; CA; 90025-1030; US Patent Application Number: 20030158133 Date filed: June 19, 2002

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Abstract: The present invention concerns methods and compositions related to type 3 phosphodiesterases (PDE3). Certain embodiments concern isolated peptides corresponding to various PDE3A isoforms and/or site-specific mutants of PDE3A isoforms, along with expression vectors encoding such isoforms or mutants. In specific embodiments, methods for identifying isoform selective inhibitors or activators of PDE3 are provided, along with methods of use of such inhibitors or activators in the treatment of dilated cardiomyopathy, pulmonary hypertension and/or other medical conditions related to PDE3 effects on cAMP levels in different intracellular compartments. Excerpt(s): The present invention relates to the field of cardiovascular and other diseases. More particularly, the present invention concerns compositions and methods of identification and use of isoform selective activators or inhibitors of type 3 phosphodiesterase (PDE3). Other embodiments of the invention concern highthroughput screening for novel pharmaceuticals directed against PDE3 isoforms. In certain embodiments, the compositions and methods disclosed herein are of use for treatment of cardiomyopathy, pulmonary hypertension and related conditions. PDE3 cyclic nucleotide phosphodiesterases hydrolyze cAMP and cGMP and thereby modulate cAMP- and cGMP-mediated signal transduction (Shakur et al., 2000a). These enzymes have a major role in the regulation of contraction and relaxation in cardiac and vascular myocytes. PDE3 inhibitors, which raise intracellular cAMP and cGMP content, have inotropic effects attributable to the activation of cAMP-dependent protein kinase (PK-A) in cardiac myocytes and vasodilatory effects attributable to the activation of cGMPdependent protein kinase (PK-G) in vascular myocytes (Shakur et al., 2000a). When used in the treatment of dilated cardiomyopathy, PDE3 inhibitors such as milrinone, enoximone and amrinone initially elicit favorable haemodynamic responses, but longterm administration increases mortality by up to 40% (Nony et al., 1994). This linkage of short-term benefits of PDE3 inhibition to deleterious effects on long-term survival in dilated cardiomyopathy is one of the most perplexing problems in cardiovascular therapeutics. However, it is thought that these biphasic effects reflect the compartmentally-nonselect- ive increases in intracellular cAMP content in cardiac myocytes current inhibitors display. Clinical trials of the use of.beta.-adrenergic receptor agonists--which, like PDE3 inhibitors, increase intracellular cAMP content in cardiac myocytes--were terminated prior to completion because of increased mortality in treated patients, while.beta.-adrenergic receptor antagonists, which reduce intracellular cAMP content, have been shown to improve long-term survival despite initially adverse haemodynamic effects. These findings suggest that both the short-term benefits and long-term adverse effects of PDE3 inhibition are attributable to increases in intracellular cAMP content in cardiac myocytes (Movsesian, 1999). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method and apparatus for nitric oxide generation Inventor(s): Fine, David H.; (Lincoln, MA), Jarvis, George; (Arlington, MA), MacDonald, Stephen J.; (Salem, NH), Rolfe, Jonathan L.; (N. Easton, MA), Rounbehler, David; (West Harwich, MA), Wheeler, David; (Lunenburg, MA) Correspondence: Fish & Richardson P.C.; 1425 K Street, N.W.; 11th Floor; Washington; DC; 20005-3500; US Patent Application Number: 20030062043 Date filed: August 28, 2002

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Abstract: Inhalation of low levels of nitric oxide can rapidly and safely decrease pulmonary hypertension in mammals. Precise delivery of nitric oxide at therapeutic levels of 20 to 100 ppm and inhibition of reaction of nitric oxide with oxygen to form toxic impurities such as nitrogen dioxide can provide effective inhalation therapy for pulmonary hypertension. Excerpt(s): This application claims the benefit of U.S. Application No. 60/316,964 filed on Sep. 5, 2001, which is incorporated by reference in its entirety. The present application is related to co-pending application (Attorney Docket No. 10897-022001) entitled "Controlled Generation of Nitric Oxide," filed concurrently herewith, and copending application (Attorney Docket No. 10897-023001) entitled "Nitric Oxide Delivery System," also filed concurrently herewith, each of which is incorporated by reference in its entirety. This invention relates to an apparatus and a method for controllably generating nitric oxide. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method and compositions for treating persistent pulmonary hypertension using aralkyl ester soft drugs Inventor(s): Aouthmany, Moustafa M.; (Sylvania, OH), Erhardt, Paul W.; (Sylvania, OH) Correspondence: Emch, Schaffer, Schaub & Porcello CO; P O Box 916; One Seagate Suite 1980; Toledo; OH; 43697 Patent Application Number: 20030130236 Date filed: November 18, 2002 Abstract: A method and compositions for treating persistent pulmonary hypertension in human newborns that deploys an intravenous infusion of a modified drug formed by adding one or more of a predetermined chemical arrangement to an efficacious parent drug compound so as to retain efficacy while re-directing a preferred route and rate of the parent drug compound's metabolism to an inactive or very weakly active and nontoxic metabolite are disclosed. The chemical arrangement is 1wherein.phi. is a phenyl, substituted aryl or heteroaryl system that is already present in the parent drug compound or is specifically added to the parent drug compound via a metabolically stable connection;R is an alkyl or alkene containing chain either branched or unbranched from 0 to 10 carbons that is already present in the parent drug compound or is added to the parent drug compound via a metabolically stable connection to.phi.;X is a carboxyl, sulfoxyl or phosphatyl function that is specifically added to the parent drug compound via a metabolically stable connection to R; and,R' is an added alkyl, alkenyl or aralkyl group either branched or unbranched containing from 1 to 10 carbons, or is a structural element already present as an inherent portion of the parent drug compound. Excerpt(s): The present invention is a continuation-in part of U.S. Ser. No. 09/570,485 filed May 12, 2000, still pending, which is expressly incorporated herein by reference. Pharmaceutical agents or drugs exhibit desirable therapeutic properties because they contain distinct molecular arrangements called pharmacophores. Oftentimes, however, the pharmacophores or the presence of other chemical components within such compounds, provide a less than ideal overall profile relative to the final deployment of a given drug for a particular clinical indication. In some cases this situation can be improved by altering chemical features associated with a drug's distribution, metabolism or elimination (DME). This process, when successful, results in what is now referred to in the pharmaceutical community as a "soft drug" version of the original or

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parent drug compound: Soft Drugs. XX. Design, Synthesis and Evaluation of Ultra-Short Acting beta-Blockers, H.-S. Yang, W.-M, Wu and N. Bodor, Pharm. Res., 12, 329 (1995); and Synthesis and Enzymatic Hydrolysis of Esters, Constituting Simple Models of Soft Drugs, M. Graffner-Nordberg, K. Sjodin, A. Tunek and A. Hallberg, Chem. Pharm. Bull., 46, 591 (1998). However, unless there is compelling preclinical data which suggests that the clinical application of a lead compound is going to become problematic, DMErelated features are typically not rigorously evaluated in a chemical manner during the early process of new drug discovery and development. This situation has arisen, in part, because substantial clinical experience is often required to accurately define the sometimes subtle parameters of an undesirable DME feature relative to the beneficial aspects of a new drug while the latter is within the close purview of its actual clinical use in a specific pathophysiological setting. The problem of not knowing exactly what DME and toxicity-related properties may need to be addressed is additionally confounded by not having ready chemical blueprints for how to generally proceed even when a particular DME or toxicity issue becomes suspected. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for delivering benzidine prostaglandins by inhalation Inventor(s): Cloutier, Gilles; (Chapel Hill, NC), Crow, James; (Chapel Hill, NC), Loyd, James E.; (Nashville, TN), Parker, Richard E.; (Spring Hill, TN), Wade, Michael; (Chapel Hill, NC) Correspondence: Foley And Lardner; Suite 500; 3000 K Street NW; Washington; DC; 20007; US Patent Application Number: 20030053958 Date filed: August 6, 2002 Abstract: A method of delivering benzindene prostaglandins to a patient by inhalation is discussed. A benzindene prostaglandin known as UT-15 has unexpectedly superior results when administered by inhalation compared to parenterally administered UT-15 in sheep with induced pulmonary hypertension. Excerpt(s): This application is a continuation of U.S. application Ser. No. 09/525,471, filed on Mar. 15, 2000, which claims priority to provisional U.S. Application Serial No. 60/124,999, filed Mar. 18, 1999. Benzindene prostaglandins are now known to be useful to treat a variety of conditions. U.S. Pat. No. 5,153,222 describes the use of a preferred class of benzindene prostaglandins in the treatment of pulmonary hypertension, including both primary and secondary pulmonary hypertension. In particular, this patent discusses the use of the compound compound 9-deoxy-2',9-alpha-methano-3-oxa4,5,6-trinor-3,7-(1',3- '-interphenylene)-13,14-dihydro-prostaglandin F.sub.1 (also known as UT-15). However, this patent does not specifically suggest the administration of such benzindene prostaglandins by inhalation or the surprising benefits that result from their delivery by inhalation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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•

Method of diagnosing pulmonary hypertension Inventor(s): Foroud, Tatiana; (Indianapolis, IN), Lane, Kirk B.; (Brentwood, TN), Loyd, James E.; (Nashville, TN), Machado, Rajiv D.; (Leicester, GB), Nichols, William C.; (Loveland, OH), Pauciulo, Michael W.; (Blue Ash, OH), Phillips, John A. III; (Brentwood, TN), Thomson, Jennifer R.; (Leeds, GB), Trembath, Richard C.; (Rutland, GB) Correspondence: Needle & Rosenberg, P.C.; The Candler Building, Suite 1200; 127 Peachtree Street, N.E.; Atlanta; GA; 30303-1811; US Patent Application Number: 20020102576 Date filed: July 17, 2001 Abstract: This invention relates generally to a method of identifying an individual having an increased susceptibility to developing Familial Primary Pulmonary Hypertension (FPPH), as well as to a method for diagnosing an individual suffering from FPPH. The invention also relates to a method of identifying an individual having an increased susceptibility to developing (non-familial) Primary Pulmonary Hypertension (PPH), as well as to a method for diagnosing an individual suffering from PPH. Excerpt(s): This application claims benefit of U.S. Provisional Application No. 60/218,740, filed Jul. 17, 2000, and U.S. Provisional Application No. 60/220,133, filed Jul. 21, 2000. Application Ser. No. 60/218,740, filed Jul. 17, 2000, and U.S. Provisional Application No. 60/220,133, filed Jul. 21, 2000, are hereby incorporated herein by reference. Primary pulmonary hypertension (PH) is characterized by sustained elevation of pulmonary artery pressure (greater than 25 mmHg at rest and greater than 30 mmHg during exercise) and with no identifiable cause, such as recurrent thromboembolism, chronic hypoxic lung disease or left-sided cardiac disease. PPH is twice as common in females than males and symptoms develop typically in the 3.sup.rd and 4.sup.th decades of life, although the disease may occur at any age. Despite advances in therapy, mortality in PPH remains high with mean survival from onset of disease only 2.5 year. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Method of treatment and pharmaceutical composition Inventor(s): Gasparo, Marc de; (Es Planches, CH), Webb, Randy Lee; (Flemington, NJ) Correspondence: Thomas Hoxie; Novartis Corporation; Patent And Trademark Dept; 564 Morris Avenue; Summit; NJ; 079011027 Patent Application Number: 20010049384 Date filed: January 9, 2001 Abstract: The invention relates to a method for the treatment or prevention of a condition or disease selected from the group consisting of hypertension, (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, myocardial infarction and its sequelae, supraventricular and ventricular arrhythmias, atrial fibrillation or atrial flutter, atherosclerosis, angina (whether stable or ustable), renal insufficiency (diabetic and non-diabetic), heart failure, angina pectoris, diabetessecondary aldosteronism, primary and secondary pulmonary hyperaldosteronism, primary and pulmonary hypertension, renal failure conditions, such as diabetic nephropathy,glomerulonephritis, scleroderma, glomerular sclerosis,

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proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such as Alzheimer's), and stroke, comprising administering a therapeutically effective amount of combination of (i) the AT.sub.1-antagonists valsartan or a pharmaceutically acceptable salt thereof and (ii) a Calcium channel blocker or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a mammal in need of such treatment and to corresponding pharmaceutical combination composition. Excerpt(s): (iii) a pharmaceutically acceptable carrier. Valsartan is disclosed in EP 0443983 A. A CCB useful in said combination is preferably selected from the group consisting of amlodipine, diltiazem, felodipine, fendiline, flunarizine, gallopamil, isradipine, lacidipine, mibefradil, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, nivaldipine, ryosidine, tiapamil and verapamil, and in each case, a pharmaceutically acceptable salt thereof. All these drugs are therapeutically used as CCBs, e.g. as anti-hypertensive, anti-angina pectoris or antiarrhythmic drugs. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

METHOD OF TREATMENT AND PREVENTION OF NITRIC OXIDE DEFICIENCYRELATED DISORDERS WITH CITRULLINE AND CITRULLINE DERIVATIVES Inventor(s): CHWALISZ, KRISTOF; (BERLIN, DE), GARFIELD, ROBERT E.; (FRIENDSWOOD, TX), SHI, SHAO-QUING; (GALVESTON, TX) Correspondence: Millen, White, Zelano & Branigan, P.C.; 2200 Clarendon BLVD.; Suite 1400; Arlington; VA; 22201; US Patent Application Number: 20010056068 Date filed: March 4, 1998 Abstract: The invention provides methods for control, management, treatment and prevention of conditions related to nitric oxide deficiency such as hypertension, cardiovascular disease, osteoporosis, diabetes mellitus, preeclampsia HELLP, syndrome and fetal growth retardation; uterine contractility disorders such as preterm labor and dysmenorrhea, cervical dystocia, infertility and early pregnancy loss; male impotence; urinary incontinence; intestinal tract disorders (e.g. altered motility and pyloric stenosis), respiratory system diseases (e.g. asthma, neonatal respiratory distress syndrome, pulmonary hypertension, and adult respiratory distress syndrome); inflammatory diseases (e.g. acute inflammation, resistance to infection, SLE-lupus, anaphylactic reaction, allograft rejection); Alzheimer's disease, stroke, growth hormone disorders, and behavior changes; dermatological conditions such as atopic eczema, topical hair loss, and burn injury; by administering citrulline or a citrulline analogue, optionally in combination with other enhancing or modulating agents, e.g., an estrogenic, partial estrogenic, progestagenic, or androgenic agent, and pharmaceutical preparations for such uses. Excerpt(s): This invention concerns a method and agents for control, management, treatment and prevention of disorders and diseases related to nitric oxide deficiency or those disorders or diseases which can be improved by enhancing endogenous nitric oxide synthesis by providing to a mammal citrulline or a citrulline analogue alone or in combination with other enhancing or modulating agent. This invention relates to nitric oxide dependent disorders and diseases including, hypertension, cardiovascular

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disease, atherosclerosis, myocardial ischemia, preeclampsia, HELLP (severe preeclampsia (Hemolysis+Elevated Liver enzymes+Low Platelets) syndrome), and fetal growth retardation, osteoporosis, uterine contractility disorders, such as preterm labor and dysmenorrhea, cervical dystocia, male impotence, urinary incontinence, renal arterial stenosis. In addition, this invention relates to a method and agents for treatment of infertility by improving implantation rates or controlling ovulation. Furthermore, this invention relates to a method and agents for hormone replacement therapy (HRT) alone or in combination with steroid hormones or other enhancing or modulating agents in females during the menopause to prevent climacteric disorders such as hot flushes, abnormal clotting patterns, urogenital discomfort, increased incidence of cardiovascular diseases, etc., associated with the reduction in ovarian function in middle-aged women. This invention also concerns a method and agents for HRT alone or in combination with steroid hormones or other enhancing or modulating agents in males to prevent cardiovascular disease, osteoporosis and impotence. There are also other potential uses of citrulline or citrulline analogues in those clinical situations in which nitric oxide plays a modulatory role. For example (1) regarding the cardiovascular system: regulation of vascular conductance, regulation of blood flow, regulation of blood pressure, (2) regarding the gastrointestinal tract and pancreas pathology: altered motility, pyloric stenosis, diabetes mellitus, (3) regarding respiratory system: asthma, treatment of premature babies to increase lung function (neonatal respiratory distress syndrome), pulmonary hypertension, adult respiratory distress syndrome, (4) in inflammation: autoimmune and immune diseases, acute inflammation, resistance to infection, SLElupus, anaphylactic reaction, allograft rejection, within the central nervous system: Alzheimer's disease, stroke, growth hormone disorders, behavior changes, (5) in dermatological conditions: atopic eczema, topical hair loss, and burn injury. One of the most exciting recent advances in biology and medicine is the discovery that the diffusible molecule nitric oxide is produced by endothelial cells and that it is involved in the regulation of vascular tone, plate-let aggregation, peripheral nitrergic transmission at smooth muscle, intra-cellular communication in the CNS, and macrophage defense mechanisms following exposure to bacterial products (Furchgott R F, Zawadzki J V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetycholine. Nature 1980; 288:373-376.; Moncada S and Higgs E A. The L-arginine-nitric oxide pathway. New Engl J Med 1993; 329:2002-2012). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method to treat pulmonary hypoplasia in the newborn Inventor(s): Moskowitz, David W.; (St. Louis, MO) Correspondence: Patrea L. Pabst; Holland & Knight Llp; Suite 2000, One Atlantic Center; 1201 West Peachtree Street, N.E.; Atlanta; GA; 30309-3400; US Patent Application Number: 20030032598 Date filed: August 8, 2002 Abstract: A method of treating pulmonary hypoplasia in infants has been developed, wherein epidermal growth factor (EGF) is administered to the pulmonary system of an infant in need of treatment thereof. The EGF is administered as an aerosol or dry powder directly to the pulmonary tree, or into the amniotic fluid before birth if a situation such as oligohydramnios is recognized pre-term. The method can also be used to treat persistent pulmonary hypertension of the newborn. A hydrophobic angiotensin

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I-converting enzyme (ACE) inhibitor such as ramipril can also be used for the oral treatment of persistent pulmonary hypertension of the newborn. Excerpt(s): This application claims priority to U.S. Ser. No. 60/311,663 filed Aug. 13, 2001. This application is generally in the field of methods and epidermal growth factor compositions for treatment of pulmonary hypoplasia in newborn infants. The main problem with babies born prematurely is secondary pulmonary immaturity (hypoplasia). Persistent pulmonary hypertension of the newborn (PPHN) is the result of elevated pulmonary vascular resistance to the point that venous blood is diverted to some degree through fetal channels into the systemic circulation and bypasses the lungs, resulting in systemic arterial hypoxemia. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods and pharmaceutical formulations for the treatment of pulmonary hypertension and methods for screening compounds useful in the treatment of pulmonary hypertension Inventor(s): Schwarz, Margaret A.; (La Canada-Flintridge, CA) Correspondence: Myers Bigel Sibley & Sajovec; Post Office Box 37428; Raleigh; NC; 27627; US Patent Application Number: 20010031738 Date filed: December 15, 2000 Abstract: A method of treating pulmonary hypertension in a subject in need of such treatment comprises inhibiting EMAP II activity in the subject by an amount effective to treat the pulmonary hypertension in the subject (e.g., in the lungs and more particularly in the pulmonary vasculature). Pharmaceutical formulations useful for carrying out such methods (e.g., an antibody that specifically binds to EMAP II in a pharmaceutically acceptable carrier) and screening techniques useful for identifying additional compounds that can be used for carrying out such methods are also disclosed. Excerpt(s): This application claims the benefit of U.S. Provisional Application Ser. No. 60/177,008, filed Jan. 19, 2000 and U.S. Provisional Application Ser. No. 60/197,492, filed Apr. 17, 2000, the disclosures of both of which are incorporated by reference herein in their entirety. This invention relates to pulmonary hypertension and compounds, formulations and methods useful in the treatment thereof. Pulmonary hypertension (PHTN) is a serious disorder characterized by an increase in pulmonary vascular resistance and classified clinically as either primary pulmonary hypertension or secondary pulmonary hypertension. In its most common form, pulmonary hypertension usually presents as a manifestation of an obvious or explicable increase in vascular resistance, such as obstruction to blood flow by pulmonary emboli, malfunction of the heart's valves or muscle in handling blood after its passage through the lungs, diminution in pulmonary vessel diameter as a reflex response to hypoventilation and/or low oxygenation, or a mismatch of vascular capacity and essential blood flow, such as shunting of blood in congenital abnormalities or surgical removal of lung tissue. Such pulmonary hypertension is referred to as secondary pulmonary hypertension. Secondary pulmonary hypertension may be a result of chronic obstructive or interstitial lung disease, recurrent pulmonary emboli, liver disease, or pre-existing heart disease. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Methods of treatment and pharmaceutical composition Inventor(s): Ksander, Gary Michael; (Amherst, NH), Webb, Randy Lee; (Flemington, NJ) Correspondence: Thomas Hoxie; Novartis, Corporate Intellectual Property; One Health Plaza 430/2; East Hanover; NJ; 07936-1080; US Patent Application Number: 20030144215 Date filed: January 14, 2003 Abstract: The invention relates a pharmaceutical composition comprising a combination of:(i) the AT 1-antagonist valsartan or a pharmaceutically acceptable salt thereof; and(ii) a NEP inhibitor or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier and to a method for the treatment or prevention of a condition or diseaseselected from the group consisting of hypertension, heart failure, such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non-diabetic), heart failure, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction, such as Alzheimer's, glaucoma and stroke, comprising administering a therapeutically effective amount of the pharmaceutical composition to a mammal in need thereof. Excerpt(s): The renin angiotensin system is a complex hormonal system comprised of a large molecular weight precursor, angiotensinogen, two processing enzymes, renin and angiotensin converting enzyme (ACE), and the vasoactive mediator angiotensin II (Ang II). See J. Cardiovasc. Pharmacol., Vol. 15, Suppl. B, pp. S1-S5 (1990). The enzyme renin catalyzes the cleavage of angiotensinogen into the decapeptide angiotensin I, which has minimal biological activity on its own and is converted into the active octapeptide Ang II by ACE. Ang II has multiple biological actions on the cardiovascular system, including vasoconstriction, activation of the sympathetic nervous system, stimulation of aldosterone production, anti-natriuresis, stimulation of vascular growth and stimulation of cardiac growth. Ang II functions as a pressor hormone and is involved the pathophysiology of several forms of hypertension. The vasoconstrictive effects of angiotensin II are produced by its action on the non-striated smooth muscle cells, the stimulation of the formation of the adrenergenic hormones epinephrine and norepinephrine, as well as the increase of the activity of the sympathetic nervous system as a result of the formation of norepinephrine. Ang II also has an influence on electrolyte balance, produces, e.g., anti-natriuretic and anti-diuretic effects in the kidney and thereby promotes the release of, on the one hand, the vasopressin peptide from the pituitary gland and, on the other hand, of aldosterone from the adrenal glomerulosa. All these influences play an important part in the regulation of blood pressure, in increasing both circulating volume and peripheral resistance. Ang II is also involved in cell growth and migration and in extracellular matrix formation. Ang II interacts with specific receptors on the surface of the target cell. It has been possible to identify receptor subtypes that are termed, e.g., AT 1- and AT 2-receptors. In recent times great efforts have been made to identify substances that bind to the AT 1-receptor. Such active ingredients are often termed Ang II antagonists. Because of the inhibition of the AT 1-

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receptor such antagonists can be used, e.g., as anti-hypertensives or for the treatment of congestive heart failure, among other indications. Ang II antagonists are therefore understood to be those active ingredients which bind to the AT 1-receptor subtype. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use Inventor(s): Earl, Richard A.; (Westford, MA), Garvey, David S.; (Dover, MA), Khanapure, Subhash P.; (Clinton, MA), Tejada, Inigo Saenz de; (Pozuelo de Alarcon, ES) Correspondence: Edward D Grieff; Hale & Dorr Llp; 1455 Pennsylvania Ave, NW; Washington; DC; 20004; US Patent Application Number: 20020019405 Date filed: August 30, 2001 Abstract: The present invention describes novel nitrosated and/or nitrosylated phosphodiesterase inhibitors, and novel compositions containing at least one nitrosated and/or nitrosylated phosphodiesterase inhibitor, and, optionally, one or more compounds that donate, transfer or release nitric oxide, elevate endogenous levels of endothelium-derived relaxing factor, stimulate endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or one or more vasoactive agents. The present invention also provides novel compositions containing at least one phosphodiesterase inhibitor, and one or more compounds that donate, transfer or release nitric oxide, elevate endogenous levels of endothelium-derived relaxing factor, stimulate endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or one or more vasoactive agents. The present invention also provides methods for treating or preventing sexual dysfunctions in males and females, for enhancing sexual responses in males and females, and for treating or preventing diseases induced by the increased metabolism of cyclic guanosine 3',5'-monophosphate (cGMP), such as hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infraction, stable, unstable and variant (Prinzmetal) angina, atherosclerosis, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, dementia, immunodeficiency, premature labor, dysmenorrhoea, benign prostatic hyperplasis (BPH), bladder outlet obstruction, incontinence, conditions of reduced blood vessel patency, e.g., postpercutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, allergic rhinitis, glucoma, and diseases characterized by disorders of gut motility, e.g., irritable bowel syndrome (IBS). Excerpt(s): This is a continuation-in-part of U.S. application Ser. No. 09/145,142, filed Sep. 1, 1998, allowed, which is a continuation-in-part of U.S. application Ser. No. 08/740,764, filed Nov. 1, 1996, issued as U.S. Pat. No. 5,874,437; and is a continuation-inpart of PCT/US97/19870, filed Oct. 31, 1997, which claims priority to U.S. application Ser. No. 08/740,764, filed Nov. 1, 1996, issued as U.S. Pat. No. 5,874,437. The present invention describes novel nitrosated and/or nitrosylated phosphodiesterase inhibitors, and novel compositions comprising at least one nitrosated and/or nitrosylated phosphodiesterase inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase, and/or at least one vasoactive agent. The present invention also provides novel compositions comprising at least one phosphodiesterase inhibitor, and at

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least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase, and/or at least one vasoactive agent. The present invention also provides methods for treating or preventing sexual dysfunctions in males and females, for enhancing sexual responses in males and females, and for treating or preventing diseases induced by the increased metabolism of cyclic guanosine 3',5'-monophosphate (cGMP), such as hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infraction, stable, unstable and variant (Prinzmetal) angina, atherosclerosis, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, dementia, immunodeficiency, premature labor, dysmenorrhoea, benign prostatic hyperplasis (BPH), bladder outlet obstruction, incontinence, conditions of reduced blood vessel patency, e.g., postpercutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, allergic rhinitis, and glucoma, and diseases characterized by disorders of gut motility, such as irritable bowel syndrome (IBS). Adequate sexual function is a complex interaction of hormonal events and psychosocial relationships. There are four stages to sexual response as described in the International Journal of Gynecology & Obstetrics, 51(3):265-277 (1995). The first stage of sexual response is desire. The second stage of sexual response is arousal. Both physical and emotional stimulation may lead to breast and genital vasodilation and clitoral engorgement (vasocongestion). In the female, dilation and engorgement of the blood vessels in the labia and tissue surrounding the vagina produce the "orgasmic platform," an area at the distal third of the vagina where blood becomes sequestered. Localized perivaginal swelling and vaginal lubrication make up the changes in this stage of sexual response. Subsequently, ballooning of the proximal portion of the vagina and elevation of the uterus occurs. In the male, vasodilation of the cavemosal arteries and closure of the venous channels that drain the penis produce an erection. The third stage of sexual response is orgasm, while the fourth stage is resolution. Interruption or absence of any of the stages of the sexual response cycle can result in sexual dysfunction. One study found that 35% of males and 42% of females reported some form of sexual dysfunction. Read et al, J. Public Health Med., 19(4):387-391 (1997). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Pharmaceutical formulation comprising thienopyrimidines and antithrombotics, calcium antagonists, prostaglandins or prostaglandin derivatives (2) Inventor(s): Eggenweiler, Hans-Michael; (Darmstadt, DE), Eiermann, Volker; (Rodermark, DE) Correspondence: Millen, White, Zelano & Branigan, P.C.; 2200 Clarendon BLVD.; Suite 1400; Arlington; VA; 22201; US Patent Application Number: 20040058940 Date filed: June 19, 2003 Abstract: The invention relates to a pharmaceutical formulation containing at least one compound of formula (1) wherein R.sup.1, R.sup.2, and X have the same meaning as cited in claim 1, and the physiologically acceptable salts thereof and/or solvates and a) at least one antithrombotic or b) at least one calcium antagonist or c) at least one prostaglandin or prostaglandin derivative for producing a medicament for treating angina, high blood pressure, pulmonary hypertension, congestive heart failure (CHF),

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chronic obstructive pulmonary disease (COPD), pulmonary heart disease, right ventricular failure, atheriosclerosis, permeability conditions of reduced cardiovascular patency, peripheral vascular illnesses, cerebral apoplexy, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumours, kidney failure, cirrhosis of the liver and for treating female sexual problems. 1 Excerpt(s): The invention relates to pharmaceutical formulations comprising at least one phosphodiesterase V inhibitor and/or physiologically acceptable salts and/or solvates thereof and at least one antithrombotic. c) at least one prostaglandin or prostaglandin derivative. The invention furthermore relates to the use of the formulation for the preparation of a medicament for the treatment of angina, high blood pressure, pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonale, dextrocardiac insufficiency, atherosclerosis, conditions of reduced patency of heart vessels, peripheral vascular diseases, strokes, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumours, renal insufficiency, liver cirrhosis and for the treatment of female sexual disorders. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Polymer compositions comprising antifibrotic agents, and methods of treatment, pharmaceutical compositions, and methods of preparation therefor Inventor(s): Kemnitzer, John E. II; (San Diego, CA), Kohn, Joachim; (South Plainfield, NJ), Poiani, George; (Mount Crawford, VA), Riley, David; (New Brunswick, NJ) Correspondence: Perkins Coie Llp; Post Office Box 1208; Seattle; WA; 98111-1208; US Patent Application Number: 20030186869 Date filed: October 30, 2002 Abstract: A method for treating pulmonary hypertension and other diseases involving a defect in collagen metabolism, by administration of an effective amount of a liposome encapsulated copolymer conjugate antifibrotic composition, is disclosed. The antifibrotic agent is preferably proline analogs, such as cis-4-hydroxy-L-proline (CHOP), 3,4dehydro-DL-proline (DHP), (R)-(-)-2-thiazolidine-4-carboxylic acid (THP), and (S)-(-)-2azetidinecarboxylic acid (ACA). Consistent, high loadings (>90%) of the antifibrotic agent are achieved by first forming a dipeptide with L-lysine, after which the dipeptide is copolymerized with the polymer component to form the copolymer conjugate. The polymer is preferably poly(ethylene glycol) having a weight average molecular weight of from about 500 to about 15,000. Efficient delivery and consistent release of the antifibrotic agent inhibits collagen accumulation and treats the diseases involved. Accordingly, there is a substantial reduction in the quantity of antifibrotic agent necessary, and thus a corresponding reduction in the potential for toxicity that would otherwise result from its prolonged administration. Excerpt(s): This application is a continuation-in-part of co-pending application Ser. No. 08/650,324 filed May 20, 1996; which is a continuation-in-part of application Ser. No. 08/479,150 filed Jun. 7, 1995, now U.S. Pat. No. 5,660,822; which is a divisional application of application Ser. No. 08/260,080 filed Jun. 15, 1994, now U.S. Pat. No. 5,720,950; which is (1) a division of Ser. No. 07/934,818, filed Aug. 24, 1992, now U.S. Pat. No. 5,372,807, which is a continuation-in-part of application Ser. No. 07/864,361 filed on Apr. 6, 1992, now abandoned, which is a continuation of application Ser. No. 07/523,232 filed on May 14, 1990, now abandoned; and which is also (2) a continuation

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in part of application Ser. No. 07/726,301 filed Jul. 5, 1991, now U.S. Pat. No. 5,219,564; which is a continuation of application Ser. No. 07/549,494 filed on Jul. 6, 1990, now abandoned. All of the above-enumerated applications are incorporated herein by reference, each in its entirety. The present invention relates generally to the treatment of fibrotic conditions, and to the use of antifibrotic agents for the amelioration and modification of such diseases. The present invention is also concerned with therapeutic compositions in which antifibrotic agents are chemically combined with carriers such as polymers in order to enhance the pharmacokinetic profile of the antifibrotic agents. The fibrotic conditions that the present invention is intended to treat include changes in the structure and function of various organs in connection with the metabolism of collagen and other biomolecules. One of the long-term sequelae of hypertension is the deposition of connective tissue in walls of blood vessels. In hypertensive rats, collagen biosynthesis and deposition are increased in the aorta, and these effects are reversed when blood pressure is lowered by antihypertensive drugs. Treatment of animals having experimental hypertension with agents that selectively inhibit collagen formation and reduce vascular collagen content suggest that increased collagen contributes to the maintenance of hypertension. Although the use of antifibrotic agents has increased the understanding of the role of collagen in hypertension and vascular disease, their application as potential therapeutic agents for chronic conditions has been limited. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Preventives and remedies for pulmonary hypertension Inventor(s): Egashira, Kensuke; (Fukuoka, JP), Ikeda, Yasuhiro; (Fukuoka, JP), Inada, Yoshiyuki; (Hyogo, JP), Sueishi, Katsuo; (Fukuoka, JP), Yonemitsu, Yoshikazu; (Fukuoka, JP) Correspondence: Takeda Pharmaceuticals North America, Inc; Intellectual Property Department; 475 Half Day Road; Suite 500; Lincolnshire; IL; 60069; US Patent Application Number: 20030162737 Date filed: March 22, 2003 Abstract: The present invention provides a prophylactic and/or therapeutic agent for pulmonary hypertension, comprising an antagonistic mutein of MCP-1 or a salt thereof, a DNA molecule comprising a nucleotide sequence encoding the antagonistic mutein of MCP-1, or a neutralizing antibody against MCP-1.The antagonistic mutein of MCP-1 or a salt thereof, the DNA molecule having a nucleotide sequence encoding the antagonistic mutein of MCP-1, or the neutralizing antibody against MCP-1 has hypotensive activity, and thus is useful as a pharmaceutical agent for preventing and/or treating pulmonary hypertension (primary pulmonary hypertension, in particular). Excerpt(s): The present invention relates to novel prophylactic and/or therapeutic agents for pulmonary hypertension. MPC-1 (Monocyte chemoattractant protein-1: macrophage chemotactic factor) is a member of the C--C chemokine family and is known to be highly expressed in the arteriosclerotic (e.g. atherosclerotic) lesion (Takeya, M. et al., Hum. Pathol. 24: 534-539 (1993); Yla-Herttuala, S. et al., Proc. Natl. Acad. Sci. USA, 88: 5252-5257 (1991)). On the other hand, primary pulmonary hypertension (PH) is a disease with poor prognosis, and heart-lung transplantation is the only therapy for this disease at present. However, heart-lung transplantation has considerable difficulty being used as a practical treatment due to the limited supply of donors. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Pulmonary vasodilator surfactant compositions and method of use Inventor(s): Ahmad, Magdy; (East Lansing, MI) Correspondence: Mcleod & Moyne, P.C.; 2190 Commons Parkway; Okemos; MI; 48864; US Patent Application Number: 20030170223 Date filed: January 31, 2003 Abstract: Compositions and methods for use for treating, pulmonary hypertension, in particular neonatal pulmonary hypertension and early lung inflammation, are described. In a first embodiment, the composition comprises pulmonary vasodilators and mitochondrial targeted antioxidants in mixture with a lung surfactant. Preferably, the composition comprises one or more chemicals selected from the group consisting of a long-acting nitric oxide donors, antioxidants, endothelin-1 receptor antagonists, and antithromboxanes in mixture with a lung surfactant. In a second embodiment, the present invention provides a composition for treating neonatal pulmonary hypertension and early lung inflammation in mammals who do not respond to nitric oxide treatment alone. In this embodiment, the composition comprises liposomes comprising a pulmonary or lung surfactant and which contains vasodilators and chemicals which modulate development of acute inflammation. In a preferred embodiment, the liposome contains a long-acting nitric oxide donor, a recombinant human I.kappa.B-.alpha., an NF-.kappa.B inhibitor, an anti-TNF-.alpha., and an iNOS inhibitor. The composition can further include one or more of the components comprising the first embodiment. Excerpt(s): This application claims benefit of U.S. Provisional Patent Application No. 60/353,149 filed Feb. 1, 2002, and U.S. Provisional Patent Application No. 60/376,293 filed Apr. 29, 2002. Not Applicable. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Pyrazole compositions Inventor(s): Banks, Bernard Joseph; (Sandwich, GB), Eshelby, James John; (Sandwich, GB), Logan, Nathan Anthony; (Sandwich, GB), Schulz, Darren John; (Sandwich, GB) Correspondence: Pfizer INC.; Patent Department, Ms8260-1611; Eastern Point Road; Groton; CT; 06340; US Patent Application Number: 20030232848 Date filed: April 2, 2003 Abstract: Compounds of formulae (IA) and (IB): 1wherein R.sup.1, R.sup.2, R.sup.3, Ar.sup.1 and X are as defined above, are endothelin antagonists. The compounds are therefore useful in the treatment of a variety of conditions mediated by endothelin, such as restenosis, renal failure and systemic and pulmonary hypertension. Excerpt(s): This invention relates to pyrazole derivatives useful in the treatment of a variety of conditions mediated by endothelin and to pharmaceutical formulations containing such compounds useful for the treatment of humans and non-human mammals. Endothelin (ET) is a potent vasoconstrictor synthesised and released by endothelial cells. There are three distinct isoforms of ET: ET-1, ET-2 and ET-3, all being

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21-amino acid peptides and herein the term `endothelin` refers to any or all of the isoforms. Two receptor subtypes, ET.sub.A and ET.sub.B have been pharmacologically defined (see for example H. Arai et al., Nature, 348, 730, 1990) and further subtypes have recently been reported. Stimulation of ET.sub.A promotes vasoconstriction and stimulation of ET.sub.B receptors causes either vasodilation or vasoconstriction. The main effects of ET are observed in the cardiovascular system, particularly in the coronary, renal, cerebral and mesenteric circulation, and the effects of endothelin are often long-lasting. Stimulation of ET receptors also mediate further biological responses in cardiovascular and non-cardiovascular tissues such as cell proliferation and matrix formation. Increased circulating levels of endothelin have been observed in patients who have undergone percutaneous transluminal coronary angioplasty (PTCA) (A. Tahara et al., Metab. Clin. Exp. 40, 1235, 1991) and ET-1 has been found to induce neointimal formation in rats after balloon angioplasty (S. Douglas et al., J. Cardiovasc. Pharm., 22 (Suppl 8), 371, 1993). The same workers have found that an endothelin antagonist, SB209670, causes a 50% reduction in neointimal formation relative to control animals (S. Douglas et al., Circ Res, 75, 1994). Antagonists of the endothelin receptor may thus be useful in preventing restenosis post PTCA. The ET.sub.A/B receptor antagonist Bosentan reportedly decreased blood pressure in hypertensive patients (H. Krum et al., New Eng. J. Med. (1998) 338, 784-790). Antagonists of ET.sub.B receptors such as BQ-788 have been demonstrated to increase peripheral resistance in man (Hypertension (1999) 33, 581-585). Thus ET.sub.A-selective receptor antagonists are most likely to be of benefit in hypertension. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Role of PPH1 gene in pulmonary hypertension Inventor(s): Knowles, James A.; (Rowaytn, CT), Morse, Jane H.; (Bronx, NY) Correspondence: John P. White; Cooper & Dunham Llp; 1185 Avenue OF The Americas; New York; NY; 10036; US Patent Application Number: 20020022229 Date filed: July 12, 2001 Abstract: This invention provides a method of detecting whether a subject is either predisposed to or afflicted with a pulmonary disease which comprises (1) obtaining a suitable sample from the subject; (2) detecting in the sample a bone morphogenetic protein receptor-II mutation which is not present in wildtype bone morphogenetic protein receptor-II, wherein the presence of a mutation indicates that the subject is predisposed to or afflicted with the pulmonary disease. In one embodiment, the pulmonary disease is Familial Primary Pulmonary Hypertension. Excerpt(s): This application is a continuation-in-part and claims the benefit of U.S. Provisional Application No. 60/217,773, filed Jul. 12, 2000, the contents of which are hereby incorporated by reference into this application. The invention disclosed herein was made with Government support under NIH Grant No. HL60056-02 from the National Heart, Lung and Blood Institute. Accordingly, the government has certain rights in this invention. Throughout this application, various publications are referenced within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citations for these references may be found immediately preceding the claims.

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Stereo pulse oximeter Inventor(s): Al-Ali, Ammar; (Costa Mesa, CA), Diab, Mohamed K.; (Mission Viejo, CA), Kiani, Massi E.; (Laguna Niguel, CA), Kopotic, Robert James; (Jamul, CA), Tobler, David; (Westminster, CO) Correspondence: Knobbe Martens Olson & Bear Llp; 620 Newport Center Drive; Sixteenth Floor; Newport Beach; CA; 92660; US Patent Application Number: 20020082488 Date filed: December 21, 2001 Abstract: An improved pulse oximeter provides for simultaneous, noninvasive oxygen status and photoplethysmograph measurements at both single and multiple sites. In particular, this multiple-site, multiple-parameter pulse oximeter, or "stereo pulse oximeter" simultaneously measures both arterial and venous oxygen saturation at any specific site and generates a corresponding plethysmograph waveform. A corresponding computation of arterial minus venous oxygen saturation is particularly advantageous for oxygen therapy management. An active pulse-inducing mechanism having a scattering-limited drive generates a consistent pulsatile venous signal utilized for the venous blood measurements. The stereo pulse oximeter also measures arterial oxygen saturation and plethysmograph shape parameters across multiple sites. A corresponding calculation of delta arterial saturation and comparison of plethysmograph shape parameters between multiple sites is particularly advantageous for the detection and management of persistent pulmonary hypertension in neonates (PPHN), a patent ductus arteriosis (PDA), and aortic coarctation. Excerpt(s): The measurement of oxygen delivery to the body and the corresponding oxygen consumption by its organs and tissues is vitally important to medical practitioners in the diagnosis and treatment of various medical conditions. Oxygen delivery, the transport of oxygen from the environment to organs and tissues, depends on the orchestration of several interrelated physiologic systems. Oxygen uptake is determined by the amount of oxygen entering the lung and the adequacy of gas exchange within the lung. This gas exchange is determined by the diffusion of oxygen from the alveolar space to the blood of the pulmonary capillaries. Oxygen is subsequently transported to all organs and tissues by blood circulation maintained by the action of the heart. The availability of oxygen to the organs and tissues is determined both by cardiac output and by the oxygen content in the blood. Oxygen content, in turn, is affected by the concentration of available hemoglobin and hemoglobin oxygen saturation. Oxygen consumption is related to oxygen delivery according to Fick's axiom, which states that oxygen consumption in the peripheral tissues is equal to oxygen delivery via the airway. Oxygen delivery and oxygen consumption can be estimated from a number of measurable parameters. Because of the diagnostic impracticalities of measuring oxygen uptake and cardiac output, oxygen delivery is typically assessed from the oxygen status of arterial blood alone, such as arterial oxygen partial pressure, P.sub.aO.sub.2, and arterial oxygen saturation, S.sub.aO.sub.2. P.sub.aO.sub.2 represents the relatively small amount of oxygen dissolved in the blood plasma. S.sub.aO.sub.2 represents the much larger amount of oxygen chemically bound to the blood hemoglobin. Oxygen consumption is typically assessed from the oxygen status of mixed venous blood, i.e. the oxygen saturation of blood from the pulmonary artery, S.sub.vO.sub.2, which is used to estimate the O.sub.2 concentration of blood returning

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from all tissues and organs of the body. These parameters can be measured by both invasive and non-invasive techniques, except S.sub.vO.sub.2, which requires an invasive measurement. Invasive techniques include blood gas analysis using the in vitro measurement of extracted arterial or venous blood, drawn with a syringe and needle or an intervascular catheter. Arterial blood is commonly obtained by puncturing the brachial, radial or femoral artery. Venous blood can be obtained from an arm vein, but such a sample reflects only local conditions. To obtain mixed venous blood, which represents the composite of all venous blood, a long catheter is typically passed through the right heart and into the main pulmonary artery from a peripheral vein. Extracted blood gas analysis utilizes blood gas machines or oximeters. A blood gas machine measures the partial pressure of oxygen, PO.sub.2, using a "Clark electrode" that detects the current generated by oxygen diffusing to a sealed platinum electrode across a gas permeable membrane. An oximeter measures the oxygen saturation, SO.sub.2, of oxygenated and deoxygenated hemoglobin using spectrophotometry techniques that detect the differential absorption of particular wavelengths of light by these blood components. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Therapeutic antisense phosphodiesterase inhibitors Inventor(s): Arrow, Amy; (Bethel, ME), Dale, Roderic M.K.; (Wilsonville, OR), Thompson, Terry; (West Linn, OR) Correspondence: Morgan Lewis & Bockius Llp; 1111 Pennsylvania Avenue NW; Washington; DC; 20004; US Patent Application Number: 20030045490 Date filed: February 19, 2002 Abstract: This patent describes the invention of a series of novel therapeutic oligonucleotides targeted at inhibiting expression of genes coding for Phosphodiesterase 4. They are useful as analytical tools in the study of individual PDE isoforms and in the therapeutic treatment of depression, thrombosis, cystic fibrosis, gastric lesions, pulmonary hypertension, glaucoma, multiple sclerosis, atopic dermatitis, asthma and other allergic disorders as well as other illnesses in which an increase of cyclic AMP or a decrease in phosphodiesterase levels is useful. Excerpt(s): This application is a continuation-in-part of our earlier filed application Ser. No. 09/223,586, filed Dec. 30, 1998, to which we claim priority under 35 U.S.C.sctn.120 and which is incorporated herein by reference in its entirety. The enzyme phosphodiesterase (PDE), along with adenylate cyclase and guanylate cyclase, are enzymes responsible for maintaining the correct balance of cyclic AMP and cyclic GMP in cells. There are multiple distinct phosphodiesterases (PDE 1 through PDE 9), most of which exist as two or more isozymes or splice variants that can differ in their cellular distribution, specificity toward hydrolysis of cAMP or cGMP, selective inhibition by various compounds, and sensitivity to regulation by calcium, calmodulin, cAMP, and cGMP (J. A. Beavo in Cyclic Nucleotide Phosphodiesterases: Structure, Regulation and Drug Action. Multiple Phosphodiesterase Isozymes: Background, Nomenclature, and Implications. Eds. Beavo, J. and Houslay, M. D., John Wiley and Son, New York, 1990, pp. 3-15 and T. J. Torphy et al., "Novel Phosphodiesterases Inhibitors for the Therapy of Asthma", Drug News & Prospective, 6(4) May 1993, pp. 203-214). The PDE4 family, which is specific for cAMP, is composed of at least 4 isozymes (a-d), and multiple splice variants (Houslay, M. D., et al. in Advances in Pharmacology 44, Eds. J. August et al.,

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p.225, 1998). In total, there may be over 20 PDE4 isoforms expressed in a cell specific pattern regulated by a number of different promoters. PDE inhibitors influence multiple functional pathways, act on multiple immune and inflammatory pathways, and influence synthesis or release of numerous immune mediators (J. M. Hanifin and S. C. Chan, "Atopic Dermatitis-Therapeutic Implication for New Phosphodiesterase Inhibitors, Monocyte Dysregulation of T Cells" in AACI News, 7/2, 1995; J. M. Hanifin et al., "Type 4 Phosphodiesterase Inhibitors Have Clinical and In Vitro Antiinflammatory Effects in Atopic Dermatitis," J. of Invest. Derm., 1996, 107.51-56 and Cohen, V. L. in INC's 7th Annual Conference on Asthma and Allergy (Oct. 27-28, 1997)-Phosphodiesterase 4 Inhibitors: Second Generation and Beyond). Clinical use of inhibitors of PDE4 have shown them to be broad spectrum anti-inflammatory agents with impressive activity in models of asthma and other allergic disorders, including atopic dermatitis and hay fever. PDE4 inhibitors that have been used clinically include theophylline, rolipram, denbufylline, CDP 840 (a tri-aryl ethane) and CP80633 (a pyrimidone). PDE4 inhibitors have been shown to influence eosinophil responses, decrease basophil histamine release, decrease IgE, PGE2, and IL10 synthesis, and decrease anti-CD3 stimulated IL4 production. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Therapeutic combination of amlodipine and benazepril Inventor(s): Daley, William Lionel; (Morris Plains, NJ), Webb, Randy Lee; (Flemington, NJ) Correspondence: Thomas Hoxie; Novartis, Corporate Intellectual Property; One Health Plaza 430/2; East Hanover; NJ; 07936-1080; US Patent Application Number: 20040048905 Date filed: July 31, 2003 Abstract: The present invention especially relates to the use of a combination comprising (1) an ACEI selected from the group consisting of benazepril, benazeprilat, and pharmaceutically acceptable salts thereof, and (2) amlodipine or pharmaceutically acceptable salt thereof, for the manufacture a medicament for the treatment or prevention or delay of progression of a condition selected from the group consisting of hypertension, congestive heart failure, angina, myocardial infarction, artherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, blood pressurerelated cerebrovasular disease, stroke, pulmonary disease or pulmonary hypertension and headache; wherein (i) the amount of amlodipine or a phamaceutically acceptable salt thereof corresponds to 6 mg to 40 mg of the free base and (ii) the amount of the ACE inhibitor or a pharmaceutically thereof corresponds to 20 mg to 160 mg of benazepril hydrochloride. Excerpt(s): Calcium channel blockers (CCBs) and angiotensin converting enzyme inhibitors (ACEIs) are widely used for the treatment of hypertension and related diseases and conditions. A representative of the class of CCBs is amlodipine, while a representative of the class of ACEIs is benazepril or benazeprilat. Amlodipine is 2-[(2aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5pyridinedicarboxylic acid 3-ethyl 5-methyl ester. It is sold commercially in the form of its besylate salt under the trademark NORVASC.RTM. as an antihypertensive. Amlodipine may be administered in free or pharmaceutically aceptable salt form. Where amlodipine dosages are set forth herein, it is understood that the amounts are the

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amounts corresponding to amlodipine free base equivalents, irrespective of the salt form used, unless otherwise indicated. It is known that a chronic anti-hypertensive therapy with amlodipine is often associated with side effects such as dose-limiting peripheral edema, especially ankle edema. The amlodipine induced ankle edema, for example, is believed to be due to a preferential dilation of the precapillary arterioles in the leg and a resultant efflux of fluid into the interstitial space. The upper limit of mono-therapy with amlodipine is 10 mg per day, and lower doses are preferred for chronic treatments. Higher dosage formulations than 10 mg per day are not approved by regulatory authorities or marketed, as in many susceptible individuals, side effects, such as those mentioned above, may limit efficacy and may ultimately result in discontinuation of the therapy. As used herein, a "high dose" or a "higher dose" of amlodipine refers to daily dosage amounts greater than 5 mgs amlodipine, preferably from 6-40 mgs, more preferably 7.5-20 mgs, for example, 7.5, 10, 15, or 20 mgs, more preferably at least 10 mgs, e.g., 10, 12.5, 15, or 20 mgs, most preferably 10 or 20 mgs. For administration every other day, dosages of 10-60mgs, preferably 20 to 40 mgs, for example 20, 30, or 40 mgs, especially 40 mgs, are preferred. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Treatment of pulmonary hypertension Inventor(s): Ghazzi, Maha; (Ann Arbor, MI), Pressler, Milton Lethan; (Saline, MI) Correspondence: Charles W. Ashbrook; Warner-lambert Company; 2800 Plymouth Road; Ann Arbor; MI; 48105; US Patent Application Number: 20020128259 Date filed: October 3, 2001 Abstract: Disclosed is a method for treating pulmonary hypertension using a vasopressin antagonist. Excerpt(s): This invention relates to vasopressin antagonists for use in treating pulmonary hypertension. Specifically, this invention relates to the use of conivaptan for treating pulmonary hypertension. Pulmonary hypertension (PH) is a condition of increased pulmonary vascular resistance and pulmonary arterial pressure which interferes with ventilation-perfusion relationships. PH typically is characterized by increased blood pressure (above 30 mm Hg systolic and 12 mm Hg diastolic) within the pulmonary circulation. There are two subsets of pulmonary hypertension: primary (idiopathic or "unexplained") and secondary. The secondary form is by far the more prevalent. The most common causes of secondary pulmonary hypertension are heart disease and lung disease. Regardless of the root cause of the pulmonary hypertension, the resistance (precapillary) vessels of the lungs undergo anatomic change that contributes to the progression of pulmonary hypertension. Pulmonary arterial hypertension secondary to acquired heart disease begins with a disorder of the left ventricle that leads to pulmonary venous hypertension followed by pulmonary arterial hypertension. Arginine vasopressin, also known as antidiuretic hormone (ADH), is synthesized in the magnocellular neurosecretory cells of the paraventricular and supraoptic nuclei of the hypothalamus and stored in the posterior pituitary. There are 2 classes of AVP receptors, V.sub.1 and V.sub.2. There are 2 subclasses of V.sub.1 receptors, namely V.sub.1A and V.sub.1B. V.sub.1A receptors are found in the vasculature, and mediate the pressor response of AVP by increasing the contraction of blood vessels. Recent in vitro studies in the rat suggest that the lung contains the V.sub.1A receptor subtype. V.sub.1A receptors are also found on platelets, where they

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mediate platelet aggregation. V.sub.1B receptors are located in the anterior pituitary and mediate adrenocorticotropic hormone (ACTH) release. V.sub.2 receptors are located in the collecting ducts of the kidney; they are coupled to aquaporine channels and modulate free water clearance. Arginine vasopressin is released into the circulation in response to an increase in plasma osmolality (mediated by osmoreceptors) or a decrease in plasma volume or blood pressure (mediated by baroreceptors). However, there are other stimuli for AVP release, including norepinephrine, angiotensin II, emotion, nausea and vomiting, and fever. Elevated levels of AVP have been reported in patients with cardiac failure, although its pathophysiologic role is unknown. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

UPREGULATION OF TYPE III ENDOTHELIAL CELL NITRIC OXIDE SYNTHASE BY AGENTS THAT DISRUPT ACTIN CYTOSKELETAL ORGANIZATION Inventor(s): LIAO, JAMES K.; (WESTON, MA) Correspondence: Edward R Gates; Wolf Greenfield & Sacks; 600 Atlanntic Avenue; Boston; MA; 02210 Patent Application Number: 20020082281 Date filed: July 14, 1998 Abstract: A use for agents that disrupt actin cytoskeletal organization is provided. In the instant invention, agents that disrupt actin cytoskeletal organization are found to upregulate endothelial cell Nitric Oxide Synthase activity. As a result, agents that disrupt actin cytoskeletal organization are useful in treating or preventing conditions that result from the abnormally low expression and/or activity of endothelial cell Nitric Oxide Synthase. Such conditions include pulmonary hypertension, ischemic stroke, impotence, heart failure, hypoxia-induced conditions, insulin deficiency, progressive renal disease, gastric or esophageal motility syndrome, etc. Subjects thought to benefit mostly from such treatments include nonhyperlipidemics and nonhypercholesterolemics, but not necessarily exclude hyperlipidemics and hypercholesterolemics. Excerpt(s): This invention relates to the use of agents that disrupt actin cytoskeletal organization as upregulators of Type III endothelial cell Nitric Oxide Synthase. Further, this invention relates to methods that employ agents that disrupt actin cytoskeletal organization to treat conditions that result from the abnormally low expression and/or activity of endothelial cell Nitric Oxide Synthase in a subject. Nitric oxide (NO) has been recognized as an unusual messenger molecule with many physiologic roles, in the cardiovascular, neurologic and immune systems (Griffith, T M et al., J Am Coll Cardiol, 1988, 12:797-806). It mediates blood vessel relaxation, neurotransmission and pathogen suppression. NO is produced from the guanidino nitrogen of L-arginine by NO Synthase (Moncada, S and Higgs, E A, Eur J Clin Invest, 1991, 21(4):361-374). In mammals, at least three isoenzymes of NO Synthase have been identified. Two, expressed in neurons (nNOS) and endothelial cells (Type III-ecNOS), are calciumdependent, whereas the third is calcium-independent and is expressed by macrophages and other cells after induction with cytokines (Type II-iNOS) (Bredt, D S and Snyder, S H, Proc Natl Acad Sci USA, 1990, 87:682-685, Janssens, S P et al., J Biol Chem, 1992, 267:22964, Lyons, C R et al., J Biol Chem, 1992, 267:6370-6374). The various physiological and pathological effects of NO can be explained by its reactivity and different routes of formation and metabolism. Recent studies suggest that a loss of endothelial-derived NO activity may contribute to the atherogenic process (O'Driscoll, G, et al., Circulation, 1997,

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95:1126-1131). For example, endothelial-derived NO inhibits several components of the atherogenic process including monocyte adhesion to the endothelial surface (Tsao, P S et al., Circulation, 1994, 89:2176-2182), platelet aggregation (Radomski, M W, et al., Proc Natl Acad Sci USA, 1990, 87:5193-5197), vascular smooth muscle cell proliferation (Garg, U C and Hassid, A, J Clin Invest, 1989, 83:1774-1777), and vasoconstriction (Tanner, F C et al., Circulation, 1991, 83:2012-2020). In addition, NO can prevent oxidative modification of low-density lipoprotein (LDL) which is a major contributor to atherosclerosis, particularly in its oxidized form (Cox, D A and Cohen, M L, Pharm Rev, 1996, 48:3-19). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Use of a defective recombinant adenovirus comprising a nucleic acid encoding an angiogenic factor for treating pulmonary hypertension Inventor(s): Adnot, Serge; (Saint Maur, FR), Branellec, Didier; (Lyon, FR) Correspondence: Finnegan, Henderson, Farabow,; Garrett & Dunner, L.L.P.; 1300 I Street, N.W.; Washington; DC; 20005-3315; US Patent Application Number: 20020086004 Date filed: October 26, 2001 Abstract: The present invention relates to the use of a vector which comprises a nucleic acid encoding an angiogenic factor for preventing, ameliorating or treating pulmonary hypertension. It also relates to specific pharmaceutical compositions which enable these vectors to be administered locally and efficiently. Excerpt(s): Pulmonary hypertension is a commonly occurring disorder which is fatal in its serious forms and which currently lacks any treatment apart from transplantation. The disorder is generally characterized by an increase in pulmonary arterial resistance, which hinders right ventricular ejection and compromises cardiac output. Several functional and structural anomalies of the pulmonary vascular wall are involved in the development of pulmonary hypertension, including: hyperplasia of the smooth muscle cells, together with medial and intimal hypertrophy, a build-up of the extracellular matrix, and vascular rarefaction with reduction in peripheral capillary density. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Use of thienopyrimidines Inventor(s): Eggenweiler, Hans-Michael; (Eggenweiler, DE), Eiermann, Volker; (Rodermark, DE) Correspondence: Millen, White, Zelano & Branigan, P.C.; 2200 Clarendon BLVD.; Suite 1400; Arlington; VA; 22201; US Patent Application Number: 20040034040 Date filed: May 27, 2003 Abstract: The invention relates to the use of thienopyrimidines of formula (I)--wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and X have the designations cited in claim 1--and the physiologically acceptable salts thereof, for producing a medicament for the treatment of angina, hypertension, pulmonary hypertension, congestive heart failure, arteriosclerosis, conditions of reduced patency of the heart vessels, peripheral vascular

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diseases, apoplexy, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumours, kidney failure, and cirrhosis of the liver, and for the treatment of female sexual disorders. Excerpt(s): and their physiologically acceptable salts and/or solvates, for the preparation of a medicament for the treatment of angina, high blood pressure, high pulmonary pressure, congestive heart failure, atherosclerosis, conditions of reduced patency of heart vessels, peripheral vascular diseases, strokes, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumours, renal insufficiency, liver cirrhosis and for the treatment of female sexual disorders. Pyrimidine derivatives are disclosed, for example, in EP 201 188 or WO 93/06104. The use of other PDE-V inhibitors is described, for example, in WO 94/28902. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Use of urokinase inhibitors for the treatment and/or prevention of pulmonary hypertension and/or cardiac remodelling Inventor(s): Carmeliet, Peter; (Landen, BE), Collen, Desire; (Winksele, BE), Heymans, Stephane; (Heverlee, BE), Levi, Marcel; (Amsterdam, NL) Correspondence: Elie H Gendloff; Amster Rothstein & Ebenstein; 90 Park Avenue; New York; NY; 10016; US Patent Application Number: 20030125233 Date filed: December 23, 2002 Abstract: The present invention relates to methods of treatment and/or prevention of pulmonary hypertension and to methods of treatment and/or prevention of cardiac remodelling and more specifically to cardiac remodelling induced by systemic hypertension in a mammal, particularly a human being. In particular, the invention shows a novel, negative role for urokinase-type plasminogen activator in the pathogenesis of cardiac remodelling, leading to subsequent cardiac dysfunction, and in the pathogenesis of pulmonary hypertension usually complicated by subsequent right ventricular hypertrophy. Consequently, the use of selective inhibitors of u-PA activity can be of benefit for treatment of patients suffering from pulmonary hypertension and/or cardiac remodelling. Excerpt(s): More than 10 percent of Western population suffers from severe hypertension. In young patients, severe hypertension first results in pronounced hypertrophic cardiomyopathy. The magnitude of left ventricular (LV) hypertophy in these patients is a strong and independent predictor of the risk of sudden death and indeed more than 20 percent of young patients with severe hypertrophic cardiomyopathy die of sudden death before the age of 40 years (Spirito et al., (2000), N. Engl. J. Med., 342, 1778). In older patients, long-term hypertension may end in congestive heart failure. The prognosis of progressive heart failure is poor: more than 50 percent of these patients die within one year (Ju et al. (1996) Can. J. Cardiol. 12, 1259). Left ventricular (LV) hypertrophy initially occurs as an adaptation of the heart to an increased systolic wall stress. Major increase in myocyte volume and collagen deposition around the larger coronary vessels and in the interstitium characterizes the initial stage of hypertension and results in hypertrophic cardiomyopathy. When hypertrophy becomes chronic, myocytes degenerate, die and are replaced by matrixproducing fibroblasts. Myocyte necrosis and related fibrosis result in increased myocardial stiffness, systolic dysfunction, and ultimately in progressive cardiac failure

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(Jaffe et al. (1997), Adv. Exp. Med. Biol. 430, 257). Increased matrix metalloproteinase (MMP) and plasminogen activator (PA) activity have been demonstrated during LV remodeling after acute myocardial infarction. Pharmacological proteinase inhibition reduces LV dilatation after acute myocardial infarction and prevents cardiac dysfunction in a pacing model of LV failure. Direct evidence for a role of MMP proteinases in hypertrophy of the myocardial cell and in progression to cardiac failure during severe hypertension is, however, lacking. In addition, the role of the plasminogen system, comprising urokinase-type plasminogen activator (u-PA), tissuetype PA (t-PA) and their PA inhibitor-1 (PAI-1), in myocyte hypertrophy and cardiac failure during LV hypertension remains completely undetermined. The present invention shows that deficiency of u-PA or an uPA-inhibition by adenoviral gene transfer of PAI-1 impairs LV hypertrophy and prevents cardiac dysfunction during pressure-overload induced hypertension indicating a central, novel role of u-PAmediated proteolytic activity in hypertensive cardiomyopathy. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Keeping Current In order to stay informed about patents and patent applications dealing with pulmonary hypertension, 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 “pulmonary hypertension” (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 pulmonary hypertension. You can also use this procedure to view pending patent applications concerning pulmonary hypertension. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

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CHAPTER 6. BOOKS ON PULMONARY HYPERTENSION Overview This chapter provides bibliographic book references relating to pulmonary hypertension. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on pulmonary hypertension include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.

Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “pulmonary hypertension” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “pulmonary hypertension” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “pulmonary hypertension” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

Clinical Pulmonary Hypertension (Portland Press Research Monograph, 8) by A. K. Morice (Editor); ISBN: 1855780747; http://www.amazon.com/exec/obidos/ASIN/1855780747/icongroupinterna

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Inflammatory Vascular Diseases-Endo-Myocardial Fibrosis-Pulmonary Hypertension: Proceedings - Conference of the International Society of Geographical by J. R. Ruettner (Editor), International Society Of Geographical Pa; ISBN: 3805523114; http://www.amazon.com/exec/obidos/ASIN/3805523114/icongroupinterna

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Inhalation Therapy for Pulmonary Hypertension: The Proceedings of a Symposium Held at the Annual Congress of the European Respiratory Society, Berlin, September 2001 by Timothy Higenbottam (Editor), et al; ISBN: 1842141848; http://www.amazon.com/exec/obidos/ASIN/1842141848/icongroupinterna

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Pathology of Pulmonary Hypertension by Cornelis Adriaan. Wagenvoort; ISBN: 0471913553; http://www.amazon.com/exec/obidos/ASIN/0471913553/icongroupinterna

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Primary Pulmonary Hypertension by Lewis J. Rubin (Editor), Stuart Rich (Editor); ISBN: 0824795059; http://www.amazon.com/exec/obidos/ASIN/0824795059/icongroupinterna

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Primary pulmonary hypertension (SuDoc HE 20.3202:P 96/8) by U.S. Dept of Health and Human Services; ISBN: B00010D23Q; http://www.amazon.com/exec/obidos/ASIN/B00010D23Q/icongroupinterna

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Primary pulmonary hypertension : report on a WHO meeting, Geneva, 15-17 October 1973; ISBN: 9241560444; http://www.amazon.com/exec/obidos/ASIN/9241560444/icongroupinterna

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Pulmonary Hypertension by Alfred P., Md. Fishman, Alfred P. Fishman M.D.; ISBN: 0070220565; http://www.amazon.com/exec/obidos/ASIN/0070220565/icongroupinterna

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Pulmonary Hypertension: Proceedings of the International Symposium on Pulmonary Circulation II, Prague, June 17-19, 1974 by Jiri Widimsky; ISBN: 3805521715; http://www.amazon.com/exec/obidos/ASIN/3805521715/icongroupinterna

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The Diagnosis and Treatment of Pulmonary Hypertension; ISBN: 0879932066; http://www.amazon.com/exec/obidos/ASIN/0879932066/icongroupinterna

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The Diagnosis and Treatment of Pulmonary Hypertension by E. Kenneth Weir, et al; ISBN: 0879935162; http://www.amazon.com/exec/obidos/ASIN/0879935162/icongroupinterna

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The Official Patient's Sourcebook on Primary Pulmonary Hypertension by Icon Health Publications, et al; ISBN: 0597831548; http://www.amazon.com/exec/obidos/ASIN/0597831548/icongroupinterna

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Treatment of Pulmonary Hypertension by Inhaled Delivery: International Symposium on Pulmonary Circulation Vii, Wednesday 30 Kune 1999, Prague, Czech Republic by Czechos International Symposium on Pulmonary Circulation 1999 Prague, et al; ISBN: 1842140809; http://www.amazon.com/exec/obidos/ASIN/1842140809/icongroupinterna

Chapters on Pulmonary Hypertension In order to find chapters that specifically relate to pulmonary hypertension, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and pulmonary hypertension 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 “pulmonary hypertension” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on pulmonary hypertension: •

Hepato-cellular Failure Source: in Sherlock, S.; Dooley, J. Diseases of the Liver and Biliary System. Malden, MA: Blackwell Science, Inc. 2002. p.81-92.

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Contact: Available from Blackwell Science, Inc. 350 Main Street, Commerce Place, Malden, MA 02148. (800) 215-1000 or (617) 388-8250. Fax (617) 388-8270. E-mail: [email protected]. Website: www.blackwell-science.com. PRICE: $178.95. ISBN: 0632055820. Summary: This chapter on hepatocellular failure is from a textbook that presents a comprehensive and up-to-date account of diseases of the liver and biliary system. The authors note that hepatocellular failure can complicate almost all forms of liver disease. Although the clinical features may differ, the overall picture and treatment are similar, regardless of etiology (cause). Topics include the general failure of health, jaundice, vasodilation and hyperdynamic circulation, pulmonary hypertension, fever and septicemia, fetor hepaticus, changes in nitrogen metabolism, skin changes, vascular spiders, palmar erythema (liver palms), white nails, mechanism of skin changes, endocrine changes, hypogonadism, hypothalamic-pituitary function, metabolism of hormones, general treatment considerations and precipitating factors. Each section has its own list of references, for further reading. 15 figures. 2 tables. 76 references. •

Central Nervous System and Pulmonary Complications of End-Stage Liver Diseases Source: in Textbook of Gastroenterology. 4th ed. [2-volume set]. Hagerstown, MD: Lippincott Williams and Wilkins. 2003. p. 2445-2468. Contact: Available from Lippincott Williams and Wilkins. P.O. Box 1600, Hagerstown, MD 21741. (800) 638-6423. Fax: (301) 223-2400. Website: www.lww.com. PRICE: $289.00. ISBN: 781728614. Summary: This chapter on the central nervous system and pulmonary (lung) complications of end stage liver diseases is from a comprehensive gastroenterology textbook that provides an encyclopedic discussion of virtually all the disease states encountered in a gastroenterology practice. In this chapter, the authors discuss hepatic encephalopathy, hepatopulmonary syndrome, and portopulmonary hypertension. Specific topics include definitions and pathophysiology of each syndrome, the role of gut-derived neurotoxins, the role of altered neurotransmitters, modifications in energy metabolism, mechanisms involved in fulminant hepatic failure, the signs and symptoms of overt hepatic encephalopathy, imaging modalities, biochemical markers, hepatic encephalopathy without liver disease, prognosis, differential diagnosis, pulmonary vasodilation, and treatment strategies. 5 figures. 6 tables. 216 references.

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Special Considerations for Children with Fluctuating-Progressive Hearing Loss Source: in Bess, F.H.; Gravel, J.S.; Tharpe, A.M., eds. Amplification for Children with Auditory Deficits. Nashville, TN: Bill Wilkerson Center Press. 1996. p. 339-365. Contact: Available from Bill Wilkerson Center Press. 1114 19th Avenue South, Nashville, TN 37212-2197. (615) 936-5023. Fax (615) 936-5013. PRICE: $55.00 plus shipping and handling. ISBN: 096314393X. Summary: This chapter, from a textbook on amplification for children with auditory deficits, discusses special considerations for children with fluctuating or progressive hearing loss. One consideration, particularly for younger children, is that audiologists may assume that changes in audiometric results reflect attention or nonsensory factors, as opposed to true changes in hearing sensitivity. The author attempts to raise the reader's level of suspicion for fluctuating or progressive hearing loss in children by reviewing several causes and patterns of such changes. The causes discussed include genetic hearing loss without associated abnormalities, including autosomal dominant

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progressive SNHL, x-linked progressive hearing loss, and otosclerosis; genetic hearing loss with associated abnormalities, including Albers-Schonberg disease, Alport's syndrome, branchio-oto-renal (BOR) syndrome, CHARGE syndrome, mucopolysaccharidosis syndrome (MPS), neurofibromatosis, osteogenesis imperfecta, retinitis pigmentosa, Stickler syndrome, and Waardenburg's syndrome; acquired hearing loss, including prenatal causes such as infections or inner ear malformations, perinatal causes such as hyperbilirubinemia and persistent pulmonary hypertension of the newborn, and postnatal causes, such as autoimmune inner ear disease, Meniere's disease, meningitis, otitis media, and perilymphatic fistula. The author makes recommendations for the audiologic management of children with fluctuating or progressive hearing loss. The chapter concludes with the presentation of three relevant case reports. 4 figures. 124 references.

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CHAPTER 7. PERIODICALS AND NEWS ON PULMONARY HYPERTENSION Overview In this chapter, we suggest a number of news sources and present various periodicals that cover pulmonary hypertension.

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

Multiple agents helpful in primary pulmonary hypertension Source: Reuters Industry Breifing Date: March 12, 2004

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•

Ultrasound detects pulmonary hypertension, mortality risk in sickle cell disease Source: Reuters Medical News Date: February 26, 2004

•

Epoprostenol lowers pulmonary vascular resistance in primary pulmonary hypertension Source: Reuters Industry Breifing Date: February 23, 2004

•

Iloprost formulations compared in children with pulmonary hypertension Source: Reuters Industry Breifing Date: November 25, 2003

•

HHV-8 may play role in primary pulmonary hypertension Source: Reuters Medical News Date: September 17, 2003

•

Trial data show Tracleer effective for HIV-related pulmonary hypertension Source: Reuters Medical News Date: September 02, 2003

•

Sildenafil shows promise as adjunct therapy for severe pulmonary hypertension Source: Reuters Industry Breifing Date: July 02, 2003

•

Arginine promising as treatment for pulmonary hypertension in sickle cell patients Source: Reuters Industry Breifing Date: July 01, 2003

•

Hypoxia-inducible factor deficit curbs murine pulmonary hypertension Source: Reuters Medical News Date: May 30, 2003

•

Vasoactive intestinal peptide may be effective against primary pulmonary hypertension Source: Reuters Medical News Date: May 15, 2003

•

Sildenafil may treat non-operable chronic thromboembolic pulmonary hypertension Source: Reuters Industry Breifing Date: May 13, 2003

•

Prostacyclin improves hemodynamics in severe thromboembolic pulmonary hypertension Source: Reuters Industry Breifing Date: March 05, 2003

•

Pulmonary hypertension linked by defects in signaling pathways Source: Reuters Medical News Date: February 06, 2003

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Sildenafil alleviates pulmonary hypertension secondary to lung fibrosis Source: Reuters Industry Breifing Date: September 19, 2002

•

Epoprostenol improves long-term survival of primary pulmonary hypertension Source: Reuters Industry Breifing Date: August 26, 2002

Periodicals and News 189

•

Inhaled iloprost an effective option for severe pulmonary hypertension Source: Reuters Industry Breifing Date: August 01, 2002

•

Newly designed agent improves oxygenation in neonatal pulmonary hypertension Source: Reuters Industry Breifing Date: July 11, 2002

•

Sitaxsentan therapy improves exercise capacity in pulmonary hypertension Source: Reuters Medical News Date: July 05, 2002

•

FDA approves Remodulin for pulmonary hypertension Source: Reuters Medical News Date: May 22, 2002

•

Sildenafil may be potential therapy for pulmonary hypertension in newborns Source: Reuters Medical News Date: April 29, 2002

•

Bosentan seems effective for pulmonary hypertension Source: Reuters Industry Breifing Date: March 20, 2002

•

Pulmonary hypertension in myocarditis increases mortality Source: Reuters Medical News Date: March 18, 2002

•

Severe pulmonary hypertension may improve with oral beraprost Source: Reuters Industry Breifing Date: December 25, 2001

•

Oxygen therapy benefits patients with pulmonary hypertension Source: Reuters Medical News Date: December 07, 2001

•

Actelion gets FDA approval for oral pulmonary hypertension drug Source: Reuters Medical News Date: November 21, 2001

•

Serotonin transporter key in pathogenesis of primary pulmonary hypertension Source: Reuters Medical News Date: October 31, 2001

•

Endothelin-receptor blocker shown beneficial in pulmonary hypertension Source: Reuters Industry Breifing Date: October 04, 2001

•

Pulmonary hypertension drug gets FDA approvable letter Source: Reuters Medical News Date: September 18, 2001

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Genetic basis of primary pulmonary hypertension clarified Source: Reuters Medical News Date: August 01, 2001

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Sildenafil might be novel treatment for pulmonary hypertension Source: Reuters Industry Breifing Date: July 27, 2001

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•

ICOS, Texas Biotech launch study of sitaxsentan for pulmonary hypertension Source: Reuters Industry Breifing Date: May 30, 2001

•

NSAID use in pregnancy linked to persistent pulmonary hypertension in newborns Source: Reuters Industry Breifing Date: March 09, 2001

•

High rate of persistent pulmonary hypertension seen in babies born by C-section Source: Reuters Medical News Date: March 01, 2001

•

Almitrine infusion may harm ARDS patients who have pulmonary hypertension Source: Reuters Industry Breifing Date: February 09, 2001

•

United Therapeutics files for French approval of pulmonary hypertension drug Source: Reuters Industry Breifing Date: February 05, 2001

•

Pulmonary hypertension not linked with poorer long-term outcome after lung transplant Source: Reuters Medical News Date: January 29, 2001

•

Adrenomedullin use may benefit patients with pulmonary hypertension Source: Reuters Medical News Date: December 13, 2000

•

Epoprostenol effective for HIV-associated pulmonary hypertension Source: Reuters Medical News Date: December 04, 2000

•

Inhaled NO after congenital heart surgery reduces risk of pulmonary hypertension Source: Reuters Medical News Date: October 26, 2000

•

United Therapeutics wins priority review for pulmonary hypertension drug Source: Reuters Industry Breifing Date: October 19, 2000

•

United Therapeutics files NDA for first non-IV treatment for pulmonary hypertension Source: Reuters Industry Breifing Date: October 16, 2000

•

Hearing loss due to pulmonary hypertension of newborn may have delayed onset Source: Reuters Medical News Date: August 15, 2000

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Gene responsible for many cases of familial primary pulmonary hypertension identified Source: Reuters Industry Breifing Date: July 24, 2000

•

Pulmonary hypertension increases risk for reperfusion injury after lung transplant Source: Reuters Medical News Date: July 21, 2000

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•

Long-term iloprost aerosol therapy effective in primary pulmonary hypertension Source: Reuters Industry Breifing Date: June 22, 2000

•

New therapy may reverse pulmonary hypertension Source: Reuters Health eLine Date: May 31, 2000

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Elastase inhibitors completely reverse pulmonary hypertension in rats Source: Reuters Medical News Date: May 31, 2000

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Double lung transplantation unnecessary for patients with secondary pulmonary hypertension Source: Reuters Medical News Date: March 23, 2000

•

Epoprostenol, inhaled iloprost promising for treatment of pulmonary hypertension Source: Reuters Medical News Date: March 21, 2000

•

Fenfluramine use linked to increased risk of primary pulmonary hypertension Source: Reuters Medical News Date: March 13, 2000 The NIH

Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “pulmonary hypertension” (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 “pulmonary hypertension” (or synonyms). If you know the name of a company that is relevant to pulmonary hypertension, 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 “pulmonary hypertension” (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 “pulmonary hypertension” (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 pulmonary hypertension: •

Meeting At Lutheran General Hospital. May 5, 1996, Lung Involvement Source: Schleroderma Update. 14(1):1-2; 1995. Contact: Scleroderma Foundation of Greater Chicago, 330 South Wells Street, Rm. 1318, Chicago, Ill 60606. Summary: This newsletter article describes a particular type of scleroderma called Calcinosis, Raynaud's phenomena, Esophagea dysfunction, Sclerodactly, and Telangiectasia (CREST), as it inflicts the lung. CREST damages the small vessels of the lung and diminishes oxygen transfer. To compensate, the lung increases blood pressure to increase the oxygen supply. Taking blood pressure from the right side of the heart using a catheter will reveal high blood pressure in the lung. Present treatments involve calcium channel blockers or alpha blockers and drugs to prevent spasm of blood vessels. General scleroderma, by contrast, only effects the blood vessels feeding blood to the lungs, so pulmonary hypertension does not occur. Treatment usually involves penicillamine. Pleurisy is another lung-related problem of scleroderma that inflames the lung's inner lining. The recommended treatment is prednisone to reduce the inflammation.

•

Update on Management of Scleroderma Source: Bulletin on the Rheumatic Diseases. 49(10): 1-4. 2001.

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Contact: Available from Arthritis Foundation. 1330 West Peachtree Street, Atlanta, GA 30309. (404) 872-7100. Fax (404) 872-9559. Summary: This newsletter article provides health professionals with information on the management of scleroderma. This chronic disease targets the skin, heart, lungs, gastrointestinal tract, kidneys, muscles, and joints. Scleroderma is classified into limited and diffuse cutaneous forms. Almost all patients with scleroderma have Raynaud's phenomenon (RP). The most effective way to prevent RP is to avoid exposure to cold. Calcium channel blockers are currently the most effective and safest vasodilators for scleroderma related RP. Other useful medications include coated aspirin and intravenous prostaglandins. Options for managing gastrointestinal disease include elevating the head of the bed, using antacids, making dietary changes, and taking oral motility agents. Prostaglandins and their analogs are now available to treat pulmonary hypertension. Immunosuppressive agents can be useful in treating interstitial lung disease. Renal disease can be treated with angiotensin converting enzyme inhibitors. Disease modifying agents that can be used to treat early diffuse scleroderma include colchicine, paraaminobenzoic acid, and D-penicillamine. Other drugs that have been investigated for treating early diffuse scleroderma include relaxin, halofuginone, glucocorticoids, methotrexate, thalidomide, and cyclophosphamide. People who have scleroderma are more likely to experience major depression, so good pain control and the use of antidepressants are important. 1 table and 12 references.

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

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CHAPTER 8. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.

U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for pulmonary hypertension. 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). Below, we have compiled a list of medications associated with pulmonary hypertension. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks,

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etc.). The following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to pulmonary hypertension: Epoprostenol •

Systemic - U.S. Brands: Flolan http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203429.html

Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.

Mosby’s Drug Consult Mosby’s Drug Consult database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee.

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 pulmonary hypertension 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 “pulmonary hypertension” (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

Researching Medications 197

information. From there, visit the Pharmacopeia Web site and type the name of each orphan drug into the search box at http://www.nlm.nih.gov/medlineplus/druginformation.html. You may need to contact the sponsor or NORD for further information. NORD conducts “early access programs for investigational new drugs (IND) under the Food and Drug Administration’s (FDA’s) approval ‘Treatment INDs’ programs which allow for a limited number of individuals to receive investigational drugs before FDA marketing approval.” If the orphan product about which you are seeking information is approved for marketing, information on side effects can be found on the product’s label. If the product is not approved, you may need to contact the sponsor. The following is a list of orphan drugs currently listed in the NORD Orphan Drug Designation Database for pulmonary hypertension: •

Nitric oxide http://www.rarediseases.org/nord/search/nodd_full?code=230

•

Epoprostenol (trade name: Flolan) http://www.rarediseases.org/nord/search/nodd_full?code=410

•

Beractant (trade name: Survanta Intratracheal Suspension) http://www.rarediseases.org/nord/search/nodd_full?code=591

•

CY-1503 (trade name: Cylexin) http://www.rarediseases.org/nord/search/nodd_full?code=694

•

15AU81 http://www.rarediseases.org/nord/search/nodd_full?code=871

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

201

APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute11: •

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

•

National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/

•

National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html

•

National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25

•

National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm

•

National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm

•

National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375

•

National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/

11

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

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•

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

•

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

•

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

•

National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm

•

National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/

•

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

•

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

•

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

•

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

•

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

•

National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm

•

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

•

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

•

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

•

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

•

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

•

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

•

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

Physician Resources 203

NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.12 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:13 •

Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html

•

HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

•

NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html

•

Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/

•

Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html

•

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

•

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

•

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

•

Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html

•

Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html

•

MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html

12

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 13 See http://www.nlm.nih.gov/databases/databases.html.

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•

Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html

•

Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html

The NLM Gateway14 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.15 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “pulmonary hypertension” (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 19273 122 757 22 202 20376

HSTAT16 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.17 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.18 Simply search by “pulmonary hypertension” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

14

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

15

The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 16 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 17 18

The HSTAT URL is http://hstat.nlm.nih.gov/.

Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.

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Coffee Break: Tutorials for Biologists19 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.20 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.21 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

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

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

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

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

from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 21 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process. 22 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.

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To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “pulmonary hypertension” (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 pulmonary hypertension: •

Pulmonary Hypertension, Familial Persistent, of the Newborn Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=265380

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Pulmonary Hypertension, Primary; PPH1 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=178600

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Pulmonary Hypertension, Primary Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=265400

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Vater-Like Defects with Pulmonary Hypertension, Laryngeal Webs, and Growth Deficiency Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608406 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

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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

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Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan

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

23

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

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separate each one with the word “and” or “or” (using “or” might be useful when using synonyms).

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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 pulmonary hypertension can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.

Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to pulmonary hypertension. 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 pulmonary hypertension. 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 “pulmonary hypertension”:

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Bacterial Infections http://www.nlm.nih.gov/medlineplus/bacterialinfections.html Pulmonary Fibrosis http://www.nlm.nih.gov/medlineplus/pulmonaryfibrosis.html Pulmonary Hypertension http://www.nlm.nih.gov/medlineplus/pulmonaryhypertension.html Respiratory Diseases http://www.nlm.nih.gov/medlineplus/respiratorydiseases.html Severe Acute Respiratory Syndrome http://www.nlm.nih.gov/medlineplus/severeacuterespiratorysyndrome.html

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

General/Overviews Primary Pulmonary Hypertension (PPH) Source: American Lung Association http://www.lungusa.org/diseases/pphfac.html Pulmonary Hypertension http://circ.ahajournals.org/cgi/reprint/106/24/e192.pdf

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Diagnosis/Symptoms Echocardiogram Source: National Institutes of Health, Clinical Center http://www.cc.nih.gov/ccc/patient_education/procdiag/echocardiogram.pdf Understanding PFT's (Pulmonary Function Testing) Source: Alpha 1 Association http://www.alpha1.org/what/lunginfo_pfts.htm

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Specific Conditions/Aspects Primary or Unexplained Pulmonary Hypertension Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=4752

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Children Persistent Pulmonary Hypertension of the Newborn (PPHN) Source: Nemours Foundation http://kidshealth.org/parent/medical/heart/pphn.html

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From the National Institutes of Health Primary Pulmonary Hypertension Source: National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/health/public/lung/other/pph_doc.htm

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

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Statistics Pulmonary Hypertension Source: National Center for Chronic Disease Prevention and Health Promotion http://www.cdc.gov/cvh/library/fs_pulmonary_hypertension.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 pulmonary hypertension. 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: •

Pulmonary Hypertension and HIV Contact: Project Inform, National HIV/AIDS Treatment Hotline, 205 13th St Ste 2001, San Francisco, CA, 94103, (415) 558-8669, http://www.projectinform.org. Summary: This information sheet, for individuals with the human immunodeficiency syndrome (HIV)/acquired immune deficiency syndrome (AIDS), provides information about pulmonary hypertension (PH) and its relationship to HIV/AIDS. The information sheet discusses PH symptoms, how PH affects HIV-positive persons, and available treatments for persons with HIV/AIDS.

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Pulmonary Hypertension Source: Danvers, MA: Scleroderma Foundation. 1998. 6 p. Contact: Available from Scleroderma Foundation. 12 Kent Way, Suite 101, Byfield, MA 01922. (800) 722-4673 or (978) 463-5843. Fax (978) 463-5809. E-mail: [email protected]. Website: www.scleroderma.org. PRICE: Single copy $1.00.

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Summary: This pamphlet for people with scleroderma uses a question and answer format to provide information about pulmonary artery hypertension. This type of high blood pressure involves the arteries that take blood from the right side of the heart to the lungs. The pamphlet describes the types of pulmonary artery hypertension that occur in scleroderma, including hypertension with or without scarring of the lung tissue. It also presents the symptoms of pulmonary artery hypertension, highlights the tests that might be conducted to diagnose pulmonary artery hypertension, explains the natural course of this condition in scleroderma, and discusses options for treating this type of hypertension. Pulmonary hypertension not related to scleroderma may be treated with oxygen therapy and anticoagulation therapy. Right-heart failure may be treated with various medications, including calcium channel blockers, diuretics, and an experimental drug known as prostacyclin. In addition, the pamphlet presents the mission of the Scleroderma Foundation. 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 “pulmonary hypertension” (or synonyms). The following was recently posted: •

(1) Part I. Guidelines for the management of severe traumatic brain injury. In: Management and prognosis of severe traumatic brain injury. (2) Update notice. Guidelines for the management of severe traumatic brain injury: cerebral perfusion pressure Source: American Association of Neurological Surgeons - Medical Specialty Society; 2000 (revised 2003); 165 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3794&nbr=3020&a mp;string=pulmonary+AND+hypertension

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1999 update: ACC/AHA guidelines for the management of patients with acute myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infar Source: American College of Cardiology Foundation - Medical Specialty Society; 1996 November 1 (revised 1999 Sep); 22 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2006&nbr=1232&a mp;string=pulmonary+AND+hypertension

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ACC/AHA 2002 guideline update for exercise testing. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing) Source: American College of Cardiology Foundation - Medical Specialty Society; 1997 July (revised 2002 Sep); 59 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3427&nbr=2653&a mp;string=pulmonary+AND+hypertension

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ACC/AHA 2002 guideline update for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for the Managemen Source: American College of Cardiology Foundation - Medical Specialty Society; 1999 June (revised 2002); 127 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3588&nbr=2814&a mp;string=pulmonary+AND+hypertension

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ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Source: American College of Cardiology Foundation - Medical Specialty Society; 2000 (revised online 2002 Mar); 95 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3190&nbr=2416&a mp;string=pulmonary+AND+hypertension

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ACC/AHA guideline update on perioperative cardiovascular evaluation for noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperati Source: American College of Cardiology Foundation - Medical Specialty Society; 1996 March 15 (revised 2002); 58 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3149&nbr=2375&a mp;string=pulmonary+AND+hypertension

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ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evalua Source: American College of Cardiology Foundation - Medical Specialty Society; 1995 November 1 (revised 2001 Dec); 56 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3114&nbr=2340&a mp;string=pulmonary+AND+hypertension

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ACR Appropriateness Criteriatm for acute chest pain--suspected pulmonary embolism Source: American College of Radiology - Medical Specialty Society; 1995 (revised 1999); 7 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2381&nbr=1607&a mp;string=pulmonary+AND+hypertension

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ACR Appropriateness Criteriatm for growth disturbances: risk of intrauterine growth restriction Source: American College of Radiology - Medical Specialty Society; 1996 (revised 2001); 10 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3253&nbr=2479&a mp;string=pulmonary+AND+hypertension

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ACR Appropriateness Criteriatm for needle biopsy in the thorax Source: American College of Radiology - Medical Specialty Society; 1996 (revised 1999); 12 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2498&nbr=1724&a mp;string=pulmonary+AND+hypertension

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ACR Appropriateness Criteriatm for suspected bacterial endocarditis Source: American College of Radiology - Medical Specialty Society; 1998; 5 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2390&nbr=1616&a mp;string=pulmonary+AND+hypertension

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ACR Appropriateness Criteriatm for suspected congenital heart disease in the adult Source: American College of Radiology - Medical Specialty Society; 1998 (revised 2002); 6 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3563&nbr=2789&a mp;string=pulmonary+AND+hypertension

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Altered nutritional status Source: American Medical Directors Association - Professional Association; 2001; 32 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3304&nbr=2530&a mp;string=pulmonary+AND+hypertension

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American Association of Clinical Endocrinologists medical guidelines for the clinical use of dietary supplements and nutraceuticals Source: American Association of Clinical Endocrinologists - Medical Specialty Society; 2003 Sep-October; 54 pages http://www.guideline.gov/summary/summary.aspx?doc_id=4265&nbr=3265&a mp;string=pulmonary+AND+hypertension

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American Gastroenterological Association medical position statement on obesity Source: American Gastroenterological Association - Medical Specialty Society; 2002 September; 3 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3490&nbr=2716&a mp;string=pulmonary+AND+hypertension

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American Gastroenterological Association medical position statement: evaluation and management of occult and obscure gastrointestinal bleeding Source: American Gastroenterological Association - Medical Specialty Society; 1999 July 18 (reviewed 2001); 4 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3062&nbr=2288&a mp;string=pulmonary+AND+hypertension

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Angina pectoris and coronary artery disease (CAD) Source: Finnish Medical Society Duodecim - Professional Association; 2001 April 30 (revised 2003 October 5); Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=4372&nbr=3294&a mp;string=pulmonary+AND+hypertension

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Antithrombotic agents in coronary artery disease. In: Sixth ACCP Consensus Conference on Antithrombotic Therapy Source: American College of Chest Physicians - Medical Specialty Society; 2001 January; 25 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2729&nbr=1955&a mp;string=pulmonary+AND+hypertension

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Antithrombotic and thrombolytic therapy for ischemic stroke. In: Sixth ACCP Consensus Conference on Antithrombotic Therapy Source: American College of Chest Physicians - Medical Specialty Society; 2001 January; 21 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2733&nbr=1959&a mp;string=pulmonary+AND+hypertension

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Antithrombotic therapy for venous thromboembolic disease. In: Sixth ACCP Consensus Conference on Antithrombotic Therapy Source: American College of Chest Physicians - Medical Specialty Society; 2001 January; 18 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2725&nbr=1951&a mp;string=pulmonary+AND+hypertension

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Antithrombotic therapy. A national clinical guideline Source: Scottish Intercollegiate Guidelines Network - National Government Agency [Non-U.S.]; 1999 March; 70 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2907&nbr=2133&a mp;string=pulmonary+AND+hypertension

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Cardiac rehabilitation. A national clinical guideline Source: Scottish Intercollegiate Guidelines Network - National Government Agency [Non-U.S.]; 2002 January; 32 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3185&nbr=2411&a mp;string=pulmonary+AND+hypertension

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Chemotherapy and biotherapy: guidelines and recommendations for practice Source: Oncology Nursing Society - Professional Association; 2001; 226 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3209&nbr=2435&a mp;string=pulmonary+AND+hypertension

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Clinical policy: critical issues in the evaluation and management of adult patients presenting with suspected lower-extremity deep venous thrombosis Source: American College of Emergency Physicians - Medical Specialty Society; 2003 July; 12 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3867&nbr=3077&a mp;string=pulmonary+AND+hypertension

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Clinical practice guideline for post-deployment health evaluation and management Source: Department of Defense - Federal Government Agency [U.S.]; 2000 September (revised 2001 Dec); Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=3223&nbr=2449&a mp;string=pulmonary+AND+hypertension

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Clinical practice guideline for the management of postoperative pain Source: Department of Defense - Federal Government Agency [U.S.]; 2001 July (revised 2002 May); Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=3284&nbr=2510&a mp;string=pulmonary+AND+hypertension

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Clinical practice guideline for the management of rheumatoid arthritis Source: Advanced Research Techniques in the Health Services - Private For Profit Research Organization; 2001; 170 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3683&nbr=2909&a mp;string=pulmonary+AND+hypertension

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Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient Source: American College of Critical Care Medicine - Professional Association; 1995 (revised 2002); 15 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3170&nbr=2396&a mp;string=pulmonary+AND+hypertension

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Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock Source: American College of Critical Care Medicine - Professional Association; 2002 June; 14 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3433&nbr=2659&a mp;string=pulmonary+AND+hypertension

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Congestive heart failure in adults Source: Institute for Clinical Systems Improvement - Private Nonprofit Organization; 1997 October (revised 2002 Jan); 71 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3165&nbr=2391&a mp;string=pulmonary+AND+hypertension

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Diagnosis and management of aortic dissection Source: European Society of Cardiology - Medical Specialty Society; 2001 September; 40 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2975&nbr=2201&a mp;string=pulmonary+AND+hypertension

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Diagnosis and management of asthma Source: Institute for Clinical Systems Improvement - Private Nonprofit Organization; 1994 August (revised 2003 May); 49 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3874&nbr=3083&a mp;string=pulmonary+AND+hypertension

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Diagnosis and treatment of obstructive sleep apnea Source: Institute for Clinical Systems Improvement - Private Nonprofit Organization; 2003 April; 53 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3755&nbr=2981&a mp;string=pulmonary+AND+hypertension

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Diagnosis of chest pain Source: Institute for Clinical Systems Improvement - Private Nonprofit Organization; 1995 July (revised 2002 Oct); 50 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3674&nbr=2900&a mp;string=pulmonary+AND+hypertension

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Discharge guidelines for the technology dependent infant Source: National Association of Neonatal Nurses - Professional Association; 1999; 26 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2145&nbr=1371&a mp;string=pulmonary+AND+hypertension

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Essential hypertension Source: University of Michigan Health System - Academic Institution; 1997 (revised 2002 Aug); 14 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3539&nbr=2765&a mp;string=pulmonary+AND+hypertension

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Exercise testing for evaluation of hypoxemia and/or desaturation: 2001 revision and update. Source: American Association for Respiratory Care - Professional Association; 2001 May; 9 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2844&nbr=2070&a mp;string=pulmonary+AND+hypertension

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Global initiative for asthma. Global strategy for asthma management and prevention Source: National Heart, Lung, and Blood Institute (U.S.) - Federal Government Agency [U.S.]; 1995 January (revised 2002); 176 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3203&nbr=2429&a mp;string=pulmonary+AND+hypertension

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Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease Source: National Heart, Lung, and Blood Institute (U.S.) - Federal Government Agency [U.S.]; 2001; Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=2779&nbr=2005&a mp;string=pulmonary+AND+hypertension

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Glomerulonephritis Source: National Committee on Renal Care (Singapore); 2001 October; 132 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2971&nbr=2197&a mp;string=pulmonary+AND+hypertension

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Guidelines for emergency tracheal intubation immediately following traumatic injury Source: Eastern Association for the Surgery of Trauma - Professional Association; 2002; 80 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3222&nbr=2448&a mp;string=pulmonary+AND+hypertension

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Guidelines for referral to pediatric surgical specialists Source: American Academy of Pediatrics - Medical Specialty Society; 2002 July; 5 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3420&nbr=2646&a mp;string=pulmonary+AND+hypertension

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Guidelines for the diagnosis and treatment of chronic heart failure Source: European Society of Cardiology - Medical Specialty Society; 2001 September; 34 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2976&nbr=2202&a mp;string=pulmonary+AND+hypertension

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Guidelines on diagnosis and management of acute pulmonary embolism Source: European Society of Cardiology - Medical Specialty Society; 2000 August; 36 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2592&nbr=1818&a mp;string=pulmonary+AND+hypertension

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Heart failure Source: American Medical Directors Association - Professional Association; 1996 (revised 2002); 18 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3303&nbr=2529&a mp;string=pulmonary+AND+hypertension

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Herniated disc. In: North American Spine Society phase III clinical guidelines for multidisciplinary spine care specialists Source: North American Spine Society - Medical Specialty Society; 2000; 104 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2803&nbr=2029&a mp;string=pulmonary+AND+hypertension

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Hypertension Source: University of Texas Medical Branch Correctional Managed Care - Academic Institution; 1997 March (revised 2002 Apr); 6 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3475&nbr=2701&a mp;string=pulmonary+AND+hypertension

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Hypertension diagnosis and treatment Source: Institute for Clinical Systems Improvement - Private Nonprofit Organization; 1995 June (revised 2003 Apr); 47 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3759&nbr=2985&a mp;string=pulmonary+AND+hypertension

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Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology Source: American Society of Hematology - Medical Specialty Society; 1996 January 25 (reviewed 2001) http://www.guideline.gov/summary/summary.aspx?doc_id=1922&nbr=1148&a mp;string=pulmonary+AND+hypertension

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Joint Committee on Infant Hearing. Year 2000 position statement. Principles and guidelines for early hearing detection and intervention programs Source: Joint Committee on Infant Hearing - Independent Expert Panel; 2000 June; 21 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2622&nbr=1848&a mp;string=pulmonary+AND+hypertension

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Liver transplantation Source: American Association for the Study of Liver Diseases - Private Nonprofit Research Organization; 2000 January; 14 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3449&nbr=2675&a mp;string=pulmonary+AND+hypertension

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Management of acute coronary syndromes in patients presenting without persistent ST- segment elevation Source: European Society of Cardiology - Medical Specialty Society; 2000 September (revised 2002 Dec); 32 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3518&nbr=2744&a mp;string=pulmonary+AND+hypertension

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Management of chronic kidney disease and pre-ESRD in the primary care setting Source: Department of Defense - Federal Government Agency [U.S.]; 2000 November; Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=3099&nbr=2325&a mp;string=pulmonary+AND+hypertension

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Management of preterm labour Source: Chapter of Obstetricians and Gynaecologists, Academy of Medicine (Singapore) - Medical Specialty Society; 2001 May; 28 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2889&nbr=2115&a mp;string=pulmonary+AND+hypertension

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Management of type 2 diabetes mellitus Source: Institute for Clinical Systems Improvement - Private Nonprofit Organization; 1996 March (revised 2002 Sep); 77 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3499&nbr=2725&a mp;string=pulmonary+AND+hypertension

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Myocardial infarction Source: Finnish Medical Society Duodecim - Professional Association; 2001 April 30 (revised 2003 July 11); Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=4373&nbr=3295&a mp;string=pulmonary+AND+hypertension

•

National High Blood Pressure Education Program: Working Group report on high blood pressure in pregnancy Source: National Heart, Lung, and Blood Institute (U.S.) - Federal Government Agency [U.S.]; 1990 (revised 2000 Jul); 39 pages http://www.guideline.gov/summary/summary.aspx?doc_id=1478&nbr=704&am p;string=pulmonary+AND+hypertension

•

Part II. Early indicators of prognosis in severe traumatic brain injury. In: Management and prognosis of severe traumatic brain injury Source: American Association of Neurological Surgeons - Medical Specialty Society; 2000; 116 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3122&nbr=2348&a mp;string=pulmonary+AND+hypertension

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Periodic health examination, 1999 update: 1. Detection, prevention and treatment of obesity Source: Canadian Task Force on Preventive Health Care - National Government Agency [Non-U.S.]; 1999; 12 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2054&nbr=1280&a mp;string=pulmonary+AND+hypertension

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Physical activity in the prevention, treatment and rehabilitation of diseases Source: Finnish Medical Society Duodecim - Professional Association; 2002 May 7; Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=3398&nbr=2624&a mp;string=pulmonary+AND+hypertension

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Postmenopausal hormone replacement therapy for the primary prevention of chronic conditions: recommendations and rationale Source: United States Preventive Services Task Force - Independent Expert Panel; 1996 (revised 2002); 17 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3455&nbr=2681&a mp;string=pulmonary+AND+hypertension

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Practice guidelines for the management of cryptococcal disease Source: Infectious Diseases Society of America - Medical Specialty Society; 2000 April; 9 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2666&nbr=1892&a mp;string=pulmonary+AND+hypertension

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Practice management guidelines for the optimal timing of long bone fracture stabilization in polytrauma patients Source: Eastern Association for the Surgery of Trauma - Professional Association; 2000; 39 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2795&nbr=2021&a mp;string=pulmonary+AND+hypertension

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Practice parameters for the role of actigraphy in the study of sleep and circadian rhythms: an update for 2002 Source: American Academy of Sleep Medicine - Professional Association; 1995 (revised 2003 May 1); 5 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3807&nbr=3033&a mp;string=pulmonary+AND+hypertension

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Preoperative evaluation Source: Institute for Clinical Systems Improvement - Private Nonprofit Organization; 1997 September (revised 2002 Mar); 27 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3357&nbr=2583&a mp;string=pulmonary+AND+hypertension

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Preterm birth prevention Source: Institute for Clinical Systems Improvement - Private Nonprofit Organization; 1995 July (revised 2002 Aug); 59 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3443&nbr=2669&a mp;string=pulmonary+AND+hypertension

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Prevention of thromboembolism in spinal cord injury Source: Consortium for Spinal Cord Medicine - Private Nonprofit Organization; 1997 February (updated 1999 Sep); 29 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2965&nbr=2191&a mp;string=pulmonary+AND+hypertension

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Preventive health recommendations for adults with mental retardation Source: Massachusetts Department of Mental Retardation - State/Local Government Agency [U.S.]; 2003 September 19; 2 pages http://www.guideline.gov/summary/summary.aspx?doc_id=4201&nbr=3209&a mp;string=pulmonary+AND+hypertension

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Preventive services for adults Source: Institute for Clinical Systems Improvement - Private Nonprofit Organization; 1995 June (revised 2002 Sep); 50 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3501&nbr=2727&a mp;string=pulmonary+AND+hypertension

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Procedure guideline for myocardial perfusion imaging Source: Society of Nuclear Medicine, Inc - Medical Specialty Society; 1999 February; 27 pages http://www.guideline.gov/summary/summary.aspx?doc_id=1353&nbr=611&am p;string=pulmonary+AND+hypertension

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Pulmonary rehabilitation Source: American Association for Respiratory Care - Professional Association; 2002; 9 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3211&nbr=2437&a mp;string=pulmonary+AND+hypertension

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Screening for obesity in adults: recommendations and rationale Source: United States Preventive Services Task Force - Independent Expert Panel; 1996 (revised 2003 December 2); 13 pages http://www.guideline.gov/summary/summary.aspx?doc_id=4118&nbr=3163&a mp;string=pulmonary+AND+hypertension

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Single-breath carbon monoxide diffusing capacity, 1999 update Source: American Association for Respiratory Care - Professional Association; 1999 January; 9 pages http://www.guideline.gov/summary/summary.aspx?doc_id=1767&nbr=993&am p;string=pulmonary+AND+hypertension

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Sixth ACCP Consensus Conference on Antithrombotic Therapy Source: American College of Chest Physicians - Medical Specialty Society; 2001 January; 370 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2720&nbr=1946&a mp;string=pulmonary+AND+hypertension

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Specialty referral guidelines for cardiovascular evaluation and management Source: American Healthways, Inc - Public For Profit Organization; 2002; 26 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3168&nbr=2394&a mp;string=pulmonary+AND+hypertension

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Suctioning of the patient in the home Source: American Association for Respiratory Care - Professional Association; 1999 January; 8 pages http://www.guideline.gov/summary/summary.aspx?doc_id=1769&nbr=995&am p;string=pulmonary+AND+hypertension

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Summary of policy recommendations for periodic health examinations Source: American Academy of Family Physicians - Medical Specialty Society; 1996 November (revised 2003 Aug); 13 pages http://www.guideline.gov/summary/summary.aspx?doc_id=4183&nbr=3208&a mp;string=pulmonary+AND+hypertension

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The management of diabetes mellitus in the primary care setting Source: Department of Defense - Federal Government Agency [U.S.]; 1999 December; 147 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2583&nbr=1809&a mp;string=pulmonary+AND+hypertension

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The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Source: National Heart, Lung, and Blood Institute (U.S.) - Federal Government Agency [U.S.]; 1997 (revised 2003 May 21); 22 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3744&nbr=2970&a mp;string=pulmonary+AND+hypertension

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The solitary pulmonary nodule Source: American College of Chest Physicians - Medical Specialty Society; 2003 January; 8 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3638&nbr=2864&a mp;string=pulmonary+AND+hypertension

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Treatment for stimulant use disorders Source: Substance Abuse and Mental Health Services Administration (U.S.) - Federal Government Agency [U.S.]; 1999; Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=2540&nbr=1766&a mp;string=pulmonary+AND+hypertension

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Treatment of acute myocardial infarction Source: Institute for Clinical Systems Improvement - Private Nonprofit Organization; 1996 May (revised 2002 Nov); 68 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3659&nbr=2885&a mp;string=pulmonary+AND+hypertension

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Use of antithrombotic agents during pregnancy. In: Sixth ACCP Consensus Conference on Antithrombotic Therapy Source: American College of Chest Physicians - Medical Specialty Society; 2001 January; 10 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2723&nbr=1949&a mp;string=pulmonary+AND+hypertension

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Venous thromboembolism Source: Institute for Clinical Systems Improvement - Private Nonprofit Organization; 1998 June (revised 2003 Apr); 93 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3757&nbr=2983&a mp;string=pulmonary+AND+hypertension

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VHA/DOD clinical practice guideline for the management of chronic obstructive pulmonary disease. Source: Department of Defense - Federal Government Agency [U.S.]; 1999 August; Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=2584&nbr=1810&a mp;string=pulmonary+AND+hypertension

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VHA/DOD clinical practice guideline for the management of major depressive disorder in adults Source: Department of Defense - Federal Government Agency [U.S.]; 1997 (updated 2000); Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=2585&nbr=1811&a mp;string=pulmonary+AND+hypertension Healthfinder™

Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: •

Pulmonary Hypertension Support Groups Summary: An online listing of national and international pulmonary hypertension support groups provided as a service to patients and their families by the Pulmonary Hypertension Association. Source: Pulmonary Hypertension Association http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=5609

•

What is Pulmonary Hypertension? Summary: Pulmonary hypertension (PH) is a rare lung disorder occurring as a primary idiopathic disease or as a complication of a large number of respiratory and cardiac diseases. Source: PHCentral http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=7769 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 pulmonary hypertension. 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

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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/

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

•

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

Associations and Pulmonary Hypertension The following is a list of associations that provide information on and resources relating to pulmonary hypertension: •

Pulmonary Hypertension Association Telephone: (301) 565-3004 Toll-free: (800) 748-7274 Fax: (301) 565-3994 Email: [email protected] Web Site: http://www.phassociation.org Background: The Pulmonary Hypertension Association (PHA) is an international notfor-profit voluntary organization that provides educational information and fellowship to people with primary or secondary pulmonary hypertension. Pulmonary hypertension is a condition characterized by abnormally high blood pressure in the arteries that supply the lungs. Pulmonary hypertension may be an isolated condition that may occur for unknown reasons (primary pulmonary hypertension) or may occur due to or in association with other underlying disorders or conditions (secondary pulmonary hypertension). Established in 1992, the organization addresses issues pertinent to people with these disorders such as current research, early detection, orphan drug designations, organ donor awareness, and organ transplantation. It conducts international conferences; provides a networking service; offers referrals; and publishes a quarterly newsletter, 'Pathlight.'. Relevant area(s) of interest: Pulmonary Hypertension

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Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to pulmonary hypertension. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with pulmonary hypertension. 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 pulmonary hypertension. 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 “pulmonary hypertension” (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 “pulmonary hypertension”. 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 “pulmonary hypertension” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months.

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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 “pulmonary hypertension” (or a synonym) into the search box, and click “Submit Query.”

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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.

Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.25

Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.

Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of

25

Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.

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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)26: •

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

•

Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)

•

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

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

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California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html

•

California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html

•

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/

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

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

•

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/

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Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/

•

Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/

26

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

Finding Medical Libraries 235

•

Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

•

Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

•

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

•

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

•

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

•

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

•

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

Finding Medical Libraries 237

•

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

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New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

•

New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

•

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

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New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

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New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

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New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

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Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

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Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

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Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

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Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

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Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

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Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

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Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

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Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

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Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

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Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

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Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/

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South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

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

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

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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

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

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

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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

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

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

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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 pulmonary hypertension: •

Basic Guidelines for Pulmonary Hypertension ALS Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000688.htm ASD Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000157.htm Chronic obstructive pulmonary disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000091.htm Collagen vascular disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001223.htm Congenital heart disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001114.htm COPD Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000091.htm

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SLE Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000435.htm •

Signs & Symptoms for Pulmonary Hypertension Chest pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003079.htm Dyspnea Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003075.htm Edema Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003103.htm Peripheral edema Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003104.htm Syncope Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003092.htm

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Diagnostics and Tests for Pulmonary Hypertension Angiogram Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003327.htm Cardiac catheterization Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003419.htm CBC Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003642.htm Chest X-ray Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm CT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm Echocardiogram Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm EKG Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003868.htm Electrocardiogram Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003868.htm Heart catheterization Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003419.htm Left heart catheterization Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003871.htm

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Pulmonary function Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003443.htm Pulmonary function tests Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003853.htm Pulse Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003399.htm V/Q scan Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003828.htm X-ray Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003337.htm •

Surgery and Procedures for Pulmonary Hypertension Lung transplant Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003010.htm

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Background Topics for Pulmonary Hypertension Chronic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002312.htm Peripheral Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002273.htm

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

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MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

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Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

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Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

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PULMONARY HYPERTENSION DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 4-Aminopyridine: A potassium channel blocker. It is used primarily as a research tool and is helpful in characterizing subtypes of potassium channels. It has been used clinically in Lambert-Eaton syndrome and multiple sclerosis because by blocking potassium channels it prolongs action potentials thereby increasing transmitter release at the neuromuscular junction (and elsewhere). [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Ablation: The removal of an organ by surgery. [NIH] Abortion: 1. The premature expulsion from the uterus of the products of conception - of the embryo, or of a nonviable fetus. The four classic symptoms, usually present in each type of abortion, are uterine contractions, uterine haemorrhage, softening and dilatation of the cervix, and presentation or expulsion of all or part of the products of conception. 2. Premature stoppage of a natural or a pathological process. [EU] Abscess: A localized, circumscribed collection of pus. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acclimatization: Adaptation to a new environment or to a change in the old. [NIH] Acetaminophen: Analgesic antipyretic derivative of acetanilide. It has weak antiinflammatory properties and is used as a common analgesic, but may cause liver, blood cell, and kidney damage. [NIH] Acetic Acids: Acetic acid and its derivatives which may be formed by substitution reactions. Mono- and di-substituted, as well as halogenated compounds have been synthesized. [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] Acidosis: A pathologic condition resulting from accumulation of acid or depletion of the alkaline reserve (bicarbonate content) in the blood and body tissues, and characterized by an increase in hydrogen ion concentration. [EU] Actin: Essential component of the cell skeleton. [NIH] Action Potentials: The electric response of a nerve or muscle to its stimulation. [NIH] Acute renal: A condition in which the kidneys suddenly stop working. In most cases, kidneys can recover from almost complete loss of function. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different

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from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adduct: Complex formed when a carcinogen combines with DNA or a protein. [NIH] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenosine Diphosphate: Adenosine 5'-(trihydrogen diphosphate). An adenine nucleotide containing two phosphate groups esterified to the sugar moiety at the 5'-position. [NIH] Adenosine Monophosphate: Adenylic acid. Adenine nucleotide containing one phosphate group esterified to the sugar moiety in the 2'-, 3'-, or 5'-position. [NIH] Adenosine Triphosphate: Adenosine 5'-(tetrahydrogen triphosphate). An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adenylate Cyclase: An enzyme of the lyase class that catalyzes the formation of cyclic AMP and pyrophosphate from ATP. EC 4.6.1.1. [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 Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [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] 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]

Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the

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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] Afterload: The tension produced by the heart muscle after contraction. [EU] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]

Age Groups: Persons classified by age from birth (infant, newborn) to octogenarians and older (aged, 80 and over). [NIH] Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Aged, 80 and Over: A person 80 years of age and older. [NIH] Aggravation: An increasing in seriousness or severity; an act or circumstance that intensifies, or makes worse. [EU] 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] Air Pollutants: Substances which pollute the air. [NIH] 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] Aldosterone: (11 beta)-11,21-Dihydroxy-3,20-dioxopregn-4-en-18-al. A hormone secreted by the adrenal cortex that functions in the regulation of electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] 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] Alkalosis: A pathological condition that removes acid or adds base to the body fluids. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU]

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Allergic Rhinitis: Inflammation of the nasal mucous membrane associated with hay fever; fits may be provoked by substances in the working environment. [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 standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Alveoli: Tiny air sacs at the end of the bronchioles in the lungs. [NIH] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] Amino acid: Any organic compound containing an amino (-NH2 and a carboxyl (- COOH) group. The 20 a-amino acids listed in the accompanying table are the amino acids from which proteins are synthesized by formation of peptide bonds during ribosomal translation of messenger RNA; all except glycine, which is not optically active, have the L configuration. Other amino acids occurring in proteins, such as hydroxyproline in collagen, are formed by posttranslational enzymatic modification of amino acids residues in polypeptide chains. There are also several important amino acids, such as the neurotransmitter y-aminobutyric acid, that have no relation to proteins. Abbreviated AA. [EU] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acid Substitution: The naturally occurring or experimentally induced replacement of one or more amino acids in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties. [NIH] Amino Acids, Peptides, and Proteins: Amino acids and chains of amino acids connected by peptide linkages. [NIH] Amlodipine: 2-((2-Aminoethoxy)methyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5pyridinedicarboxylic acid 3-ethyl 5-methyl ester. A long-acting dihydropyridine calcium channel blocker. It is effective in the treatment of angina pectoris and hypertension. [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amnion: The extraembryonic membrane which contains the embryo and amniotic fluid. [NIH]

Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and

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kidneys. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Amrinone: A positive inotropic cardiotonic agent with vasodilator properties, phosphodiesterase inhibitory activity, and the ability to stimulate calcium ion influx into the cardiac cell. Its therapeutic use in congestive heart or left ventricular failure is associated with significant increases in the cardiac index, reductions in pulmonary capillary wedge pressure and systemic vascular resistance, and little or no change in mean arterial pressure. One of its more serious side effects is thrombocytopenia in some patients. [NIH] Anaerobic: 1. Lacking molecular oxygen. 2. Growing, living, or occurring in the absence of molecular oxygen; pertaining to an anaerobe. [EU] Anaerobic Threshold: The oxygen consumption level above which aerobic energy production is supplemented by anaerobic mechanisms during exercise, resulting in a sustained increase in lactate concentration and metabolic acidosis. The anaerobic threshold is affected by factors that modify oxygen delivery to the tissues; it is low in patients with heart disease. Methods of measurement include direct measure of lactate concentration, direct measurement of bicarbonate concentration, and gas exchange measurements. [NIH] 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] 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] Anastomosis: A procedure to connect healthy sections of tubular structures in the body after the diseased portion has been surgically removed. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgenic: Producing masculine characteristics. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anemia, Sickle Cell: A disease characterized by chronic hemolytic anemia, episodic painful crises, and pathologic involvement of many organs. It is the clinical expression of homozygosity for hemoglobin S. [NIH] Anemic: Hypoxia due to reduction of the oxygen-carrying capacity of the blood as a result of a decrease in the total hemoglobin or an alteration of the hemoglobin constituents. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angina Pectoris: The symptom of paroxysmal pain consequent to myocardial ischemia usually of distinctive character, location and radiation, and provoked by a transient stressful

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situation during which the oxygen requirements of the myocardium exceed the capacity of the coronary circulation to supply it. [NIH] Anginal: Pertaining to or characteristic of angina. [EU] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Angiography: Radiography of blood vessels after injection of a contrast medium. [NIH] Angioplasty: Endovascular reconstruction of an artery, which may include the removal of atheromatous plaque and/or the endothelial lining as well as simple dilatation. These are procedures performed by catheterization. When reconstruction of an artery is performed surgically, it is called endarterectomy. [NIH] Angiotensin converting enzyme inhibitor: A drug used to decrease pressure inside blood vessels. [NIH] Angiotensinogen: An alpha-globulin of which a fragment of 14 amino acids is converted by renin to angiotensin I, the inactive precursor of angiotensin II. It is a member of the serpin superfamily. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Ankle: That part of the lower limb directly above the foot. [NIH] Anomalies: Birth defects; abnormalities. [NIH] Anoxia: Clinical manifestation of respiratory distress consisting of a relatively complete absence of oxygen. [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] Anterior Cerebral Artery: Artery formed by the bifurcation of the internal carotid artery. Branches of the anterior cerebral artery supply the caudate nucleus, internal capsule, putamen, septal nuclei, gyrus cinguli, and surfaces of the frontal lobe and parietal lobe. [NIH] Antianginal: Counteracting angina or anginal conditions. [EU] Antiarrhythmic: An agent that prevents or alleviates cardiac arrhythmia. [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]

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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] Antidepressant: A drug used to treat depression. [NIH] Antidiuretic: Suppressing the rate of urine formation. [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] Antihypertensive: An agent that reduces high blood pressure. [EU] 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] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] 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] Antiproliferative: Counteracting a process of proliferation. [EU] 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]

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Antiviral: Destroying viruses or suppressing their replication. [EU] Anuria: Inability to form or excrete urine. [NIH] Anus: The opening of the rectum to the outside of the body. [NIH] Aorta: The main trunk of the systemic arteries. [NIH] Aortic Coarctation: Narrowing of the lumen of the aorta, caused by deformity of the aortic media. [NIH] Apnea: A transient absence of spontaneous respiration. [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] Arginase: A ureahydrolase that catalyzes the hydrolysis of arginine or canavanine to yield L-ORNITHINE and urea. Deficiency of this enzyme causes hyperargininemia. EC 3.5.3.1. [NIH]

Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Aromatic: Having a spicy odour. [EU] Arrhythmia: Any variation from the normal rhythm or rate of the heart beat. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arteriolar: Pertaining to or resembling arterioles. [EU] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriolosclerosis: Sclerosis and thickening of the walls of the smaller arteries (arterioles). Hyaline arteriolosclerosis, in which there is homogeneous pink hyaline thickening of the arteriolar walls, is associated with benign nephrosclerosis. Hyperplastic arteriolosclerosis, in which there is a concentric thickening with progressive narrowing of the lumina may be associated with malignant hypertension, nephrosclerosis, and scleroderma. [EU] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH]

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Arteriosus: Circle composed of anastomosing arteries derived from two long posterior ciliary and seven anterior ciliary arteries, located in the ciliary body about the root of the iris. [NIH]

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] Arteritis: Inflammation of an artery. [NIH] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Arthrosis: A disease of a joint. [EU] Aseptic: Free from infection or septic material; sterile. [EU] Aspartic: The naturally occurring substance is L-aspartic acid. One of the acidic-amino-acids is obtained by the hydrolysis of proteins. [NIH] Aspartic Acid: One of the non-essential amino acids commonly occurring in the L-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. [NIH] Asphyxia: A pathological condition caused by lack of oxygen, manifested in impending or actual cessation of life. [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] 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] Atopic: Pertaining to an atopen or to atopy; allergic. [EU] Atopic Eczema: Generic term for acute or chronic inflammatory conditions of the skin, typically erythematous, edematous, papular, vesicular, and crusting; often accompanied by sensations of itching and burning. [NIH] Atresia: Lack of a normal opening from the esophagus, intestines, or anus. [NIH] Atrial: Pertaining to an atrium. [EU] Atrial Fibrillation: Disorder of cardiac rhythm characterized by rapid, irregular atrial impulses and ineffective atrial contractions. [NIH] Atrial Flutter: Rapid, irregular atrial contractions due to an abnormality of atrial excitation. [NIH]

Atrioventricular: Pertaining to an atrium of the heart and to a ventricle. [EU] Atrioventricular Node: A small nodular mass of specialized muscle fibers located in the interatrial septum near the opening of the coronary sinus. It gives rise to the atrioventricular bundle of the conduction system of the heart. [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

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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] 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] Auditory: Pertaining to the sense of hearing. [EU] Autoantibodies: Antibodies that react with self-antigens (autoantigens) of the organism that produced them. [NIH] Autoantigens: Endogenous tissue constituents that have the ability to interact with autoantibodies and cause an immune response. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autonomic Nervous System: The enteric, parasympathetic, and sympathetic nervous systems taken together. Generally speaking, the autonomic nervous system regulates the internal environment during both peaceful activity and physical or emotional stress. Autonomic activity is controlled and integrated by the central nervous system, especially the hypothalamus and the solitary nucleus, which receive information relayed from visceral afferents; these and related central and sensory structures are sometimes (but not here) considered to be part of the autonomic nervous system itself. [NIH] Autopsy: Postmortem examination of the body. [NIH] Avian: A plasmodial infection in birds. [NIH] Axillary: Pertaining to the armpit area, including the lymph nodes that are located there. [NIH]

Axillary Vein: The venous trunk of the upper limb; a continuation of the basilar and brachial veins running from the lower border of the teres major muscle to the outer border of the first rib where it becomes the subclavian vein. [NIH] Azetidinecarboxylic Acid: A proline analog that acts as a stoichiometric replacement of proline. It causes the production of abnormal proteins with impaired biological activity. [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 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] Barbiturate: A drug with sedative and hypnotic effects. Barbiturates have been used as sedatives and anesthetics, and they have been used to treat the convulsions associated with

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epilepsy. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Basilar Artery: The artery formed by the union of the right and left vertebral arteries; it runs from the lower to the upper border of the pons, where it bifurcates into the two posterior cerebral arteries. [NIH] Basophil: A type of white blood cell. Basophils are granulocytes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Benign prostatic hyperplasia: A benign (noncancerous) condition in which an overgrowth of prostate tissue pushes against the urethra and the bladder, blocking the flow of urine. Also called benign prostatic hypertrophy or BPH. [NIH] Benzene: Toxic, volatile, flammable liquid hydrocarbon biproduct of coal distillation. It is used as an industrial solvent in paints, varnishes, lacquer thinners, gasoline, etc. Benzene causes central nervous system damage acutely and bone marrow damage chronically and is carcinogenic. It was formerly used as parasiticide. [NIH] Beta-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] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile duct: A tube through which bile passes in and out of the liver. [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] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving

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chemical reactions in living organisms. [EU] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] 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] Biphasic: Having two phases; having both a sporophytic and a gametophytic phase in the life cycle. [EU] Bladder: The organ that stores urine. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Gas Analysis: Measurement of oxygen and carbon dioxide in the blood. [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 Substitutes: Substances that can carry oxygen to and carbon dioxide away from the tissues when introduced into the blood stream. They are used to replace hemoglobin in severe hemorrhage and also to perfuse isolated organs. The best known are perfluorocarbon emulsions and various hemoglobin solutions. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Body Fluids: Liquid components of living organisms. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone scan: A technique to create images of bones on a computer screen or on film. A small

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amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [NIH] 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] Brachial: All the nerves from the arm are ripped from the spinal cord. [NIH] Brachiocephalic Veins: Large veins on either side of the root of the neck formed by the junction of the internal jugular and subclavian veins. They drain blood from the head, neck, and upper extremities, and unite to form the superior vena cava. [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] Bradycardia: Excessive slowness in the action of the heart, usually with a heart rate below 60 beats per minute. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Brain Stem: The part of the brain that connects the cerebral hemispheres with the spinal cord. It consists of the mesencephalon, pons, and medulla oblongata. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Breakdown: A physical, metal, or nervous collapse. [NIH] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Bronchioles: The tiny branches of air tubes in the lungs. [NIH] Bronchiolitis: Inflammation of the bronchioles. [NIH] Bronchiseptica: A small, gram-negative, motile bacillus. A normal inhabitant of the respiratory tract in man, dogs, and pigs, but is also associated with canine infectious tracheobronchitis and atrophic rhinitis in pigs. [NIH] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH] Bronchoconstriction: Diminution of the caliber of a bronchus physiologically or as a result of pharmacological intervention. [NIH] Bronchopulmonary: Pertaining to the lungs and their air passages; both bronchial and pulmonary. [EU] Bronchopulmonary Dysplasia: A chronic lung disease appearing in certain newborn infants treated for respiratory distress syndrome with mechanical ventilation and elevated concentration of inspired oxygen. [NIH] Bronchus: A large air passage that leads from the trachea (windpipe) to the lung. [NIH] Bryostatin-1: A drug used for its antitumor activity. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU]

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Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Calcification: Deposits of calcium in the tissues of the breast. Calcification in the breast can be seen on a mammogram, but cannot be detected by touch. There are two types of breast calcification, macrocalcification and microcalcification. Macrocalcifications are large deposits and are usually not related to cancer. Microcalcifications are specks of calcium that may be found in an area of rapidly dividing cells. Many microcalcifications clustered together may be a sign of cancer. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium channel blocker: A drug used to relax the blood vessel and heart muscle, causing pressure inside blood vessels to drop. It also can regulate heart rhythm. [NIH] Calcium Channel Blockers: A class of drugs that act by selective inhibition of calcium influx through cell membranes or on the release and binding of calcium in intracellular pools. Since they are inducers of vascular and other smooth muscle relaxation, they are used in the drug therapy of hypertension and cerebrovascular spasms, as myocardial protective agents, and in the relaxation of uterine spasms. [NIH] Calcium Channels: Voltage-dependent cell membrane glycoproteins selectively permeable to calcium ions. They are categorized as L-, T-, N-, P-, Q-, and R-types based on the activation and inactivation kinetics, ion specificity, and sensitivity to drugs and toxins. The L- and T-types are present throughout the cardiovascular and central nervous systems and the N-, P-, Q-, & R-types are located in neuronal tissue. [NIH] Callus: A callosity or hard, thick skin; the bone-like reparative substance that is formed round the edges and fragments of broken bone. [NIH] Calmodulin: A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels. [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] Captopril: A potent and specific inhibitor of peptidyl-dipeptidase A. It blocks the conversion of angiotensin I to angiotensin II, a vasoconstrictor and important regulator of arterial blood pressure. Captopril acts to suppress the renin-angiotensin system and inhibits pressure responses to exogenous angiotensin. [NIH] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carboxy: Cannabinoid. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs.

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[NIH]

Cardiac: Having to do with the heart. [NIH] Cardiac arrest: A sudden stop of heart function. [NIH] Cardiac catheterization: A procedure in which a thin, hollow tube is inserted into a blood vessel. The tube is then advanced through the vessel into the heart, enabling a physician to study the heart and its pumping activity. [NIH] Cardiac Output: The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). [NIH] Cardiogenic: Originating in the heart; caused by abnormal function of the heart. [EU] Cardiolipins: Acidic phospholipids composed of two molecules of phosphatidic acid covalently linked to a molecule of glycerol. They occur primarily in mitochondrial inner membranes and in bacterial plasma membranes. They are the main antigenic components of the Wassermann-type antigen that is used in nontreponemal syphilis serodiagnosis. [NIH] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] 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] Cardiopulmonary Resuscitation: The artificial substitution of heart and lung action as indicated for heart arrest resulting from electric shock, drowning, respiratory arrest, or other causes. The two major components of cardiopulmonary resuscitation are artificial ventilation and closed-chest cardiac massage. [NIH] Cardiotonic: 1. Having a tonic effect on the heart. 2. An agent that has a tonic effect on the heart. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Cataracts: In medicine, an opacity of the crystalline lens of the eye obstructing partially or totally its transmission of light. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH]

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Catheter: A flexible tube used to deliver fluids into or withdraw fluids from the body. [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] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] 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 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 Physiology: Characteristics and physiological processes of cells from cell division to cell death. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell 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]

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Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Central Nervous System Infections: Pathogenic infections of the brain, spinal cord, and meninges. DNA virus infections; RNA virus infections; bacterial infections; mycoplasma infections; Spirochaetales infections; fungal infections; protozoan infections; helminthiasis; and prion diseases may involve the central nervous system as a primary or secondary process. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Angiography: Radiography of the vascular system of the brain after injection of a contrast medium. [NIH] Cerebral Arteries: The arteries supplying the cerebral cortex. [NIH] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] Cerebral Infarction: The formation of an area of necrosis in the cerebrum caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., infarction, anterior cerebral artery), and etiology (e.g., embolic infarction). [NIH]

Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] 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] Chelation: Combination with a metal in complexes in which the metal is part of a ring. [EU] 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] Chemotherapeutic agent: A drug used to treat cancer. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chest Pain: Pressure, burning, or numbness in the chest. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that

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contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Chloride Channels: Cell membrane glycoproteins selective for chloride ions. [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] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chorioretinitis: Inflammation of the choroid in which the sensory retina becomes edematous and opaque. The inflammatory cells and exudate may burst through the sensory retina to cloud the vitreous body. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic Obstructive Pulmonary Disease: Collective term for chronic bronchitis and emphysema. [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] Cilazapril: An angiotensin-converting enzyme inhibitor that is effective in the treatment of hypertension. Preliminary results also indicate its potential in the treatment of congestive heart failure. It is a prodrug that is hydrolyzed after absorption to its main metabolite cilazaprilat. [NIH] Ciliary: Inflammation or infection of the glands of the margins of the eyelids. [NIH] Circadian: Repeated more or less daily, i. e. on a 23- to 25-hour cycle. [NIH] Circadian Rhythm: The regular recurrence, in cycles of about 24 hours, of biological processes or activities, such as sensitivity to drugs and stimuli, hormone secretion, sleeping, feeding, etc. This rhythm seems to be set by a 'biological clock' which seems to be set by recurring daylight and darkness. [NIH] Cirrhosis: A type of chronic, progressive liver disease. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by

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calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Climacteric: Physiologic period, characterized by endocrine, somatic, and psychic changes with the termination of ovarian function in the female. It may also accompany the normal diminution of sexual activity in the male. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical Protocols: Precise and detailed plans for the study of a medical or biomedical problem and/or plans for a regimen of therapy. [NIH] Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clitoral: Pertaining to the clitoris. [EU] 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] Cochlea: The part of the internal ear that is concerned with hearing. It forms the anterior part of the labyrinth, is conical, and is placed almost horizontally anterior to the vestibule. [NIH]

Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever (periodic disease). [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline,

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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] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [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] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Compress: A plug used to occludate an orifice in the control of bleeding, or to mop up secretions; an absorbent pad. [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 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]

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Concomitant: Accompanying; accessory; joined with another. [EU] Conduction: The transfer of sound waves, heat, nervous impulses, or electricity. [EU] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the "true" effect of an intervention. [NIH] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjunctivitis: Inflammation of the conjunctiva, generally consisting of conjunctival hyperaemia associated with a discharge. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Connective Tissue Diseases: A heterogeneous group of disorders, some hereditary, others acquired, characterized by abnormal structure or function of one or more of the elements of connective tissue, i.e., collagen, elastin, or the mucopolysaccharides. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Constriction: The act of constricting. [NIH] Constriction, Pathologic: The condition of an anatomical structure's being constricted beyond normal dimensions. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [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] Continuous infusion: The administration of a fluid into a blood vessel, usually over a prolonged period of time. [NIH] Contractility: Capacity for becoming short in response to a suitable stimulus. [EU] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Contrast Media: Substances used in radiography that allow visualization of certain tissues. [NIH]

Contrast medium: A substance that is introduced into or around a structure and, because of the difference in absorption of x-rays by the contrast medium and the surrounding tissues, allows radiographic visualization of the structure. [EU] 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]

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Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]

Conus: A large, circular, white patch around the optic disk due to the exposing of the sclera as a result of degenerative change or congenital abnormality in the choroid and retina. [NIH] 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] Cor: The muscular organ that maintains the circulation of the blood. c. adiposum a heart that has undergone fatty degeneration or that has an accumulation of fat around it; called also fat or fatty, heart. c. arteriosum the left side of the heart, so called because it contains oxygenated (arterial) blood. c. biloculare a congenital anomaly characterized by failure of formation of the atrial and ventricular septums, the heart having only two chambers, a single atrium and a single ventricle, and a common atrioventricular valve. c. bovinum (L. 'ox heart') a greatly enlarged heart due to a hypertrophied left ventricle; called also c. taurinum and bucardia. c. dextrum (L. 'right heart') the right atrium and ventricle. c. hirsutum, c. villosum. c. mobile (obs.) an abnormally movable heart. c. pendulum a heart so movable that it seems to be hanging by the great blood vessels. c. pseudotriloculare biatriatum a congenital cardiac anomaly in which the heart functions as a three-chambered heart because of tricuspid atresia, the right ventricle being extremely small or rudimentary and the right atrium greatly dilated. Blood passes from the right to the left atrium and thence disease due to pulmonary hypertension secondary to disease of the lung, or its blood vessels, with hypertrophy of the right ventricle. [EU] Cor pulmonale: Heart disease that results from resistance to the passage of blood through the lungs; it often leads to right heart failure. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Arteriosclerosis: Thickening and loss of elasticity of the coronary arteries. [NIH] Coronary 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] Coronary Vessels: The veins and arteries of the heart. [NIH] Corpus: The body of the uterus. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the

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internal substance. [EU] Corticosteroids: Hormones that have antitumor activity in lymphomas and lymphoid leukemias; in addition, corticosteroids (steroids) may be used for hormone replacement and for the management of some of the complications of cancer and its treatment. [NIH] 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] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH] 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] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyanosis: A bluish or purplish discoloration of the skin and mucous membranes due to an increase in the amount of deoxygenated hemoglobin in the blood or a structural defect in the hemoglobin molecule. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclin: Molecule that regulates the cell cycle. [NIH] 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] 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]

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Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Deamination: The removal of an amino group (NH2) from a chemical compound. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [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] Deferoxamine: Natural product isolated from Streptomyces pilosus. It forms iron complexes and is used as a chelating agent, particularly in the form of its mesylate. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Dehydration: The condition that results from excessive loss of body water. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Delivery of Health Care: The concept concerned with all aspects of providing and distributing health services to a patient population. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [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] Depressive Disorder: An affective disorder manifested by either a dysphoric mood or loss of interest or pleasure in usual activities. The mood disturbance is prominent and relatively persistent. [NIH] Dermatitis: Any inflammation of the skin. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Dexfenfluramine: The S-isomer of fenfluramine. It is a serotonin agonist and is used as an anorectic. Unlike fenfluramine, it does not possess any catecholamine agonist activity. [NIH] Dextroamphetamine: The d-form of amphetamine. It is a central nervous system stimulant

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and a sympathomimetic. It has also been used in the treatment of narcolepsy and of attention deficit disorders and hyperactivity in children. Dextroamphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulating release of monamines, and inhibiting monoamine oxidase. It is also a drug of abuse and a psychotomimetic. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diabetic Retinopathy: Retinopathy associated with diabetes mellitus, which may be of the background type, progressively characterized by microaneurysms, interretinal punctuate macular edema, or of the proliferative type, characterized by neovascularization of the retina and optic disk, which may project into the vitreous, proliferation of fibrous tissue, vitreous hemorrhage, and retinal detachment. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diaphragm: The musculofibrous partition that separates the thoracic cavity from the abdominal cavity. Contraction of the diaphragm increases the volume of the thoracic cavity aiding inspiration. [NIH] Diastole: Period of relaxation of the heart, especially the ventricles. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Dichloroacetate: A derivative of acetic acid which increases the activity of pyruvate dehydrogenase and rate of lipogenesis. It is used in organic synthesis, pharmaceuticals, and medicine. [NIH] Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [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] Dihydroxy: AMPA/Kainate antagonist. [NIH] Dilatation: The act of dilating. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilate: Relax; expand. [NIH] Dilated cardiomyopathy: Heart muscle disease that leads to enlargement of the heart's chambers, robbing the heart of its pumping ability. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dilator: A device used to stretch or enlarge an opening. [NIH] Diltiazem: A benzothiazepine derivative with vasodilating action due to its antagonism of the actions of the calcium ion in membrane functions. It is also teratogenic. [NIH] Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer. [NIH]

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Dimethyl: A volatile metabolite of the amino acid methionine. [NIH] Dipyridamole: A drug that prevents blood cell clumping and enhances the effectiveness of fluorouracil and other chemotherapeutic agents. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Dissection: Cutting up of an organism for study. [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] Distention: The state of being distended or enlarged; the act of distending. [EU] Diuresis: Increased excretion of urine. [EU] Dobutamine: A beta-2 agonist catecholamine that has cardiac stimulant action without evoking vasoconstriction or tachycardia. It is proposed as a cardiotonic after myocardial infarction or open heart surgery. [NIH] Domesticated: Species in which the evolutionary process has been influenced by humans to meet their needs. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dose-limiting: Describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. [NIH] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Double-blinded: A clinical trial in which neither the medical staff nor the person knows which of several possible therapies the person is receiving. [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 Delivery Systems: Systems of administering drugs through controlled delivery so that an optimum amount reaches the target site. Drug delivery systems encompass the carrier, route, and target. [NIH] Drug Design: The molecular designing of drugs for specific purposes (such as DNAbinding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic

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structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Duct: A tube through which body fluids pass. [NIH] Ductus Arteriosus: A fetal blood vessel connecting the pulmonary artery with the descending aorta. [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] Dysmenorrhea: Painful menstruation. [NIH] Dysmenorrhoea: Painful menstruation. [EU] Dysphoric: A feeling of unpleasantness and discomfort. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dyspnea: Difficult or labored breathing. [NIH] Dystocia: Difficult childbirth or labor. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Echocardiography: Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic. [NIH] Eclampsia: Onset of convulsions or coma in a previously diagnosed pre-eclamptic patient. [NIH]

Ectopic: Pertaining to or characterized by ectopia. [EU] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Effusion: The escape of fluid into a part or tissue, as an exudation or a transudation. [EU] Eicosanoids: A class of oxygenated, endogenous, unsaturated fatty acids derived from arachidonic acid. They include prostaglandins, leukotrienes, thromboxanes, and hydroxyeicosatetraenoic acid compounds (HETE). They are hormone-like substances that act near the site of synthesis without altering functions throughout the body. [NIH] Elastic: Susceptible of resisting and recovering from stretching, compression or distortion applied by a force. [EU] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] 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]

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Electric shock: A dangerous patho-physiological effect resulting from an electric current passing through the body of a human or animal. [NIH] Electrocardiogram: Measurement of electrical activity during heartbeats. [NIH] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrode: Component of the pacing system which is at the distal end of the lead. It is the interface with living cardiac tissue across which the stimulus is transmitted. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrophysiological: Pertaining to electrophysiology, that is a branch of physiology that is concerned with the electric phenomena associated with living bodies and involved in their functional activity. [EU] 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] 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] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Emulsions: Colloids of two immiscible liquids where either phase may be either fatty or aqueous; lipid-in-water emulsions are usually liquid, like milk or lotion and water-in-lipid emulsions tend to be creams. [NIH] Enalapril: An angiotensin-converting enzyme inhibitor that is used to treat hypertension. [NIH]

Enalaprilat: The active metabolite of enalapril and a potent intravenously administered angiotensin-converting enzyme inhibitor. It is an effective agent for the treatment of essential hypertension and has beneficial hemodynamic effects in heart failure. The drug produces renal vasodilation with an increase in sodium excretion. [NIH] 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] Encephalitis, Viral: Inflammation of brain parenchymal tissue as a result of viral infection. Encephalitis may occur as primary or secondary manifestation of Togaviridae infections; Herpesviridae infections; Adenoviridae infections; Flaviviridae infections; Bunyaviridae infections; Picornaviridae infections; Paramyxoviridae infections; Orthomyxoviridae infections; Retroviridae infections; and Arenaviridae infections. [NIH] Encephalopathy: A disorder of the brain that can be caused by disease, injury, drugs, or chemicals. [NIH] Endarterectomy: Surgical excision, performed under general anesthesia, of the atheromatous tunica intima of an artery. When reconstruction of an artery is performed as an endovascular procedure through a catheter, it is called atherectomy. [NIH] Endemic: Present or usually prevalent in a population or geographical area at all times; said

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of a disease or agent. Called also endemial. [EU] Endocarditis: Exudative and proliferative inflammatory alterations of the endocardium, characterized by the presence of vegetations on the surface of the endocardium or in the endocardium itself, and most commonly involving a heart valve, but sometimes affecting the inner lining of the cardiac chambers or the endocardium elsewhere. It may occur as a primary disorder or as a complication of or in association with another disease. [EU] Endocardium: The innermost layer of the heart, comprised of endothelial cells. [NIH] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] 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] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelins: 21-Amino-acid peptides produced by vascular endothelial cells and functioning as potent vasoconstrictors. The endothelin family consists of three members, endothelin-1, endothelin-2, and endothelin-3. All three peptides contain 21 amino acids, but vary in amino acid composition. The three peptides produce vasoconstrictor and pressor responses in various parts of the body. However, the quantitative profiles of the pharmacological activities are considerably different among the three isopeptides. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxin: Toxin from cell walls of bacteria. [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] Enhancers: Transcriptional element in the virus genome. [NIH] Enoximone: 1,3-Dihydro-4-methyl-5-(4-(methylthio)benzoyl)-2H-imidazol-2-one. A selective phosphodiesterase inhibitor with vasodilating and positive inotropic activity that does not

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cause changes in myocardial oxygen consumption. It is used in patients with congestive heart failure. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] Eosinophil: A polymorphonuclear leucocyte with large eosinophilic granules in its cytoplasm, which plays a role in hypersensitivity reactions. [NIH] Eosinophilic: A condition found primarily in grinding workers caused by a reaction of the pulmonary tissue, in particular the eosinophilic cells, to dust that has entered the lung. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermal Growth Factor: A 6 kD polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. epidermal growth factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and epithelial cells. [NIH] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Epitopes: Sites on an antigen that interact with specific antibodies. [NIH] 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] Erectile: The inability to get or maintain an erection for satisfactory sexual intercourse. Also

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called impotence. [NIH] Erection: The condition of being made rigid and elevated; as erectile tissue when filled with blood. [EU] Ergometer: An instrument for measuring the force of muscular contraction. [NIH] Ergometry: Any method of measuring the amount of work done by an organism, usually during exertion. Ergometry also includes measures of power. Some instruments used in these determinations include the hand crank and the bicycle ergometer. [NIH] Erythema: Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of causes. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Esophageal: Having to do with the esophagus, the muscular tube through which food passes from the throat to the stomach. [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] Estradiol: The most potent mammalian estrogenic hormone. It is produced in the ovary, placenta, testis, and possibly the adrenal cortex. [NIH] Estrogen: One of the two female sex hormones. [NIH] Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [NIH]

Ether: One of a class of organic compounds in which any two organic radicals are attached directly to a single oxygen atom. [NIH] Ethylene Glycol: A colorless, odorless, viscous dihydroxy alcohol. It has a sweet taste, but is poisonous if ingested. Ethylene glycol is the most important glycol commercially available and is manufactured on a large scale in the United States. It is used as an antifreeze and coolant, in hydraulic fluids, and in the manufacture of low-freezing dynamites and resins. [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] 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] Excrete: To get rid of waste from the body. [NIH] Exercise Test: Controlled physical activity, more strenuous than at rest, which is performed in order to allow assessment of physiological functions, particularly cardiovascular and pulmonary, but also aerobic capacity. Maximal (most intense) exercise is usually required but submaximal exercise is also used. The intensity of exercise is often graded, using criteria such as rate of work done, oxygen consumption, and heart rate. Physiological data obtained from an exercise test may be used for diagnosis, prognosis, and evaluation of disease severity, and to evaluate therapy. Data may also be used in prescribing exercise by determining a person's exercise capacity. [NIH] Exercise Tolerance: The exercise capacity of an individual as measured by endurance (maximal exercise duration and/or maximal attained work load) during an exercise test.

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[NIH]

Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exocytosis: Cellular release of material within membrane-limited vesicles by fusion of the vesicles with the cell membrane. [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] Expiration: The act of breathing out, or expelling air from the lungs. [EU] External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extracorporeal: Situated or occurring outside the body. [EU] Extracorporeal Membrane Oxygenation: Application of a life support system that circulates the blood through an oxygenating system, which may consist of a pump, a membrane oxygenator, and a heat exchanger. Examples of its use are to assist victims of smoke inhalation injury, respiratory failure, and cardiac failure. [NIH] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Felodipine: A dihydropyridine calcium antagonist with positive inotropic effects. It lowers

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blood pressure by reducing peripheral vascular resistance through a highly selective action on smooth muscle in arteriolar resistance vessels. [NIH] Femoral: Pertaining to the femur, or to the thigh. [EU] Femoral Artery: The main artery of the thigh, a continuation of the external iliac artery. [NIH] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [NIH] Fendiline: Coronary vasodilator; inhibits calcium function in muscle cells in excitationcontraction coupling; proposed as antiarrhythmic and antianginal agents. [NIH] Fenfluramine: A centrally active drug that apparently both blocks serotonin uptake and provokes transport-mediated serotonin release. [NIH] Fetal Blood: Blood of the fetus. Exchange of nutrients and waste between the fetal and maternal blood occurs via the placenta. The cord blood is blood contained in the umbilical vessels at the time of delivery. [NIH] Fetal Growth Retardation: The failure of a fetus to attain its expected growth potential at any gestational stage. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibril: Most bacterial viruses have a hollow tail with specialized fibrils at its tip. The tail fibers attach to the cell wall of the host. [NIH] Fibrillation: A small, local, involuntary contraction of muscle, invisible under the skin, resulting from spontaneous activation of single muscle cells or muscle fibres. [EU] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibrinolytic: Pertaining to, characterized by, or causing the dissolution of fibrin by enzymatic action [EU] Fibrinolytic Agents: Fibrinolysin or agents that convert plasminogen to fibrinolysin (plasmin). [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Fine-needle aspiration: The removal of tissue or fluid with a needle for examination under a microscope. Also called needle biopsy. [NIH] Fistula: Abnormal communication most commonly seen between two internal organs, or between an internal organ and the surface of the body. [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

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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] 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] Fold: A plication or doubling of various parts of the body. [NIH] Foramen: A natural hole of perforation, especially one in a bone. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fossa: A cavity, depression, or pit. [NIH] Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Friction: Surface resistance to the relative motion of one body against the rubbing, sliding, rolling, or flowing of another with which it is in contact. [NIH] Frontal Lobe: The anterior part of the cerebral hemisphere. [NIH] Fructose: A type of sugar found in many fruits and vegetables and in honey. Fructose is used to sweeten some diet foods. It is considered a nutritive sweetener because it has calories. [NIH] Fulminant Hepatic Failure: Liver failure that occurs suddenly in a previously healthy person. The most common causes of FHF are acute hepatitis, acetaminophen overdose, and liver damage from prescription drugs. [NIH] Fungemia: The presence of fungi circulating in the blood. Opportunistic fungal sepsis is seen most often in immunosuppressed patients with severe neutropenia or in postoperative patients with intravenous catheters and usually follows prolonged antibiotic therapy. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gallopamil: Coronary vasodilator that is an analog of iproveratril (verapamil) with one more methoxy group on the benzene ring. [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

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connective tissue located outside the central nervous system. [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] Gastric Mucosa: Surface epithelium in the stomach that invaginates into the lamina propria, forming gastric pits. Tubular glands, characteristic of each region of the stomach (cardiac, gastric, and pyloric), empty into the gastric pits. The gastric mucosa is made up of several different kinds of cells. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

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] 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] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU]

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Genitourinary: Pertaining to the genital and urinary organs; urogenital; urinosexual. [EU] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Germline mutation: A gene change in the body's reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; germline mutations are passed on from parents to offspring. Also called hereditary mutation. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Gestational: Psychosis attributable to or occurring during pregnancy. [NIH] Gestational Age: Age of the conceptus. In humans, this may be assessed by medical history, physical examination, early immunologic pregnancy tests, radiography, ultrasonography, and amniotic fluid analysis. [NIH] Giant Cells: Multinucleated masses produced by the fusion of many cells; often associated with viral infections. In AIDS, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium leads to cell death and thus may account for the cytopathic effect of the virus. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] 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] 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] Glottis: The vocal apparatus of the larynx, consisting of the true vocal cords (plica vocalis) and the opening between them (rima glottidis). [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose 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

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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]

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] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycans: Heteropolysaccharides which contain an N-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1,4- and 1,3-linkages consisting of either N-acetylglucosamine or Nacetylgalactosamine. [NIH] Gonadal: Pertaining to a gonad. [EU] Gonads: The gamete-producing glands, ovary or testis. [NIH] 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]

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] Grafting: The operation of transfer of tissue from one site to another. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Gram-Negative Bacteria: Bacteria which lose crystal violet stain but are stained pink when treated by Gram's method. [NIH] Gram-positive: Retaining the stain or resisting decolorization by alcohol in Gram's method of staining, a primary characteristic of bacteria whose cell wall is composed of a thick layer of peptidologlycan with attached teichoic acids. [EU] Granule: A small pill made from sucrose. [EU] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [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] Guinea Pigs: A common name used for the family Caviidae. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research. [NIH]

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Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Haplotypes: The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the major histocompatibility complex. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Hay Fever: A seasonal variety of allergic rhinitis, marked by acute conjunctivitis with lacrimation and itching, regarded as an allergic condition triggered by specific allergens. [NIH]

Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Headache Disorders: Common conditions characterized by persistent or recurrent headaches. Headache syndrome classification systems may be based on etiology (e.g., vascular headache, post-traumatic headaches, etc.), temporal pattern (e.g., cluster headache, paroxysmal hemicrania, etc.), and precipitating factors (e.g., cough headache). [NIH] Health Care Costs: The actual costs of providing services related to the delivery of health care, including the costs of procedures, therapies, and medications. It is differentiated from health expenditures, which refers to the amount of money paid for the services, and from fees, which refers to the amount charged, regardless of cost. [NIH] Health Expenditures: The amounts spent by individuals, groups, nations, or private or public organizations for total health care and/or its various components. These amounts may or may not be equivalent to the actual costs (health care costs) and may or may not be shared among the patient, insurers, and/or employers. [NIH] Heart Arrest: Sudden and usually momentary cessation of the heart beat. This sudden cessation may, but not usually, lead to death, sudden, cardiac. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart Catheterization: Procedure which includes placement of catheter, recording of intracardiac and intravascular pressure, obtaining blood samples for chemical analysis, and cardiac output measurement, etc. Specific angiographic injection techniques are also involved. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heart Transplantation: The transference of a heart from one human or animal to another. [NIH]

Heartbeat: One complete contraction of the heart. [NIH] Heart-Lung Transplantation: The simultaneous, or near simultaneous, transference of heart and lungs from one human or animal to another. [NIH] Hematoma: An extravasation of blood localized in an organ, space, or tissue. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid.

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The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemodynamics: The movements of the blood and the forces involved in systemic or regional blood circulation. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobin A: Normal adult human hemoglobin. The globin moiety consists of two alpha and two beta chains. [NIH] Hemoglobin E: An abnormal hemoglobin that results from the substitution of lysine for glutamic acid at position 26 of the beta chain. It is most frequently observed in southeast Asian populations. [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] 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 stroke: A disorder involving bleeding within ischemic brain tissue. Hemorrhagic stroke occurs when blood vessels that are damaged or dead from lack of blood supply (infarcted), located within an area of infarcted brain tissue, rupture and transform an "ischemic" stroke into a hemorrhagic stroke. Ischemia is inadequate tissue oxygenation caused by reduced blood flow; infarction is tissue death resulting from ischemia. Bleeding irritates the brain tissues, causing swelling (cerebral edema). Blood collects into a mass (hematoma). Both swelling and hematoma will compress and displace brain tissue. [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] Hepatic Encephalopathy: A condition that may cause loss of consciousness and coma. It is usually the result of advanced liver disease. Also called hepatic coma. [NIH]

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Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatocellular: Pertaining to or affecting liver cells. [EU] Hepatocellular carcinoma: A type of adenocarcinoma, the most common type of liver tumor. [NIH] Hepatocytes: The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. [NIH] Hepatopulmonary Syndrome: A syndrome consisting of the triad of liver dysfunction, pulmonary vascular dilatation, and abnormal arterial oxygenation in the absence of detectable intrinsic disease of the lung and heart. [NIH] Herbicide: A chemical that kills plants. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Hereditary mutation: A gene change in the body's reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; hereditary mutations are passed on from parents to offspring. Also called germline mutation. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Hernia: Protrusion of a loop or knuckle of an organ or tissue through an abnormal opening. [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]

High-Frequency Jet Ventilation: Respiratory support system used primarily with rates of about 100 to 200/min with volumes of from about one to three times predicted anatomic dead space. Used to treat respiratory failure and maintain ventilation under severe circumstances. [NIH] High-Frequency Ventilation: Ventilatory support system using frequencies from 60-900 cycles/min or more. Three types of systems have been distinguished on the basis of rates, volumes, and the system used. They are high frequency positive-pressure ventilation (HFPPV), high-frequency jet ventilation (HFJV), and high-frequency oscillation (HFO). [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] Histamine Release: The secretion of histamine from mast cell and basophil granules by exocytosis. This can be initiated by a number of factors, all of which involve binding of IgE, cross-linked by antigen, to the mast cell or basophil's Fc receptors. Once released, histamine binds to a number of different target cell receptors and exerts a wide variety of effects. [NIH] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Homeobox: Distinctive sequence of DNA bases. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird

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and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hormone Replacement Therapy: Therapeutic use of hormones to alleviate the effects of hormone deficiency. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH] 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] Hyperaldosteronism: Aldosteronism. [EU] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [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] Hyperoxia: An abnormal increase in the amount of oxygen in the tissues and organs. [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

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are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertension, Pulmonary: Increased pressure within the pulmonary circulation, usually secondary to cardiac or pulmonary disease. [NIH] Hypertension, Renovascular: Hypertension due to compression or obstruction of the renal artery or its branches. [NIH] Hypertonic Solutions: Solutions that have a greater osmotic pressure than a reference solution such as blood, plasma, or interstitial fluid. [NIH] Hypertrophic cardiomyopathy: Heart muscle disease that leads to thickening of the heart walls, interfering with the heart's ability to fill with and pump blood. [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] Hyperventilation: A pulmonary ventilation rate faster than is metabolically necessary for the exchange of gases. It is the result of an increased frequency of breathing, an increased tidal volume, or a combination of both. It causes an excess intake of oxygen and the blowing off of carbon dioxide. [NIH] Hypnotic: A drug that acts to induce sleep. [EU] Hypoglycemia: Abnormally low blood sugar [NIH] Hypogonadism: Condition resulting from or characterized by abnormally decreased functional activity of the gonads, with retardation of growth and sexual development. [NIH] Hypoplasia: Incomplete development or underdevelopment of an organ or tissue. [EU] Hypotension: Abnormally low blood pressure. [NIH] Hypotensive: Characterized by or causing diminished tension or pressure, as abnormally low blood pressure. [EU] Hypothalamic: Of or involving the hypothalamus. [EU] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypotrophy: Abiotrophy. [EU] Hypoventilation: A reduction in the amount of air entering the pulmonary alveoli. [NIH] Hypoxemia: Deficient oxygenation of the blood; hypoxia. [EU] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Hypoxic: Having too little oxygen. [NIH] Ibuprofen: A nonsteroidal anti-inflammatory agent with analgesic properties used in the therapy of rheumatism and arthritis. [NIH] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Iliac Artery: Either of two large arteries originating from the abdominal aorta; they supply blood to the pelvis, abdominal wall and legs. [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]

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Immaturity: The state or quality of being unripe or not fully developed. [EU] Immersion: The placing of a body or a part thereof into a liquid. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunodeficiency syndrome: The inability of the body to produce an immune response. [NIH]

Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] Impotence: The inability to perform sexual intercourse. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH]

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Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infant, Newborn: An infant during the first month after birth. [NIH] 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]

Inferior vena cava: A large vein that empties into the heart. It carries blood from the legs and feet, and from organs in the abdomen and pelvis. [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] 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] Inner ear: The labyrinth, comprising the vestibule, cochlea, and semicircular canals. [NIH] Innervation: 1. The distribution or supply of nerves to a part. 2. The supply of nervous energy or of nerve stimulus sent to a part. [EU] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol

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phospholipids are important in signal transduction. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [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, 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]

Intensive Care Units: Hospital units providing continuous surveillance and care to acutely ill patients. [NIH] Interindividual: Occurring between two or more individuals. [EU] 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] 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] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestinal Mucosa: The surface lining of the intestines where the cells absorb nutrients. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH]

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Intravascular: Within a vessel or vessels. [EU] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Intubation: Introduction of a tube into a hollow organ to restore or maintain patency if obstructed. It is differentiated from catheterization in that the insertion of a catheter is usually performed for the introducing or withdrawing of fluids from the body. [NIH] 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] Ion Transport: The movement of ions across energy-transducing cell membranes. Transport can be active or passive. Passive ion transport (facilitated diffusion) derives its energy from the concentration gradient of the ion itself and allows the transport of a single solute in one direction (uniport). Active ion transport is usually coupled to an energy-yielding chemical or photochemical reaction such as ATP hydrolysis. This form of primary active transport is called an ion pump. Secondary active transport utilizes the voltage and ion gradients produced by the primary transport to drive the cotransport of other ions or molecules. These may be transported in the same (symport) or opposite (antiport) direction. [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] 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. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Ischemic stroke: A condition in which the blood supply to part of the brain is cut off. Also called "plug-type" strokes. Blocked arteries starve areas of the brain controlling sight, speech, sensation, and movement so that these functions are partially or completely lost. Ischemic stroke is the most common type of stroke, accounting for 80 percent of all strokes. Most ischemic strokes are caused by a blood clot called a thrombus, which blocks blood flow in the arteries feeding the brain, usually the carotid artery in the neck, the major vessel bringing blood to the brain. When it becomes blocked, the risk of stroke is very high. [NIH]

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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] Isozymes: The multiple forms of a single enzyme. [NIH] Isradipine: 4-(4-Benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methyl ethyl ester. A potent calcium channel antagonist that is highly selective for vascular smooth muscle. It is effective in the treatment of chronic stable angina pectoris, hypertension, and congestive cardiac failure. [NIH] Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH]

Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Keto: It consists of 8 carbon atoms and within the endotoxins, it connects poysaccharide and lipid A. [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] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [NIH] Kinetics: The study of rate dynamics in chemical or physical systems. [NIH] Labyrinth: The internal ear; the essential part of the organ of hearing. It consists of an osseous and a membranous portion. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Lentivirus: A genus of the family Retroviridae consisting of non-oncogenic retroviruses that produce multi-organ diseases characterized by long incubation periods and persistent infection. Lentiviruses are unique in that they contain open reading frames (ORFs) between

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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] Lethal: Deadly, fatal. [EU] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]

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] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Life Expectancy: A figure representing the number of years, based on known statistics, to which any person of a given age may reasonably expect to live. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] Lipopolysaccharide: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Liposome: A spherical particle in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. [EU] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver Cirrhosis: Liver disease in which the normal microcirculation, the gross vascular anatomy, and the hepatic architecture have been variably destroyed and altered with fibrous septa surrounding regenerated or regenerating parenchymal nodules. [NIH]

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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] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] 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] Lubricants: Oily or slippery substances. [NIH] Lubrication: The application of a substance to diminish friction between two surfaces. It may refer to oils, greases, and similar substances for the lubrication of medical equipment but it can be used for the application of substances to tissue to reduce friction, such as lotions for skin and vaginal lubricants. [NIH] Luciferase: Any one of several enzymes that catalyze the bioluminescent reaction in certain marine crustaceans, fish, bacteria, and insects. The enzyme is a flavoprotein; it oxidizes luciferins to an electronically excited compound that emits energy in the form of light. The color of light emitted varies with the organism. The firefly enzyme is a valuable reagent for measurement of ATP concentration. (Dorland, 27th ed) EC 1.13.12.-. [NIH] Lumbar: Pertaining to the loins, the part of the back between the thorax and the pelvis. [EU] Lumen: The cavity or channel within a tube or tubular organ. [EU] Lung Transplantation: The transference of either one or both of the lungs from one human or animal to another. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH]

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Lysine: An essential amino acid. It is often added to animal feed. [NIH] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Magnetic Resonance Angiography: Non-invasive method of vascular imaging and determination of internal anatomy without injection of contrast media or radiation exposure. The technique is used especially in cerebral angiography as well as for studies of other vascular structures. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] 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] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malformation: A morphologic developmental process. [EU]

defect

resulting

from

an

intrinsically

abnormal

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] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Matrix metalloproteinase: A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis. [NIH] McMaster: Index used to measure painful syndromes linked to arthrosis. [NIH] Mechanical ventilation: Use of a machine called a ventilator or respirator to improve the exchange of air between the lungs and the atmosphere. [NIH] Meconium: The thick green-to-black mucilaginous material found in the intestines of a fullterm fetus. It consists of secretions of the intestinal glands, bile pigments, fatty acids, amniotic fluid, and intrauterine debris. It constitutes the first stools passed by a newborn. [NIH]

Meconium Aspiration: Syndrome caused by sucking of thick meconium into the lungs,

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usually by term or post-term infants (often small for gestational age) either in utero or with first breath. The resultant small airway obstruction may produce respiratory distress, tachypnea, cyanosis, pneumothorax, and/or pneumomediastinum. [NIH] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Median survival time: The point in time from either diagnosis or treatment at which half of the patients with a given disease are found to be, or expected to be, still alive. In a clinical trial, median survival time is one way to measure how effective a treatment is. [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 Staff: Professional medical personnel who provide care to patients in an organized facility, institution or agency. [NIH] Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Glycoproteins: Glycoproteins found on the membrane or surface of cells. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Meningitis: Inflammation of the meninges. When it affects the dura mater, the disease is termed pachymeningitis; when the arachnoid and pia mater are involved, it is called leptomeningitis, or meningitis proper. [EU] Menopause: Permanent cessation of menstruation. [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental 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]

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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]

Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesenteric: Pertaining to the mesentery : a membranous fold attaching various organs to the body wall. [EU] Mesentery: A layer of the peritoneum which attaches the abdominal viscera to the abdominal wall and conveys their blood vessels and nerves. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metaplasia: A condition in which there is a change of one adult cell type to another similar adult cell type. [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] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] Methotrexate: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of dihydrofolate reductase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [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] Mibefradil: A benzimidazoyl-substituted tetraline that binds selectively to and inhibits calcium channels, T-type. [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] Microcirculation: The vascular network lying between the arterioles and venules; includes capillaries, metarterioles and arteriovenous anastomoses. Also, the flow of blood through this network. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Micro-organism: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH]

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Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Milrinone: A positive inotropic cardiotonic agent with vasodilator properties. It inhibits cAMP phosphodiesterase activity in myocardium and vascular smooth muscle. Milrinone is a derivative of amrinone and has 20-30 times the ionotropic potency of amrinone. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitral Valve: The valve between the left atrium and left ventricle of the heart. [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] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]

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] Monocrotaline: A pyrrolizidine alkaloid and a toxic plant constituent that poisons livestock and humans through the ingestion of contaminated grains and other foods. The alkaloid causes pulmonary artery hypertension, right ventricular hypertrophy, and pathological changes in the pulmonary vasculature. Significant attenuation of the cardiopulmonary changes are noted after oral magnesium treatment. [NIH] Monocyte: A type of white blood cell. [NIH] Monophosphate: So called second messenger for neurotransmitters and hormones. [NIH] Morphine: The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Motility: The ability to move spontaneously. [EU]

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Motion Sickness: Sickness caused by motion, as sea sickness, train sickness, car sickness, and air sickness. [NIH] Mucilaginous: Pertaining to or secreting mucus. [NIH] 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] Multicenter study: A clinical trial that is carried out at more than one medical institution. [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] Muscle Relaxation: That phase of a muscle twitch during which a muscle returns to a resting position. [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] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myelofibrosis: A disorder in which the bone marrow is replaced by fibrous tissue. [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] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (myocardial infarction). [NIH] Myocardial Reperfusion: Generally, restoration of blood supply to heart tissue which is

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

Myocarditis: Inflammation of the myocardium; inflammation of the muscular walls of the heart. [EU] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myometrium: The smooth muscle coat of the uterus, which forms the main mass of the organ. [NIH] Myopathy: Any disease of a muscle. [EU] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Narcosis: A general and nonspecific reversible depression of neuronal excitability, produced by a number of physical and chemical aspects, usually resulting in stupor. [NIH] Narcotic: 1. Pertaining to or producing narcosis. 2. An agent that produces insensibility or stupor, applied especially to the opioids, i.e. to any natural or synthetic drug that has morphine-like actions. [EU] Natriuresis: The excretion of abnormal amounts of sodium in the urine. [EU] 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] Near Drowning: Non-fatal immersion or submersion in water. The subject is resuscitable. [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] Needle biopsy: The removal of tissue or fluid with a needle for examination under a microscope. Also called fine-needle aspiration. [NIH]

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Neonatal: Pertaining to the first four weeks after birth. [EU] Neonatal period: The first 4 weeks after birth. [NIH] Neonatologist: Doctor who specializes in treating the diseases and disorders of newborn babies. [NIH] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] 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] 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] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Blockade: The intentional interruption of transmission at the neuromuscular junction by external agents, usually neuromuscular blocking agents. It is distinguished from nerve block in which nerve conduction is interrupted rather than neuromuscular transmission. Neuromuscular blockade is commonly used to produce muscle relaxation as an adjunct to anesthesia during surgery and other medical procedures. It is also often used as an experimental manipulation in basic research. It is not strictly speaking anesthesia but is grouped here with anesthetic techniques. The failure of neuromuscular transmission as a result of pathological processes is not included here. [NIH] Neuromuscular Junction: The synapse between a neuron and a muscle. [NIH] Neuromuscular Junction Diseases: Conditions characterized by impaired transmission of impulses at the neuromuscular junction. This may result from disorders that affect receptor function, pre- or postsynaptic membrane function, or acetylcholinesteraseactivity. The majority of diseases in this category are associated with autoimmune, toxic, or inherited conditions. [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] Neurophysiology: The scientific discipline concerned with the physiology of the nervous system. [NIH] Neuroretinitis: Inflammation of the optic nerve head and adjacent retina. [NIH]

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Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotoxins: Toxic substances from microorganisms, plants or animals that interfere with the functions of the nervous system. Most venoms contain neurotoxic substances. Myotoxins are included in this concept. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutral Red: A vital dye used as an indicator and biological stain. Various adverse effects have been observed in biological systems. [NIH] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophil: A type of white blood cell. [NIH] Nicardipine: 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl) methyl 2(methyl(phenylmethyl)amino)-3,5-pyridinecarboxylic acid ethyl ester. A potent calcium channel blockader with marked vasodilator action. It has antihypertensive properties and is effective in the treatment of angina and coronary spasms without showing cardiodepressant effects. It has also been used in the treatment of asthma and enhances the action of specific antineoplastic agents. [NIH] Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. [NIH] Nifedipine: A potent vasodilator agent with calcium antagonistic action. It is a useful antianginal agent that also lowers blood pressure. The use of nifedipine as a tocolytic is being investigated. [NIH] Night Blindness: Anomaly of vision in which there is a pronounced inadequacy or complete absence of dark-adaptation. [NIH] Nimodipine: A calcium channel blockader with preferential cerebrovascular activity. It has marked cerebrovascular dilating effects and lowers blood pressure. [NIH] Nisoldipine: 1,4-Dihydro-2,6-dimethyl-4 (2-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 2-methylpropyl ester. Nisoldipine is a dihydropyridine calcium channel antagonist that acts as a potent arterial vasodilator and antihypertensive agent. It is also effective in patients with cardiac failure and angina. [NIH] Nitrendipine: Ethyl methyl 2,4-dihydro-2,6-dimethyl-4(3-nitrophenyl)-3,5pyridinedicarboxylate. A calcium channel blocker with marked vasodilator action. It is an effective antihypertensive agent and differs from other calcium channel blockers in that it does not reduce glomerular filtration rate and is mildly natriuretic, rather than sodium retentive. [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

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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] Nitrogen Dioxide: Nitrogen oxide (NO2). A highly poisonous gas. Exposure produces inflammation of lungs that may only cause slight pain or pass unnoticed, but resulting edema several days later may cause death. (From Merck, 11th ed) It is a major atmospheric pollutant that is able to absorb UV light that does not reach the earth's surface. [NIH] Nitrogen Oxides: Inorganic oxides that contain nitrogen. [NIH] Nitroglycerin: A highly volatile organic nitrate that acts as a dilator of arterial and venous smooth muscle and is used in the treatment of angina. It provides relief through improvement of the balance between myocardial oxygen supply and demand. Although total coronary blood flow is not increased, there is redistribution of blood flow in the heart when partial occlusion of coronary circulation is effected. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Normotensive: 1. Characterized by normal tone, tension, or pressure, as by normal blood pressure. 2. A person with normal blood pressure. [EU] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] 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] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nutritional Status: State of the body in relation to the consumption and utilization of nutrients. [NIH] Occult: Obscure; concealed from observation, difficult to understand. [EU] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Odds Ratio: The ratio of two odds. The exposure-odds ratio for case control data is the ratio of the odds in favor of exposure among cases to the odds in favor of exposure among noncases. The disease-odds ratio for a cohort or cross section is the ratio of the odds in favor of disease among the exposed to the odds in favor of disease among the unexposed. The prevalence-odds ratio refers to an odds ratio derived cross-sectionally from studies of prevalent cases. [NIH] Odour: A volatile emanation that is perceived by the sense of smell. [EU]

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Oligohydramnios: Presence of less than 300 ml of amniotic fluid at term. Principal causes include malformations of fetal urinary tracts, intra-uterine growth retardation, high maternal blood pressure, nicotine poisoning, and prolonged pregnancy. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] Oocytes: Female germ cells in stages between the prophase of the first maturation division and the completion of the second maturation division. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Open Reading Frames: Reading frames where successive nucleotide triplets can be read as codons specifying amino acids and where the sequence of these triplets is not interrupted by stop codons. [NIH] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Chiasm: The X-shaped structure formed by the meeting of the two optic nerves. At the optic chiasm the fibers from the medial part of each retina cross to project to the other side of the brain while the lateral retinal fibers continue on the same side. As a result each half of the brain receives information about the contralateral visual field from both eyes. [NIH]

Optic Disk: The portion of the optic nerve seen in the fundus with the ophthalmoscope. It is formed by the meeting of all the retinal ganglion cell axons as they enter the optic nerve. [NIH]

Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organ Transplantation: Transference of an organ between individuals of the same species or between individuals of different species. [NIH] 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] Organogenesis: Clonal propagation which involves culturing explants from roots, leaves, or stems to form undifferentiated callus tissue; after the cells form shoots, they are separated and rooted. Alternatively, if the callus is put in liquid culture, somatic embryos form. [NIH] Orgasm: The crisis of sexual excitement in either humans or animals. [NIH] Osmolality: The concentration of osmotically active particles in solution expressed in terms of osmoles of solute per kilogram of solvent. The osmolality is directly proportional to the colligative properties of solutions; osmotic pressure, boiling point elevation, freezing point depression, and vapour pressure lowering. [EU]

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Osmoles: The standard unit of osmotic pressure. [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] Ossicles: The hammer, anvil and stirrup, the small bones of the middle ear, which transmit the vibrations from the tympanic membrane to the oval window. [NIH] Ossification: The formation of bone or of a bony substance; the conversion of fibrous tissue or of cartilage into bone or a bony substance. [EU] Osteogenesis: The histogenesis of bone including ossification. It occurs continuously but particularly in the embryo and child and during fracture repair. [NIH] Osteopetrosis: Excessive formation of dense trabecular bone leading to pathological fractures, osteitis, splenomegaly with infarct, anemia, and extramedullary hemopoiesis. [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] Otitis: Inflammation of the ear, which may be marked by pain, fever, abnormalities of hearing, hearing loss, tinnitus, and vertigo. [EU] Otitis Media: Inflammation of the middle ear. [NIH] Otosclerosis: The formation of spongy bone in the labyrinth capsule. The ossicles can become fixed and unable to transmit sound vibrations, thereby causing deafness. [NIH] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overdose: An accidental or deliberate dose of a medication or street drug that is in excess of what is normally used. [NIH] Ovulation: The discharge of a secondary oocyte from a ruptured graafian follicle. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxidants: Oxidizing agents or electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (oxidation-reduction). In vivo, it appears that phagocyte-generated oxidants function as tumor promoters or cocarcinogens rather than as complete carcinogens perhaps because of the high levels of endogenous antioxidant defenses. It is also thought that oxidative damage in joints may trigger the autoimmune response that characterizes the persistence of the rheumatoid disease process. [NIH]

Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidation-Reduction: A chemical reaction in which an electron is transferred from one

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molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxides: Binary compounds of oxygen containing the anion O(2-). The anion combines with metals to form alkaline oxides and non-metals to form acidic oxides. [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Oxygenase: Enzyme which breaks down heme, the iron-containing oxygen-carrying constituent of the red blood cells. [NIH] Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] Oxygenator: An apparatus by which oxygen is introduced into the blood during circulation outside the body, as during open heart surgery. [NIH] Pachymeningitis: Inflammation of the dura mater of the brain, the spinal cord or the optic nerve. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Parietal: 1. Of or pertaining to the walls of a cavity. 2. Pertaining to or located near the parietal bone, as the parietal lobe. [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] Parturition: The act or process of given birth to a child. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Patch-Clamp Techniques: An electrophysiologic technique for studying cells, cell membranes, and occasionally isolated organelles. All patch-clamp methods rely on a very high-resistance seal between a micropipette and a membrane; the seal is usually attained by gentle suction. The four most common variants include on-cell patch, inside-out patch, outside-out patch, and whole-cell clamp. Patch-clamp methods are commonly used to voltage clamp, that is control the voltage across the membrane and measure current flow, but current-clamp methods, in which the current is controlled and the voltage is measured, are also used. [NIH] Patent ductus arteriosus: Abnormal persistence of the opening in the arterial duct that connects the pulmonary artery to the descending aorta; this opening normally closes within 24 hours of birth. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

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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 Education: The teaching or training of patients concerning their own health needs. [NIH]

Patient Selection: Criteria and standards used for the determination of the appropriateness of the inclusion of patients with specific conditions in proposed treatment plans and the criteria used for the inclusion of subjects in various clinical trials and other research protocols. [NIH] Pelvic: Pertaining to the pelvis. [EU] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Penicillamine: 3-Mercapto-D-valine. The most characteristic degradation product of the penicillin antibiotics. It is used as an antirheumatic and as a chelating agent in Wilson's disease. [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] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [NIH] Perceived risk: Estimate or evaluation of risk as observed through personal experience or personal study, and personal evaluation of consequences. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU] Perforation: 1. The act of boring or piercing through a part. 2. A hole made through a part or substance. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Pericardial Effusion: Presence of fluid within the pericardium. [NIH] Pericarditis: Inflammation of the pericardium. [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] Perioperative: Around the time of surgery; usually lasts from the time of going into the

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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 Vascular Disease: Disease in the large blood vessels of the arms, legs, and feet. People who have had diabetes for a long time may get this because major blood vessels in their arms, legs, and feet are blocked and these limbs do not receive enough blood. The signs of PVD are aching pains in the arms, legs, and feet (especially when walking) and foot sores that heal slowly. Although people with diabetes cannot always avoid PVD, doctors say they have a better chance of avoiding it if they take good care of their feet, do not smoke, and keep both their blood pressure and diabetes under good control. [NIH] Pertussis: An acute, highly contagious infection of the respiratory tract, most frequently affecting young children, usually caused by Bordetella pertussis; a similar illness has been associated with infection by B. parapertussis and B. bronchiseptica. It is characterized by a catarrhal stage, beginning after an incubation period of about two weeks, with slight fever, sneezing, running at the nose, and a dry cough. In a week or two the paroxysmal stage begins, with the characteristic paroxysmal cough, consisting of a deep inspiration, followed by a series of quick, short coughs, continuing until the air is expelled from the lungs; the close of the paroxysm is marked by a long-drawn, shrill, whooping inspiration, due to spasmodic closure of the glottis. This stage lasts three to four weeks, after which the convalescent stage begins, in which paroxysms grow less frequent and less violent, and finally cease. Called also whooping cough. [EU] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [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] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharmacotherapy: A regimen of using appetite suppressant medications to manage obesity by decreasing appetite or increasing the feeling of satiety. These medications decrease appetite by increasing serotonin or catecholamine—two brain chemicals that affect mood and appetite. [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phentermine: A central nervous system stimulant and sympathomimetic with actions and uses similar to those of dextroamphetamine. It has been used most frequently in the treatment of obesity. [NIH] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phosphodiesterase: Effector enzyme that regulates the levels of a second messenger, the

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cyclic GMP. [NIH] Phosphodiesterase Inhibitors: Compounds which inhibit or antagonize the biosynthesis or actions of phosphodiesterases. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Phototherapy: Treatment of disease by exposure to light, especially by variously concentrated light rays or specific wavelengths. [NIH] Phrenic Nerve: The motor nerve of the diaphragm. The phrenic nerve fibers originate in the cervical spinal column (mostly C4) and travel through the cervical plexus to the diaphragm. [NIH]

Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigments: Any normal or abnormal coloring matter in plants, animals, or micro-organisms. [NIH]

Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Placental Insufficiency: Failure of the placenta to deliver an adequate supply of nutrients and oxygen to the fetus. [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]

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Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [NIH] Plasmin: A product of the lysis of plasminogen (profibrinolysin) by plasminogen activators. It is composed of two polypeptide chains, light (B) and heavy (A), with a molecular weight of 75,000. It is the major proteolytic enzyme involved in blood clot retraction or the lysis of fibrin and quickly inactivated by antiplasmins. EC 3.4.21.7. [NIH] Plasminogen: Precursor of fibrinolysin (plasmin). It is a single-chain beta-globulin of molecular weight 80-90,000 found mostly in association with fibrinogen in plasma; plasminogen activators change it to fibrinolysin. It is used in wound debriding and has been investigated as a thrombolytic agent. [NIH] Plasminogen Activators: A heterogeneous group of proteolytic enzymes that convert plasminogen to plasmin. They are concentrated in the lysosomes of most cells and in the vascular endothelium, particularly in the vessels of the microcirculation. EC 3.4.21.-. [NIH] 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-Derived Growth Factor: Mitogenic peptide growth hormone carried in the alphagranules of platelets. It is released when platelets adhere to traumatized tissues. Connective tissue cells near the traumatized region respond by initiating the process of replication. [NIH] 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]

Plethysmograph: An instrument for measuring swelling or expansion of the body or part of it, such as a limb or digit, commonly used for the indirect measurement of blood flow or other displacement of internal fluids. [NIH]

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Pleura: The thin serous membrane enveloping the lungs and lining the thoracic cavity. [NIH] Pleural: A circumscribed area of hyaline whorled fibrous tissue which appears on the surface of the parietal pleura, on the fibrous part of the diaphragm or on the pleura in the interlobar fissures. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Pneumonitis: A disease caused by inhaling a wide variety of substances such as dusts and molds. Also called "farmer's disease". [NIH] Pneumothorax: Accumulation of air or gas in the space between the lung and chest wall, resulting in partial or complete collapse of the lung. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [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] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Pons: The part of the central nervous system lying between the medulla oblongata and the mesencephalon, ventral to the cerebellum, and consisting of a pars dorsalis and a pars ventralis. [NIH] Portal Hypertension: High blood pressure in the portal vein. This vein carries blood into the liver. Portal hypertension is caused by a blood clot. This is a common complication of cirrhosis. [NIH] Portal Vein: A short thick vein formed by union of the superior mesenteric vein and the splenic vein. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postoperative: After surgery. [NIH] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potassium Channels: Cell membrane glycoproteins selective for potassium ions. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis,

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therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precipitating Factors: Factors associated with the definitive onset of a disease, illness, accident, behavioral response, or course of action. Usually one factor is more important or more obviously recognizable than others, if several are involved, and one may often be regarded as "necessary". Examples include exposure to specific disease; amount or level of an infectious organism, drug, or noxious agent, etc. [NIH] 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] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Preoperative: Preceding an operation. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Priapism: Persistent abnormal erection of the penis, usually without sexual desire, and accompanied by pain and tenderness. It is seen in diseases and injuries of the spinal cord, and may be caused by vesical calculus and certain injuries to the penis. [EU] Primary Prevention: Prevention of disease or mental disorders in susceptible individuals or populations through promotion of health, including mental health, and specific protection, as in immunization, as distinguished from the prevention of complications or after-effects of existing disease. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Progeria: An abnormal congenital condition characterized by premature aging in children, where all the changes of cell senescence occur. It is manifested by premature greying, hair loss, hearing loss, cataracts, arthritis,osteoporosis, diabetes mellitus, atrophy of subcutaneous fat, skeletal hypoplasia, and accelerated atherosclerosis. Many affected individuals develop malignant tumors, especially sarcomas. [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]

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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] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Progressive disease: Cancer that is increasing in scope or severity. [NIH] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] 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] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Proportional: Being in proportion : corresponding in size, degree, or intensity, having the same or a constant ratio; of, relating to, or used in determining proportions. [EU] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandin: Any of a group of components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway that are extremely potent mediators of a diverse group of physiologic processes. The abbreviation for prostaglandin is PG; specific compounds are designated by adding one of the letters A through I to indicate the type of substituents found on the hydrocarbon skeleton and a subscript (1, 2 or 3) to indicate the number of double bonds in the hydrocarbon skeleton e.g., PGE2. The predominant naturally occurring prostaglandins all have two double bonds and are synthesized from arachidonic acid (5,8,11,14-eicosatetraenoic acid) by the pathway shown in the illustration. The 1 series and 3 series are produced by the same pathway with fatty acids having one fewer double bond (8,11,14-eicosatrienoic acid or one more double bond (5,8,11,14,17-eicosapentaenoic acid) than arachidonic acid. The subscript a or ß indicates the configuration at C-9 (a denotes a substituent below the plane of the ring, ß, above the plane). The naturally occurring PGF's have the a configuration, e.g., PGF2a. All of the prostaglandins act by binding to specific cell-surface receptors causing an increase in the level of the intracellular second messenger cyclic AMP (and in some cases cyclic GMP also). The effect produced by the cyclic AMP increase depends on the specific cell type. In some cases there is also a positive feedback effect. Increased cyclic AMP increases prostaglandin synthesis leading to further increases in cyclic AMP. [EU] Prostaglandin Endoperoxides: Precursors in the biosynthesis of prostaglandins and thromboxanes from arachidonic acid. They are physiologically active compounds, having effect on vascular and airway smooth muscles, platelet aggregation, etc. [NIH] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring

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secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH] Prostaglandins B: Physiologically active prostaglandins found in many tissues and organs. They are potent pressor substances and have many other physiological activities. [NIH] Prostaglandins D: Physiologically active prostaglandins found in many tissues and organs. They show pressor activity, are mediators of inflammation, and have potential antithrombotic effects. [NIH] Prostaglandins F: (9 alpha,11 alpha,13E,15S)-9,11,15-Trihydroxyprost-13-en-1-oic acid (PGF(1 alpha)); (5Z,9 alpha,11,alpha,13E,15S)-9,11,15-trihydroxyprosta-5,13-dien-1-oic acid (PGF(2 alpha)); (5Z,9 alpha,11 alpha,13E,15S,17Z)-9,11,15-trihydroxyprosta-5,13,17-trien-1oic acid (PGF(3 alpha)). A family of prostaglandins that includes three of the six naturally occurring prostaglandins. All naturally occurring PGF have an alpha configuration at the 9carbon position. They stimulate uterine and bronchial smooth muscle and are often used as oxytocics. [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] Prostatic Hyperplasia: Enlargement or overgrowth of the prostate gland as a result of an increase in the number of its constituent cells. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protective Agents: Synthetic or natural substances which are given to prevent a disease or disorder or are used in the process of treating a disease or injury due to a poisonous agent. [NIH]

Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein. EC 2.7.1.37. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proteoglycan: A molecule that contains both protein and glycosaminoglycans, which are a type of polysaccharide. Proteoglycans are found in cartilage and other connective tissues. [NIH]

Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Proteome: The protein complement of an organism coded for by its genome. [NIH]

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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] Proximal: Nearest; closer to any point of reference; opposed to distal. [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] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] 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] Pulmonary: Relating to the lungs. [NIH] Pulmonary Alveoli: Small polyhedral outpouchings along the walls of the alveolar sacs, alveolar ducts and terminal bronchioles through the walls of which gas exchange between alveolar air and pulmonary capillary blood takes place. [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 Circulation: The circulation of blood through the lungs. [NIH] Pulmonary Diffusing Capacity: The amount of a gas, usually oxygen or carbon dioxide, taken up by pulmonary capillary blood per minute per unit of average oxygen pressure gradient between alveolar gas and pulmonary capillary blood. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulmonary Embolism: Embolism in the pulmonary artery or one of its branches. [NIH] Pulmonary Fibrosis: Chronic inflammation and progressive fibrosis of the pulmonary alveolar walls, with steadily progressive dyspnea, resulting finally in death from oxygen lack or right heart failure. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] Pulmonary Veins: The veins that return the oxygenated blood from the lungs to the left atrium of the heart. [NIH] Pulmonary Ventilation: The total volume of gas per minute inspired or expired measured in liters per minute. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Pupil: The aperture in the iris through which light passes. [NIH] Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] Pyloric Stenosis: Obstruction of the pyloric canal. [NIH]

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Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quaternary: 1. Fourth in order. 2. Containing four elements or groups. [EU] 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] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Ramipril: A long-acting angiotensin-converting enzyme inhibitor. It is a prodrug that is transformed in the liver to its active metabolite ramiprilat. [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] Rarefaction: The reduction of the density of a substance; the attenuation of a gas. [NIH] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of

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diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Receptors, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reflex: An involuntary movement or exercise of function in a part, excited in response to a stimulus applied to the periphery and transmitted to the brain or spinal cord. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractory: Not readily yielding to treatment. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Regurgitation: A backward flowing, as the casting up of undigested food, or the backward flowing of blood into the heart, or between the chambers of the heart when a valve is incompetent. [EU] Relative risk: The ratio of the incidence rate of a disease among individuals exposed to a specific risk factor to the incidence rate among unexposed individuals; synonymous with risk ratio. Alternatively, the ratio of the cumulative incidence rate in the exposed to the cumulative incidence rate in the unexposed (cumulative incidence ratio). The term relative risk has also been used synonymously with odds ratio. This is because the odds ratio and relative risk approach each other if the disease is rare ( 5 percent of population) and the number of subjects is large. [NIH] Relaxin: Hormone produced by the ovaries during pregnancy that loosens ligaments that hold the hip bones together. [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

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cancer in the body. [NIH] Renal Artery: A branch of the abdominal aorta which supplies the kidneys, adrenal glands and ureters. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Renin: An enzyme which is secreted by the kidney and is formed from prorenin in plasma and kidney. The enzyme cleaves the Leu-Leu bond in angiotensinogen to generate angiotensin I. EC 3.4.23.15. (Formerly EC 3.4.99.19). [NIH] Renin-Angiotensin System: A system consisting of renin, angiotensin-converting enzyme, and angiotensin II. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. The converting enzyme contained in the lung acts on angiotensin I in the plasma converting it to angiotensin II, the most powerful directly pressor substance known. It causes contraction of the arteriolar smooth muscle and has other indirect actions mediated through the adrenal cortex. [NIH] Renovascular: Of or pertaining to the blood vessels of the kidneys. [EU] Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH] Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [NIH] Research Support: Financial support of research activities. [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] Respirator: A mechanical device that helps a patient breathe; a mechanical ventilator. [NIH] Respiratory distress syndrome: A lung disease that occurs primarily in premature infants; the newborn must struggle for each breath and blueing of its skin reflects the baby's inability to get enough oxygen. [NIH] Respiratory failure: Inability of the lungs to conduct gas exchange. [NIH] Respiratory Paralysis: Complete or severe weakness of the muscles of respiration. This condition may be associated with motor neuron diseases; peripheral nerve disorders; neuromuscular junction diseases; spinal cord diseases; injury to the phrenic nerve; and other disorders. [NIH] Respiratory Physiology: Functions and activities of the respiratory tract as a whole or of any of its parts. [NIH] Respiratory System: The tubular and cavernous organs and structures, by means of which pulmonary ventilation and gas exchange between ambient air and the blood are brought about. [NIH]

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Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Resuscitation: The restoration to life or consciousness of one apparently dead; it includes such measures as artificial respiration and cardiac massage. [EU] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinitis: Inflammation of the retina. It is rarely limited to the retina, but is commonly associated with diseases of the choroid (chorioretinitis) and of the optic nerve (neuroretinitis). The disease may be confined to one eye, but since it is generally dependent on a constitutional factor, it is almost always bilateral. It may be acute in course, but as a rule it lasts many weeks or even several months. [NIH] Retinitis Pigmentosa: Hereditary, progressive degeneration of the neuroepithelium of the retina characterized by night blindness and progressive contraction of the visual field. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It 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] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Retrovirus: A member of a group of RNA viruses, the RNA of which is copied during viral replication into DNA by reverse transcriptase. The viral DNA is then able to be integrated into the host chromosomal DNA. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series of complex reactions in response to visible light resulting in the transmission of nerve impulses to the brain. [NIH] Ribonuclease: RNA-digesting enzyme. [NIH] Ribonucleoside Diphosphate Reductase: An enzyme of the oxidoreductase class that

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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] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rod: A reception for vision, located in the retina. [NIH] Rolipram: A phosphodiesterase inhibitor with antidepressant properties. [NIH] Ryanodine: Insecticidal alkaloid isolated from Ryania speciosa; proposed as a myocardial depressant. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Saphenous: Applied to certain structures in the leg, e. g. nerve vein. [NIH] Saphenous Vein: The vein which drains the foot and leg. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] 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, 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]

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Scimitar Syndrome: Anomalous venous drainage of the right lung into the inferior vena cava, with hypoplasia of the right lung. The scimitar-shaped radiographic shadow of the anomalous vein gives the syndrome its name. [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] Second Messenger Systems: Systems in which an intracellular signal is generated in response to an intercellular primary messenger such as a hormone or neurotransmitter. They are intermediate signals in cellular processes such as metabolism, secretion, contraction, phototransduction, and cell growth. Examples of second messenger systems are the adenyl cyclase-cyclic AMP system, the phosphatidylinositol diphosphate-inositol triphosphate system, and the cyclic GMP system. [NIH] 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] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [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] Sella: A deep depression in the shape of a Turkish saddle in the upper surface of the body of the sphenoid bone in the deepest part of which is lodged the hypophysis cerebri. [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] Semicircular canal: Three long canals of the bony labyrinth of the ear, forming loops and opening into the vestibule by five openings. [NIH] 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] Septal: An abscess occurring at the root of the tooth on the proximal surface. [NIH] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU] Septicemia: Systemic disease associated with the presence and persistence of pathogenic microorganisms or their toxins in the blood. Called also blood poisoning. [EU] Septum: A dividing wall or partition; a general term for such a structure. The term is often used alone to refer to the septal area or to the septum pellucidum. [EU] Septum Pellucidum: A triangular double membrane separating the anterior horns of the lateral ventricles of the brain. It is situated in the median plane and bounded by the corpus callosum and the body and columns of the fornix. [NIH]

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Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Shedding: Release of infectious particles (e. g., bacteria, viruses) into the environment, for example by sneezing, by fecal excretion, or from an open lesion. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Shock, Septic: Shock due to circulatory insufficiency caused most commonly by gramnegative bacteremia. It is less often the result of the persistent presence of other microorganisms in the blood (fungemia, viremia); in rare instances, it is caused by gram-positive organisms, but with different symptomatology. [NIH] Shunt: A surgically created diversion of fluid (e.g., blood or cerebrospinal fluid) from one area of the body to another area of the body. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH]

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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] Sleep apnea: A serious, potentially life-threatening breathing disorder characterized by repeated cessation of breathing due to either collapse of the upper airway during sleep or absence of respiratory effort. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smoke Inhalation Injury: Pulmonary injury following the breathing in of toxic smoke from burning materials such as plastics, synthetics, building materials, etc. This injury is the most frequent cause of death in burn patients. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Sneezing: Sudden, forceful, involuntary expulsion of air from the nose and mouth caused by irritation to the mucous membranes of the upper respiratory tract. [NIH] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Social 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 Bicarbonate: A white, crystalline powder that is commonly used as a pH buffering agent, an electrolyte replenisher, systemic alkalizer and in topical cleansing solutions. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Sound wave: An alteration of properties of an elastic medium, such as pressure, particle displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] Spasm: An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. [NIH] Spasmodic: Of the nature of a spasm. [EU]

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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] Spectrophotometry: The art or process of comparing photometrically the relative intensities of the light in different parts of the spectrum. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spinal Cord Diseases: Pathologic conditions which feature spinal cord damage or dysfunction, including disorders involving the meninges and perimeningeal spaces surrounding the spinal cord. Traumatic injuries, vascular diseases, infections, and inflammatory/autoimmune processes may affect the spinal cord. [NIH] Spinal Stenosis: Narrowing of the spinal canal. [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] Splenomegaly: Enlargement of the spleen. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Stabilization: The creation of a stable state. [EU] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Status Epilepticus: Repeated and prolonged epileptic seizures without recovery of consciousness between attacks. [NIH] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stem cell 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 ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stenosis: Narrowing or stricture of a duct or canal. [EU] Stent: A device placed in a body structure (such as a blood vessel or the gastrointestinal

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tract) to provide support and keep the structure open. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] 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] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Streptococcal: Caused by infection due to any species of streptococcus. [NIH] Streptococcus: A genus of gram-positive, coccoid bacteria whose organisms occur in pairs or chains. No endospores are produced. Many species exist as commensals or parasites on man or animals with some being highly pathogenic. A few species are saprophytes and occur in the natural environment. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stricture: The abnormal narrowing of a body opening. Also called stenosis. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stupor: Partial or nearly complete unconsciousness, manifested by the subject's responding only to vigorous stimulation. Also, in psychiatry, a disorder marked by reduced responsiveness. [EU] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclavian: The direct continuation of the axillary vein at the lateral border of the first rib. It passes medially to join the internal jugular vein and form the brachiocephalic vein on each side. [NIH] Subclavian Artery: Artery arising from the brachiocephalic trunk on the right side and from the arch of the aorta on the left side. It distributes to the neck, thoracic wall, spinal cord, brain, meninges, and upper limb. [NIH] Subclavian Vein: The continuation of the axillary vein which follows the subclavian artery and then joins the internal jugular vein to form the brachiocephalic vein. [NIH] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Submaxillary: Four to six lymph glands, located between the lower jaw and the

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submandibular salivary gland. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] Suction: The removal of secretions, gas or fluid from hollow or tubular organs or cavities by means of a tube and a device that acts on negative pressure. [NIH] Sudden death: Cardiac arrest caused by an irregular heartbeat. The term "death" is somewhat misleading, because some patients survive. [NIH] Superior vena cava: Vein which returns blood from the head and neck, upper limbs, and thorax. It is formed by the union of the two brachiocephalic veins. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [NIH] 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] Supraventricular: Situated or occurring above the ventricles, especially in an atrium or atrioventricular node. [EU] Surfactant: A fat-containing protein in the respiratory passages which reduces the surface tension of pulmonary fluids and contributes to the elastic properties of pulmonary tissue. [NIH]

Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Symptomatology: 1. That branch of medicine with treats of symptoms; the systematic discussion of symptoms. 2. The combined symptoms of a disease. [EU] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but, according to the general view, there is no direct contiguity. [NIH]

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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] Systemic: Affecting the entire body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tachycardia: Excessive rapidity in the action of the heart, usually with a heart rate above 100 beats per minute. [NIH] Tachykinins: A family of biologically active peptides sharing a common conserved Cterminal sequence, -Phe-X-Gly-Leu-Met-NH2, where X is either an aromatic or a branched aliphatic amino acid. Members of this family have been found in mammals, amphibians, and mollusks. Tachykinins have diverse pharmacological actions in the central nervous system and the cardiovascular, genitourinary, respiratory, and gastrointestinal systems, as well as in glandular tissues. This diversity of activity is due to the existence of three or more subtypes of tachykinin receptors. [NIH] Tachyphylaxis: 1. Rapid immunization against the effect of toxic doses of an extract or serum by previous injection of small doses. 2. Rapidly decreasing response to a drug or physiologically active agent after administration of a few doses. [EU] Tachypnea: Rapid breathing. [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] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] 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]

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Thalidomide: A pharmaceutical agent originally introduced as a non-barbiturate hypnotic, but withdrawn from the market because of its known tetratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppresive and anti-angiogenic activity. It inhibits release of tumor necrosis factor alpha from monocytes, and modulates other cytokine action. [NIH] Theophylline: Alkaloid obtained from Thea sinensis (tea) and others. It stimulates the heart and central nervous system, dilates bronchi and blood vessels, and causes diuresis. The drug is used mainly in bronchial asthma and for myocardial stimulation. Among its more prominent cellular effects are inhibition of cyclic nucleotide phosphodiesterases and antagonism of adenosine receptors. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH] Third Ventricle: A narrow cleft inferior to the corpus callosum, within the diencephalon, between the paired thalami. Its floor is formed by the hypothalamus, its anterior wall by the lamina terminalis, and its roof by ependyma. It communicates with the fourth ventricle by the cerebral aqueduct, and with the lateral ventricles by the interventricular foramina. [NIH] Thoracic: Having to do with the chest. [NIH] Thoracic Surgery: A surgical specialty concerned with diagnosis and treatment of disorders of the heart, lungs, and esophagus. Two major types of thoracic surgery are classified as pulmonary and cardiovascular. [NIH] Thorax: A part of the trunk between the neck and the abdomen; the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thrombocytopenia: A decrease in the number of blood platelets. [NIH] 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] Thrombolytic Therapy: Use of infusions of fibrinolytic agents to destroy or dissolve thrombi in blood vessels or bypass grafts. [NIH] 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] 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] Thromboxanes: Physiologically active compounds found in many organs of the body. They

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are formed in vivo from the prostaglandin endoperoxides and cause platelet aggregation, contraction of arteries, and other biological effects. Thromboxanes are important mediators of the actions of polyunsaturated fatty acids transformed by cyclooxygenase. [NIH] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]

Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Tidal Volume: The volume of air inspired or expired during each normal, quiet respiratory cycle. Common abbreviations are TV or V with subscript T. [NIH] Tin: A trace element that is required in bone formation. It has the atomic symbol Sn, atomic number 50, and atomic weight 118.71. [NIH] Tinnitus: Sounds that are perceived in the absence of any external noise source which may take the form of buzzing, ringing, clicking, pulsations, and other noises. Objective tinnitus refers to noises generated from within the ear or adjacent structures that can be heard by other individuals. The term subjective tinnitus is used when the sound is audible only to the affected individual. Tinnitus may occur as a manifestation of cochlear diseases; vestibulocochlear nerve diseases; intracranial hypertension; craniocerebral trauma; and other conditions. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tolazoline: A vasodilator that apparently has direct actions on blood vessels and also increases cardiac output. Tolazoline can interact to some degree with histamine, adrenergic, and cholinergic receptors, but the mechanisms of its therapeutic effects are not clear. It is used in treatment of persistent pulmonary hypertension of the newborn. [NIH] 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] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tonus: A state of slight tension usually present in muscles even when they are not undergoing active contraction. [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] 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

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microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Tracer: A substance (such as a radioisotope) used in imaging procedures. [NIH] Traction: The act of pulling. [NIH] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transcutaneous: Transdermal. [EU] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] 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]

Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] 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] Triad: Trivalent. [NIH] Tricuspid Atresia: Absence of the orifice between the right atrium and ventricle, with the presence of an atrial defect through which all the systemic venous return reaches the left heart. As a result, there is left ventricular hypertrophy because the right ventricle is absent or not functional. [NIH] Tricuspid Valve: The valve consisting of three cusps situated between the right atrium and right ventricle of the heart. [NIH] Trophic: Of or pertaining to nutrition. [EU]

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Tropism: Directed movements and orientations found in plants, such as the turning of the sunflower to face the sun. [NIH] Tropomyosin: A protein found in the thin filaments of muscle fibers. It inhibits contraction of the muscle unless its position is modified by troponin. [NIH] Troponin: One of the minor protein components of skeletal muscle. Its function is to serve as the calcium-binding component in the troponin-tropomyosin B-actin-myosin complex by conferring calcium sensitivity to the cross-linked actin and myosin filaments. [NIH] 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] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tunica: A rather vague term to denote the lining coat of hollow organs, tubes, or cavities. [NIH]

Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [NIH] 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] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ulceration: 1. The formation or development of an ulcer. 2. An ulcer. [EU] Ulcerative colitis: Chronic inflammation of the colon that produces ulcers in its lining. This condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and mucus from the bowel. [NIH] Ultrasound test: A test that bounces sound waves off tissues and internal organs and changes the echoes into pictures (sonograms). [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] 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]

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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] Urokinase: A drug that dissolves blood clots or prevents them from forming. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] 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, 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] Valine: A branched-chain essential amino acid that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. [NIH]

Valves: Flap-like structures that control the direction of blood flow through the heart. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] Vascular Resistance: An expression of the resistance offered by the systemic arterioles, and to a lesser extent by the capillaries, to the flow of blood. [NIH] Vasculitis: Inflammation of a blood vessel. [NIH] Vasoactive: Exerting an effect upon the calibre of blood vessels. [EU] Vasoactive Intestinal Peptide: A highly basic, single-chain polypeptide isolated from the intestinal mucosa. It has a wide range of biological actions affecting the cardiovascular, gastrointestinal, and respiratory systems. It is also found in several parts of the central and peripheral nervous systems and is a neurotransmitter. [NIH] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilatation: A state of increased calibre of the 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] Vasodilator: An agent that widens blood vessels. [NIH] Vasodilator Agents: Drugs used to cause dilation of the blood vessels. [NIH] Vasomotor: 1. Affecting the calibre of a vessel, especially of a blood vessel. 2. Any element or agent that effects the calibre of a blood vessel. [EU] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH]

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Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Vena: A vessel conducting blood from the capillary bed to the heart. [NIH] Venoms: Poisonous animal secretions forming fluid mixtures of many different enzymes, toxins, and other substances. These substances are produced in specialized glands and secreted through specialized delivery systems (nematocysts, spines, fangs, etc.) for disabling prey or predator. [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] Ventilation: 1. In respiratory physiology, the process of exchange of air between the lungs and the ambient air. Pulmonary ventilation (usually measured in litres per minute) refers to the total exchange, whereas alveolar ventilation refers to the effective ventilation of the alveoli, in which gas exchange with the blood takes place. 2. In psychiatry, verbalization of one's emotional problems. [EU] Ventilator: A breathing machine that is used to treat respiratory failure by promoting ventilation; also called a respirator. [NIH] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Ventricular Dysfunction: A condition in which the ventricles of the heart exhibit a decreased functionality. [NIH] Ventricular Function: The hemodynamic and electrophysiological action of the ventricles. [NIH]

Ventricular Remodeling: The geometric and structural changes that the ventricle undergoes, usually following myocardial infarction. It comprises expansion of the infarct and dilatation of the healthy ventricle segments. While most prevalent in the left ventricle, it can also occur in the right ventricle. [NIH] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Verapamil: A calcium channel blocker that is a class IV anti-arrhythmia agent. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vertebral: Of or pertaining to a vertebra. [EU] Vertigo: An illusion of movement; a sensation as if the external world were revolving around the patient (objective vertigo) or as if he himself were revolving in space (subjective vertigo). The term is sometimes erroneously used to mean any form of dizziness. [EU] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Vestibule: A small, oval, bony chamber of the labyrinth. The vestibule contains the utricle and saccule, organs which are part of the balancing apparatus of the ear. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU]

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Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] 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] Visual field: The entire area that can be seen when the eye is forward, including peripheral vision. [NIH] Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Hemorrhage: Hemorrhage into the vitreous body. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Voltage-gated: It is opened by the altered charge distribution across the cell membrane. [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]

Whooping Cough: A respiratory infection caused by Bordetella pertussis and characterized by paroxysmal coughing ending in a prolonged crowing intake of breath. [NIH] Whooping Cough: A respiratory infection caused by Bordetella pertussis and characterized by paroxysmal coughing ending in a prolonged crowing intake of breath. [NIH] 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] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment

332

Pulmonary Hypertension

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] 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]

333

INDEX 4 4-Aminopyridine, 49, 243 A Abdomen, 138, 243, 255, 272, 286, 287, 290, 303, 304, 321, 322, 325 Abdominal, 138, 243, 267, 284, 294, 303, 315, 328 Abdominal Pain, 243, 328 Ablation, 36, 105, 243 Abortion, 243, 249 Abscess, 243, 318 Acceptor, 243, 302 Acclimatization, 19, 243 Acetaminophen, 243, 276 Acetic Acids, 139, 160, 243 Acetylcholine, 243, 260, 299, 300 Acidosis, 140, 144, 243, 247 Actin, 14, 179, 243, 297, 328 Action Potentials, 243 Acute renal, 136, 139, 243, 281 Adaptability, 243, 258 Adaptation, 60, 181, 243, 244, 299 Adduct, 135, 141, 244 Adenine, 152, 244 Adenocarcinoma, 244, 282 Adenosine, 29, 41, 133, 149, 151, 152, 156, 157, 158, 244, 306, 325 Adenosine Diphosphate, 152, 244 Adenosine Monophosphate, 152, 244 Adenosine Triphosphate, 29, 152, 244, 306 Adenovirus, 8, 21, 27, 180, 244 Adenylate Cyclase, 19, 158, 159, 176, 244 Adjustment, 244 Adrenal Cortex, 244, 245, 265, 273, 309, 315 Adrenal Medulla, 244, 257, 272, 300 Adrenergic, 7, 11, 19, 161, 244, 272, 323, 326 Adverse Effect, 38, 134, 138, 161, 244, 299, 319 Aerobic, 13, 244, 247, 273, 295 Aerosol, 26, 112, 166, 191, 244 Affinity, 24, 156, 244, 245, 290, 320 Afterload, 33, 38, 147, 245 Agar, 245, 307 Age Groups, 22, 245 Age of Onset, 245, 328 Aged, 80 and Over, 245

Aggravation, 133, 149, 245 Agonist, 11, 17, 157, 245, 266, 268, 299 Air Pollutants, 134, 245 Airway, 16, 18, 26, 73, 134, 146, 156, 175, 245, 293, 310, 320 Albumin, 245, 307 Aldosterone, 66, 168, 245 Algorithms, 245, 254 Alkaline, 243, 245, 246, 256, 303 Alkaloid, 47, 245, 261, 295, 299, 317, 325 Alkalosis, 4, 51, 245 Alleles, 22, 245 Allergen, 245, 266 Allergic Rhinitis, 156, 169, 170, 171, 181, 246, 280 Allograft, 21, 165, 166, 246 Alopecia, 246, 265 Alpha Particles, 246, 313 Alternative medicine, 191, 246 Alveoli, 246, 330 Ameliorating, 46, 52, 180, 246 Amine, 246, 282 Amino Acid Sequence, 246, 248, 274, 277 Amino Acid Substitution, 246, 281 Amino Acids, Peptides, and Proteins, 141, 246 Amlodipine, 116, 165, 177, 246 Ammonia, 246, 328 Amnion, 246 Amniotic Fluid, 166, 246, 278, 292, 301 Amplification, 185, 247 Amrinone, 161, 247, 295 Anaerobic, 123, 247 Anaerobic Threshold, 123, 247 Anaesthesia, 89, 247, 286 Analgesic, 53, 243, 247, 284, 295 Analog, 78, 91, 247, 252, 276, 284 Analogous, 35, 247, 269, 327 Anastomosis, 30, 247 Anatomical, 247, 251, 259, 263, 267, 285, 318 Androgenic, 165, 247 Anemia, 32, 87, 122, 125, 207, 247, 253, 296, 302, 324 Anemia, Sickle Cell, 125, 247 Anemic, 19, 247 Anesthesia, 8, 41, 90, 96, 245, 247, 270, 298 Anesthetics, 247, 252, 272

Pulmonary hypertension

Aneurysm, 247, 329 Angina Pectoris, 133, 136, 149, 153, 164, 165, 168, 246, 247, 289 Anginal, 133, 149, 248, 299 Angiogenesis, 8, 53, 56, 60, 66, 154, 248, 292 Angiography, 67, 98, 107, 109, 248 Angioplasty, 7, 68, 136, 137, 140, 142, 146, 152, 155, 169, 170, 174, 248, 297 Angiotensin converting enzyme inhibitor, 177, 193, 248 Angiotensinogen, 168, 248, 315 Animal model, 9, 36, 40, 43, 54, 248 Anions, 245, 248, 288, 323 Ankle, 178, 248 Anomalies, 41, 180, 248, 324 Anoxia, 137, 148, 248 Antagonism, 136, 248, 267, 325 Anterior Cerebral Artery, 248, 259 Antianginal, 248, 275 Antiarrhythmic, 248, 275 Antibacterial, 248, 321 Antibiotic, 248, 276, 304, 321, 324 Antibodies, 8, 21, 248, 249, 252, 272, 280, 283, 285, 291, 295, 307, 313 Antibodies, Anticardiolipin, 248, 249 Antibodies, Antiphospholipid, 249 Antibody therapy, 157, 249 Anticoagulant, 24, 249, 311 Antidepressant, 249, 317 Antidiuretic, 178, 249 Antigen, 244, 248, 249, 257, 262, 272, 278, 282, 283, 285, 286, 287, 293, 295 Antihypertensive, 172, 177, 249, 299 Anti-inflammatory, 53, 126, 177, 243, 249, 251, 278, 284, 309 Anti-Inflammatory Agents, 177, 249, 251 Antimetabolite, 249, 276, 294 Antineoplastic, 249, 265, 276, 283, 294, 299 Antineoplastic Agents, 249, 299 Antioxidant, 33, 52, 249, 302 Antiphospholipid Syndrome, 116, 248, 249 Antiproliferative, 9, 23, 249 Antipyretic, 53, 243, 249 Antithrombotic, 170, 171, 217, 218, 226, 227, 249, 311 Antiviral, 250, 304 Anuria, 250, 289 Anus, 92, 250, 251, 255, 262 Aorta, 7, 172, 250, 257, 264, 269, 284, 303, 315, 322, 330

334

Aortic Coarctation, 175, 250 Apnea, 45, 250 Apolipoproteins, 250, 290 Apoptosis, 7, 20, 24, 28, 43, 46, 52, 54, 56, 146, 250 Aqueous, 250, 253, 266, 270, 283, 290 Arachidonic Acid, 17, 39, 250, 269, 284, 290, 310 Arginase, 134, 135, 250 Arginine, 46, 51, 66, 87, 124, 135, 138, 152, 153, 154, 166, 178, 179, 188, 250, 299 Aromatic, 160, 250, 305, 324 Arrhythmia, 42, 154, 248, 250, 330 Arteriolar, 12, 158, 159, 250, 255, 275, 315 Arterioles, 178, 250, 254, 256, 294, 296, 329 Arteriolosclerosis, 250 Arteriosclerosis, 136, 180, 250 Arteriosus, 251, 312 Arteriovenous, 63, 103, 251, 294 Arteriovenous Fistula, 63, 103, 251 Arteritis, 138, 251 Arthrosis, 251, 292 Aseptic, 251, 301, 322 Aspartic, 151, 251 Aspartic Acid, 251 Asphyxia, 66, 138, 148, 251 Aspiration, 60, 251 Aspirin, 53, 193, 251 Assay, 26, 32, 122, 251, 285 Asymptomatic, 251, 253 Ataxia, 207, 251, 324 Atopic, 165, 166, 176, 177, 251 Atopic Eczema, 165, 166, 251 Atresia, 90, 251 Atrial, 12, 36, 38, 41, 64, 67, 85, 90, 96, 104, 112, 140, 144, 164, 168, 251, 264, 327 Atrial Fibrillation, 36, 140, 144, 164, 168, 251 Atrial Flutter, 164, 168, 251 Atrioventricular, 98, 251, 264, 323 Atrioventricular Node, 251, 323 Atrium, 251, 257, 264, 295, 312, 323, 327, 330 Atrophy, 206, 207, 252, 309 Attenuation, 252, 295, 313 Atypical, 81, 252 Auditory, 185, 252 Autoantibodies, 67, 82, 249, 252 Autoantigens, 252 Autoimmune disease, 47, 58, 134, 135, 249, 252, 296 Autonomic, 36, 243, 252, 300, 305, 323

335

Autonomic Nervous System, 252, 305, 323 Autopsy, 112, 252 Avian, 138, 252 Axillary, 252, 322 Axillary Vein, 252, 322 Azetidinecarboxylic Acid, 171, 252 B Bacteremia, 252, 319 Bacterial Physiology, 244, 252 Bacteriophage, 252, 307, 327 Barbiturate, 252, 325 Basal Ganglia, 251, 253 Basal Ganglia Diseases, 251, 253 Base, 10, 20, 177, 178, 244, 245, 253, 266, 277, 289, 324 Basement Membrane, 253, 274 Basilar Artery, 148, 253 Basophil, 177, 253, 282 Benign, 137, 148, 152, 169, 170, 250, 253, 280, 298, 313 Benign prostatic hyperplasia, 137, 253 Benzene, 253, 276 Beta-Thalassemia, 125, 253 Bilateral, 68, 69, 253, 316 Bile, 253, 276, 289, 290, 292, 322 Bile duct, 253 Bile Pigments, 253, 289, 292 Biliary, 184, 185, 253 Bilirubin, 245, 253, 283 Bioavailability, 156, 253 Biochemical, 7, 11, 15, 19, 22, 32, 40, 51, 55, 58, 60, 69, 155, 185, 245, 249, 253, 276, 289, 319 Biological therapy, 254, 279 Biomarkers, 31, 254 Biopsy, 254, 304 Biotechnology, 61, 64, 126, 191, 203, 205, 206, 207, 208, 254 Biphasic, 161, 254 Bladder, 169, 170, 253, 254, 262, 286, 296, 311, 328, 329 Blood Coagulation, 254, 256, 325 Blood Gas Analysis, 176, 254 Blood Glucose, 254, 281, 287 Blood Platelets, 254, 319, 325 Blood Substitutes, 32, 254 Blot, 7, 14, 57, 254 Body Fluids, 245, 254, 256, 269, 320, 328 Bone Marrow, 253, 254, 277, 285, 291, 296, 320, 321 Bone scan, 254, 317

Bowel, 136, 137, 138, 148, 150, 169, 170, 171, 181, 255, 267, 287, 322, 328 Bowel Movement, 255, 267, 322 Brachial, 176, 252, 255 Brachiocephalic Veins, 255, 323 Brachytherapy, 255, 287, 288, 313, 332 Bradycardia, 36, 255 Bradykinin, 255, 300, 307 Brain Stem, 255, 259 Branch, 101, 222, 237, 255, 270, 304, 312, 315, 321, 323, 325 Breakdown, 255, 267, 277, 301 Bronchi, 255, 272, 325 Bronchial, 10, 158, 255, 282, 311, 325 Bronchioles, 246, 255, 312 Bronchiolitis, 102, 147, 255 Bronchiseptica, 255, 305 Bronchitis, 113, 156, 169, 170, 171, 181, 255, 260 Bronchoconstriction, 156, 157, 158, 255 Bronchopulmonary, 4, 25, 55, 70, 127, 255 Bronchopulmonary Dysplasia, 4, 25, 55, 127, 255 Bronchus, 255 Bryostatin-1, 145, 255 Buccal, 53, 126, 255, 291 Bypass, 137, 138, 140, 142, 144, 256, 297, 325 C Calcification, 250, 256 Calcium channel blocker, 165, 177, 192, 193, 214, 246, 256, 299, 330 Calcium Channel Blockers, 192, 214, 256, 299 Calcium Channels, 19, 30, 256, 294 Callus, 256, 301 Calmodulin, 176, 256 Capillary, 12, 20, 80, 108, 116, 147, 180, 247, 255, 256, 278, 312, 330 Capsules, 256, 278 Captopril, 113, 256 Carbon Dioxide, 110, 123, 254, 256, 266, 277, 284, 306, 312, 315, 330 Carboxy, 146, 256 Carcinogen, 244, 256 Carcinogenic, 253, 256, 286, 301, 310, 322 Carcinoma, 256 Cardiac arrest, 127, 137, 148, 257, 323 Cardiac catheterization, 80, 240, 257 Cardiac Output, 33, 38, 41, 175, 180, 257, 280, 326 Cardiogenic, 137, 257

Pulmonary hypertension

Cardiolipins, 249, 257 Cardiomyopathy, 161, 181, 257 Cardiopulmonary, 9, 10, 13, 15, 52, 71, 78, 112, 115, 122, 127, 140, 144, 147, 257, 295 Cardiopulmonary Bypass, 140, 144, 147, 257 Cardiopulmonary Resuscitation, 127, 257 Cardiotonic, 247, 257, 268, 295 Cardiovascular disease, 21, 39, 52, 153, 165, 166, 257 Cardiovascular System, 19, 21, 166, 168, 174, 257 Carotene, 257, 316 Carrier Proteins, 257, 307 Case report, 94, 186, 257, 261 Cataracts, 257, 309 Catecholamine, 7, 133, 149, 257, 266, 268, 305 Catheter, 34, 36, 123, 155, 176, 192, 258, 270, 280, 288 Catheterization, 12, 34, 67, 98, 107, 123, 240, 248, 258, 288, 297 Caudal, 258, 267, 284, 308 Cause of Death, 155, 258, 320 Caveolae, 50, 258 Caveolins, 258 Cell Adhesion, 44, 258, 287 Cell Death, 20, 37, 58, 250, 258, 278 Cell Differentiation, 258, 319 Cell Division, 206, 252, 258, 279, 295, 306, 310, 318 Cell Lineage, 20, 258 Cell membrane, 256, 257, 258, 260, 266, 274, 288, 303, 306, 308, 331 Cell Membrane Structures, 258 Cell Physiology, 21, 258 Cell proliferation, 9, 16, 22, 24, 37, 43, 55, 115, 141, 142, 174, 180, 250, 258, 319 Cell Respiration, 258, 295, 315 Cell Size, 258, 276 Cell Survival, 8, 60, 258, 279 Cell Transplantation, 258 Central Nervous System Infections, 259, 280 Cerebellar, 251, 259, 314 Cerebellum, 138, 259, 308, 314 Cerebral Angiography, 259, 292 Cerebral Arteries, 19, 253, 259 Cerebral Cortex, 251, 259, 273 Cerebral Infarction, 136, 137, 148, 156, 259 Cerebrospinal, 259, 319 Cerebrospinal fluid, 259, 319

336

Cerebrovascular, 19, 253, 256, 257, 259, 299, 324 Cerebrum, 259, 328 Cervical, 165, 166, 259, 306 Cervix, 243, 259 Character, 247, 259, 266 Chelation, 142, 152, 259 Chemokines, 12, 259 Chemotherapeutic agent, 259, 268 Chemotherapy, 157, 218, 259 Chest Pain, 215, 220, 259 Chin, 259, 293 Chloride Channels, 28, 260 Cholesterol, 140, 142, 253, 258, 260, 264, 290, 291, 322 Cholesterol Esters, 260, 290 Cholinergic, 260, 299, 326 Chorioretinitis, 260, 316 Choroid, 260, 264, 316 Chromatin, 250, 260 Chromosomal, 144, 247, 260, 307, 316 Chromosome, 81, 82, 260, 290, 318 Chronic Disease, 193, 213, 260 Chronic renal, 134, 135, 136, 137, 148, 150, 154, 260, 308 Chylomicrons, 260, 290 Cilazapril, 77, 260 Ciliary, 10, 251, 260 Circadian, 224, 260 Circadian Rhythm, 224, 260 Cirrhosis, 137, 148, 154, 171, 181, 260, 308 CIS, 171, 260, 316 Clamp, 14, 40, 261, 303 Climacteric, 166, 261 Clinical Medicine, 32, 35, 71, 84, 261, 309 Clinical Protocols, 34, 261 Clinical study, 261, 264 Clinical trial, 4, 6, 21, 121, 128, 161, 203, 261, 263, 264, 268, 293, 296, 304, 312, 313 Clitoral, 170, 261 Clone, 41, 261 Cloning, 41, 254, 261 Clot Retraction, 261, 307 Coagulation, 78, 136, 249, 254, 261, 281, 307, 326 Cochlea, 261, 286 Cofactor, 261, 311, 325 Colchicine, 193, 261 Colitis, 261 Collagen, 8, 31, 44, 54, 171, 172, 181, 239, 246, 253, 261, 263, 274, 275, 292, 307, 310 Collapse, 255, 262, 308, 320

337

Colon, 39, 157, 206, 261, 262, 289, 328 Complement, 262, 277, 287, 292, 307 Compliance, 38, 63, 262 Compress, 262, 281 Computational Biology, 8, 203, 205, 262 Computed tomography, 122, 262, 317 Computerized tomography, 262 Conception, 243, 262, 275, 322 Concomitant, 24, 57, 263 Conduction, 152, 251, 263, 298 Cones, 263, 316 Confounding, 7, 53, 263 Congestion, 263, 273 Conjunctivitis, 263, 280 Connective Tissue Cells, 263 Connective Tissue Diseases, 97, 249, 263 Consciousness, 247, 263, 266, 268, 281, 312, 316, 321 Constitutional, 263, 316 Constriction, 35, 101, 263, 288, 329 Constriction, Pathologic, 263, 329 Consultation, 14, 263 Consumption, 32, 123, 127, 175, 263, 300, 303 Contamination, 26, 263 Continuous infusion, 77, 93, 127, 263 Contractility, 165, 166, 263 Contraindications, ii, 263 Contrast Media, 263, 292 Contrast medium, 248, 259, 263 Control group, 41, 263 Controlled clinical trial, 21, 264 Controlled study, 7, 264 Conus, 264, 312 Convulsions, 252, 264, 269, 309 Coordination, 18, 259, 264, 296 Cor, 42, 106, 112, 113, 171, 264 Cor pulmonale, 42, 106, 171, 264 Coronary Arteriosclerosis, 264, 296 Coronary Artery Bypass, 140, 264 Coronary Circulation, 248, 264, 300 Coronary heart disease, 153, 154, 155, 257, 264 Coronary Thrombosis, 264, 294, 296 Coronary Vessels, 181, 264 Corpus, 264, 304, 309, 318, 325, 331 Cortex, 264, 314 Corticosteroids, 265, 278, 309 Cortisol, 19, 245, 265 Cortisone, 265, 309 Cranial, 259, 265, 280, 301, 305

Craniocerebral Trauma, 253, 265, 280, 324, 326 Creatine, 140, 265 Creatine Kinase, 140, 265 Creatinine, 265, 289 Critical Care, 8, 33, 51, 65, 66, 69, 71, 73, 74, 76, 77, 82, 87, 91, 92, 100, 107, 116, 219, 265 Crossing-over, 265, 314 Cultured cells, 44, 265 Curative, 265, 325 Cutaneous, 193, 265, 291 Cyanosis, 265, 281, 293 Cyclin, 15, 24, 57, 265 Cyclophosphamide, 193, 265 Cystathionine beta-Synthase, 265, 283 Cytokine, 8, 15, 16, 47, 266, 325 Cytoplasm, 150, 250, 258, 266, 272, 279, 317 Cytoskeleton, 266, 287 Cytotoxic, 266, 313, 319 D De novo, 54, 266 Deamination, 266, 328 Decarboxylation, 266, 282 Defense Mechanisms, 166, 266, 287 Deferoxamine, 142, 266 Degenerative, 264, 266, 282, 316 Dehydration, 59, 266 Deletion, 46, 74, 250, 266 Delivery of Health Care, 266, 280 Dementia, 169, 170, 266 Dendrites, 266, 298 Density, 14, 17, 20, 49, 142, 180, 266, 276, 290, 301, 313, 320 Depolarization, 13, 35, 49, 266, 319 Depressive Disorder, 228, 266 Dermatitis, 176, 177, 266 Desensitization, 38, 266 Dexfenfluramine, 46, 266 Dextroamphetamine, 266, 305 Diabetes Mellitus, 32, 165, 166, 226, 267, 278, 281, 309 Diabetic Retinopathy, 165, 168, 267, 306 Diagnostic procedure, 131, 191, 267 Dialyzer, 267, 280 Diaphragm, 267, 306, 308 Diastole, 267 Diastolic, 5, 38, 102, 109, 178, 267, 284 Dichloroacetate, 140, 144, 267 Diencephalon, 267, 284, 325

Pulmonary hypertension

Digestion, 151, 253, 255, 267, 287, 290, 322, 329 Digestive system, 129, 267, 277, 296 Dihydroxy, 245, 267, 273 Dilatation, 77, 158, 182, 243, 247, 248, 267, 282, 309, 329, 330 Dilatation, Pathologic, 267, 329 Dilate, 133, 149, 267 Dilated cardiomyopathy, 52, 62, 76, 137, 161, 267 Dilation, 41, 139, 170, 178, 255, 267, 329 Dilator, 51, 267, 300 Diltiazem, 165, 267 Dimerization, 50, 267 Dimethyl, 24, 268, 289, 299 Dipyridamole, 117, 133, 149, 268 Direct, iii, 6, 7, 24, 38, 39, 40, 43, 44, 51, 55, 123, 142, 154, 182, 195, 247, 261, 268, 295, 314, 322, 323, 326 Disease Progression, 7, 268 Dissection, 219, 268 Dissociation, 244, 268 Distal, 26, 55, 170, 264, 268, 270, 312 Distention, 60, 268 Diuresis, 268, 325 Dobutamine, 62, 65, 268 Domesticated, 268, 279 Dorsal, 268, 308 Dose-limiting, 178, 268 Double-blind, 140, 268 Double-blinded, 140, 268 Drive, ii, vi, 7, 42, 111, 175, 268, 288 Drug Delivery Systems, 7, 268 Drug Design, 196, 197, 229, 268 Drug Interactions, 196, 269 Duct, 258, 269, 274, 303, 317, 321 Ductus Arteriosus, 6, 35, 269 Duodenum, 253, 269, 322 Dura mater, 269, 293, 303 Dysmenorrhea, 165, 166, 269 Dysmenorrhoea, 169, 170, 269 Dysphoric, 266, 269 Dysplasia, 25, 80, 207, 269 Dyspnea, 240, 269, 312 Dystocia, 165, 166, 269 Dystrophy, 206, 269 E Echocardiography, 76, 80, 82, 102, 103, 104, 107, 269 Eclampsia, 269, 309 Ectopic, 15, 269

338

Edema, 59, 68, 134, 135, 169, 170, 178, 240, 267, 269, 281, 297, 300, 309 Effector, 58, 243, 262, 269, 305 Effector cell, 269 Efficacy, 7, 21, 26, 27, 34, 46, 64, 78, 125, 126, 148, 156, 162, 178, 268, 269 Effusion, 72, 108, 269 Eicosanoids, 43, 115, 269 Elastic, 91, 269, 320, 323 Elasticity, 250, 264, 269 Elastin, 119, 261, 263, 269, 274 Elective, 269 Electric shock, 257, 270 Electrocardiogram, 122, 240, 270 Electrocoagulation, 261, 270 Electrode, 176, 270 Electrolyte, 10, 168, 245, 270, 289, 308, 320 Electrophysiological, 270, 330 Emboli, 97, 167, 270 Embolus, 270, 286 Embryo, 243, 246, 258, 270, 286, 302 Emphysema, 9, 147, 157, 260, 270 Emulsions, 245, 254, 270 Enalapril, 270 Enalaprilat, 112, 270 Encapsulated, 171, 270 Encephalitis, 24, 270 Encephalitis, Viral, 270 Encephalopathy, 185, 270 Endarterectomy, 248, 270 Endemic, 270, 321 Endocarditis, 216, 271 Endocardium, 271 Endocrine System, 271 Endocrinology, 56, 271 Endocytosis, 258, 271 Endogenous, 46, 48, 49, 58, 73, 133, 134, 136, 149, 152, 165, 169, 252, 269, 271, 302, 311, 327 Endothelins, 137, 150, 271 Endothelium, 14, 16, 17, 39, 40, 44, 48, 51, 53, 55, 92, 134, 141, 151, 154, 169, 271, 299, 307 Endothelium, Lymphatic, 271 Endothelium, Vascular, 271 Endothelium-derived, 14, 44, 134, 141, 151, 169, 271, 299 Endotoxic, 136, 137, 148, 150, 271, 290 Endotoxin, 63, 136, 271, 328 End-stage renal, 260, 271, 308 Enhancers, 133, 149, 271 Enoximone, 161, 271

339

Environmental Exposure, 272, 301 Environmental Health, 36, 202, 204, 272 Enzymatic, 9, 59, 132, 135, 163, 246, 256, 257, 262, 272, 275, 282, 316 Enzyme Inhibitors, 272, 307 Eosinophil, 177, 272 Eosinophilic, 272 Epidemic, 272, 321 Epidemiological, 31, 272 Epidermal, 166, 167, 272, 293, 295 Epidermal Growth Factor, 166, 167, 272 Epidermis, 272, 312 Epigastric, 272, 303 Epinephrine, 168, 244, 272, 299, 300, 328 Epithelial, 16, 18, 47, 55, 147, 244, 272, 282 Epithelial Cells, 47, 55, 272, 282 Epithelium, 16, 18, 55, 253, 271, 272, 277 Epitopes, 21, 272 Erectile, 133, 137, 138, 154, 272, 273, 304 Erection, 170, 272, 273, 309 Ergometer, 273 Ergometry, 83, 273 Erythema, 185, 273 Erythrocytes, 247, 254, 273, 314 Esophageal, 179, 273 Esophagus, 251, 267, 273, 277, 322, 325 Essential Tremor, 207, 273 Estradiol, 50, 273 Estrogen, 50, 154, 273 Estrogen receptor, 50, 273 Ether, 137, 273 Ethylene Glycol, 171, 273 Eukaryotic Cells, 273, 301, 328 Evoke, 273, 322 Excitation, 28, 251, 273, 275, 299 Excrete, 250, 273, 289 Exercise Test, 13, 214, 273 Exercise Tolerance, 123, 124, 273 Exhaustion, 248, 274 Exocrine, 274, 303 Exocytosis, 12, 58, 274, 282 Exogenous, 51, 256, 271, 274, 277, 311, 328 Exon, 11, 157, 274 Expiration, 274, 315 External-beam radiation, 274, 288, 313, 331 Extracellular, 21, 31, 43, 54, 58, 154, 168, 180, 263, 271, 274, 275, 287, 292, 320 Extracellular Matrix, 31, 43, 54, 168, 180, 263, 274, 275, 287, 292 Extracellular Matrix Proteins, 274, 292 Extracellular Space, 274

Extracorporeal, 41, 81, 274 Extracorporeal Membrane Oxygenation, 41, 81, 274 Extremity, 218, 274 Eye Infections, 244, 274 F Family Planning, 203, 274 Fat, 140, 250, 254, 257, 264, 270, 274, 290, 296, 309, 316, 323 Fatigue, 274, 280 Fatty acids, 152, 245, 269, 274, 292, 310, 326 Felodipine, 165, 274 Femoral, 123, 176, 257, 275 Femoral Artery, 176, 257, 275 Femur, 275 Fendiline, 165, 275 Fenfluramine, 49, 69, 72, 81, 112, 191, 266, 275 Fetal Blood, 50, 269, 275 Fetal Growth Retardation, 165, 166, 275 Fetus, 19, 35, 37, 50, 60, 243, 275, 292, 306, 309, 329 Fibril, 54, 275 Fibrillation, 36, 140, 275 Fibrin, 254, 261, 275, 307, 325, 326 Fibrinogen, 275, 307, 325 Fibrinolytic, 275, 325 Fibrinolytic Agents, 275, 325 Fibroblasts, 7, 16, 20, 44, 47, 146, 181, 263, 275, 287 Fibrosis, 7, 8, 10, 105, 134, 156, 157, 169, 170, 176, 181, 183, 188, 207, 275, 312, 317, 318 Fine-needle aspiration, 275, 297 Fistula, 186, 275 Flatus, 275, 277 Flow Cytometry, 9, 275 Fluorescence, 12, 32, 35, 275, 276 Fluorescent Dyes, 275, 276 Fluorouracil, 268, 276 Fold, 137, 150, 276, 294 Foramen, 63, 260, 276 Forearm, 254, 276 Fossa, 259, 276 Fractionation, 14, 276 Free Radicals, 142, 249, 268, 276, 297 Friction, 276, 291 Frontal Lobe, 248, 259, 276 Fructose, 140, 144, 276, 288 Fulminant Hepatic Failure, 185, 276 Fungemia, 276, 319

Pulmonary hypertension

G Gallbladder, 243, 253, 267, 276, 277 Gallopamil, 165, 276 Gamma Rays, 276, 313 Ganglia, 243, 253, 276, 298, 305, 323 Gas exchange, 83, 175, 247, 277, 312, 315, 330 Gastric, 136, 137, 148, 150, 176, 179, 272, 277, 282 Gastric Mucosa, 136, 137, 148, 150, 277 Gastrin, 277, 283 Gastroenterology, 185, 277 Gastrointestinal, 166, 193, 217, 255, 272, 277, 290, 319, 321, 323, 324, 328, 329 Gastrointestinal tract, 166, 193, 277, 290, 319, 322, 328 Gene Expression, 6, 10, 18, 23, 25, 27, 37, 43, 44, 45, 46, 47, 48, 49, 57, 59, 207, 277 Gene Targeting, 21, 277 Gene Therapy, 21, 26, 73, 88, 132, 155, 244, 277 Genetic Code, 277, 300 Genetic Engineering, 132, 254, 261, 277 Genetic testing, 22, 277 Genetics, 40, 62, 69, 80, 82, 85, 97, 277 Genital, 170, 277, 278, 329 Genitourinary, 278, 324, 329 Genotype, 66, 71, 92, 278, 305 Germ Cells, 278, 301, 302, 324 Germline mutation, 69, 278, 282 Gestation, 41, 60, 278, 304, 306 Gestational, 275, 278, 293 Gestational Age, 278, 293 Giant Cells, 278, 317 Gland, 244, 265, 278, 291, 303, 306, 311, 318, 322, 323, 326 Glomerular, 41, 164, 168, 278, 288, 289, 299, 315 Glomerular Filtration Rate, 41, 278, 289, 299 Glomeruli, 278 Glomerulonephritis, 154, 164, 168, 221, 278 Glomerulus, 278 Glottis, 278, 305 Glucocorticoid, 19, 278, 309 Glucose, 206, 254, 267, 278, 281, 286, 287, 317 Glucose Intolerance, 267, 278 Glucuronic Acid, 278, 281 Glutamic Acid, 279, 281, 299, 310 Glycine, 246, 279, 299

340

Glycoprotein, 43, 275, 278, 279, 325, 328 Glycosaminoglycans, 274, 279, 311 Gonadal, 279, 322 Gonads, 279, 284 Gout, 261, 279 Governing Board, 279, 309 Gp120, 279, 304 Graft, 21, 144, 279, 283, 285, 297 Grafting, 140, 264, 279, 285 Gram-negative, 255, 271, 279, 319 Gram-Negative Bacteria, 271, 279 Gram-positive, 279, 319, 322 Granule, 58, 279, 317 Granulocytes, 253, 279, 290, 319, 331 Growth factors, 24, 56, 142, 279 Guanylate Cyclase, 52, 117, 135, 176, 279, 300 Guinea Pigs, 24, 279 H Half-Life, 135, 144, 280, 284 Haplotypes, 11, 22, 280 Haptens, 245, 280 Hay Fever, 177, 246, 280 Headache, 177, 280 Headache Disorders, 280 Health Care Costs, 158, 280 Health Expenditures, 280 Heart Arrest, 257, 280 Heart attack, 142, 257, 280 Heart Catheterization, 12, 123, 240, 280 Heart Transplantation, 95, 104, 144, 280 Heartbeat, 144, 280, 323 Heart-Lung Transplantation, 172, 280 Hematoma, 280, 281 Heme, 23, 26, 59, 79, 253, 280, 281, 303 Hemodialysis, 137, 267, 280, 289 Hemodynamics, 52, 73, 89, 188, 281 Hemoglobin, 14, 41, 48, 52, 63, 123, 141, 175, 247, 253, 254, 265, 273, 280, 281, 324 Hemoglobin A, 14, 141, 175, 281 Hemoglobin E, 123, 281 Hemoglobin M, 123, 265, 281 Hemoglobinopathies, 277, 281 Hemoglobinuria, 206, 281 Hemolytic, 87, 247, 281, 324 Hemorrhage, 20, 96, 136, 137, 138, 148, 150, 156, 254, 265, 270, 280, 281, 297, 312, 322, 331 Hemorrhagic stroke, 137, 148, 281 Hemostasis, 78, 88, 281, 287, 319 Heparin, 23, 281 Hepatic, 157, 169, 170, 185, 245, 281, 290

341

Hepatic Encephalopathy, 185, 281 Hepatitis, 123, 276, 282 Hepatocellular, 157, 185, 282 Hepatocellular carcinoma, 157, 282 Hepatocytes, 282 Hepatopulmonary Syndrome, 185, 282 Herbicide, 153, 282 Hereditary, 32, 97, 263, 278, 279, 282, 316, 324 Hereditary mutation, 278, 282 Heredity, 277, 282 Hernia, 79, 98, 147, 282 Heterodimers, 282, 287 Heterogeneity, 9, 62, 83, 93, 245, 282 High-Frequency Jet Ventilation, 282 High-Frequency Ventilation, 63, 282 Histamine, 177, 282, 326 Histamine Release, 177, 282 Histidine, 282 Histology, 61, 282 Homeobox, 43, 282 Homeostasis, 11, 36, 43, 58, 159, 282 Homologous, 245, 265, 277, 282, 318, 324 Hormonal, 86, 168, 170, 252, 283 Hormone Replacement Therapy, 166, 224, 283 Host, 21, 252, 275, 283, 285, 290, 316, 331 Hybrid, 50, 88, 261, 283 Hybridomas, 283, 287 Hydrogen, 243, 246, 253, 274, 283, 295, 299, 302, 312, 323 Hydrogen Peroxide, 283, 323 Hydrolysis, 163, 176, 250, 251, 283, 288, 306, 311 Hydrophobic, 166, 283, 290 Hydroxylysine, 262, 283 Hydroxyproline, 246, 262, 283 Hydroxyurea, 46, 283 Hyperaldosteronism, 164, 283 Hyperbilirubinemia, 186, 283, 289 Hyperhomocysteinemia, 67, 141, 265, 283 Hyperoxia, 8, 9, 20, 23, 283 Hyperplasia, 22, 24, 46, 57, 88, 148, 165, 168, 180, 283 Hypersensitivity, 245, 266, 272, 283, 290, 316 Hypertension, Pulmonary, 10, 125, 127, 134, 135, 136, 137, 154, 157, 169, 170, 180, 284 Hypertension, Renovascular, 154, 284 Hypertonic Solutions, 59, 284

Hypertrophic cardiomyopathy, 105, 164, 168, 181, 284 Hypertrophy, 7, 54, 57, 77, 139, 146, 147, 152, 177, 180, 181, 253, 264, 283, 284, 295, 327 Hyperventilation, 51, 284 Hypnotic, 252, 284, 325 Hypoglycemia, 138, 148, 284 Hypogonadism, 185, 284 Hypoplasia, 166, 167, 284, 309, 318 Hypotension, 52, 66, 264, 284 Hypotensive, 172, 284 Hypothalamic, 19, 185, 284 Hypothalamus, 178, 252, 267, 284, 306, 325 Hypotrophy, 145, 284 Hypoventilation, 167, 284 Hypoxemia, 19, 41, 98, 99, 167, 220, 284 I Ibuprofen, 53, 284 Idiopathic, 31, 45, 145, 152, 178, 222, 228, 284, 317 Iliac Artery, 275, 284 Iloprost, 67, 72, 86, 87, 89, 90, 91, 93, 94, 107, 108, 114, 116, 188, 189, 191, 284 Immaturity, 167, 285 Immersion, 285, 297 Immune response, 21, 249, 252, 265, 280, 285, 292, 323, 331 Immune system, 179, 249, 254, 269, 285, 290, 291, 292, 296, 305, 329, 331 Immunization, 285, 309, 324 Immunoassay, 74, 248, 285 Immunodeficiency, 24, 72, 169, 170, 206, 213, 285 Immunodeficiency syndrome, 213, 285 Immunofluorescence, 285, 295 Immunogenic, 285, 290 Immunoglobulin, 248, 285, 295 Immunohistochemistry, 7, 285 Immunologic, 278, 285, 313 Immunology, 72, 82, 244, 276, 285 Immunosuppressant, 276, 285, 294 Immunosuppressive, 193, 265, 278, 285 Immunotherapy, 254, 266, 285 Impairment, 43, 95, 159, 251, 274, 285, 293, 294 Implant radiation, 285, 287, 288, 313, 332 Implantation, 155, 166, 262, 285 Impotence, 147, 165, 166, 179, 273, 285 In situ, 12, 159, 285 Incision, 285, 288 Incontinence, 165, 166, 169, 170, 286

Pulmonary hypertension

Incubation, 286, 289, 305 Incubation period, 286, 289, 305 Indicative, 183, 286, 304, 329 Induction, 12, 14, 23, 89, 112, 179, 286 Infancy, 41, 286 Infant, Newborn, 245, 286 Infarction, 39, 52, 136, 137, 138, 148, 150, 153, 164, 168, 177, 182, 214, 215, 223, 227, 259, 264, 268, 281, 286, 294, 296, 315, 330 Infection, 24, 70, 72, 89, 147, 165, 166, 251, 252, 254, 260, 270, 274, 285, 286, 289, 291, 304, 305, 316, 322, 331 Inferior vena cava, 61, 286, 318 Infertility, 165, 166, 286 Infiltration, 8, 278, 286 Infusion, 42, 65, 67, 94, 123, 127, 151, 152, 162, 190, 286, 297, 327 Ingestion, 286, 295, 308 Inhalation, 32, 67, 77, 91, 93, 95, 133, 143, 162, 163, 183, 244, 286, 308 Initiation, 28, 47, 49, 286, 327 Inner ear, 186, 286 Innervation, 19, 286 Inositol, 28, 286, 318 Inotropic, 140, 161, 247, 271, 274, 287, 295 Insight, 18, 25, 33, 58, 59, 287 Insulator, 287, 296 Insulin, 179, 287, 328 Insulin-dependent diabetes mellitus, 287 Integrins, 44, 287 Intensive Care, 27, 48, 123, 140, 287 Intensive Care Units, 27, 48, 140, 287 Interindividual, 11, 40, 287 Interleukin-6, 16, 47, 287 Intermittent, 45, 91, 287 Internal Medicine, 10, 24, 29, 68, 101, 105, 107, 112, 114, 116, 117, 271, 277, 287 Internal radiation, 287, 288, 313, 332 Interstitial, 20, 59, 96, 104, 119, 146, 167, 178, 193, 255, 274, 284, 287, 288, 315, 332 Intestinal, 64, 109, 137, 138, 139, 150, 165, 188, 257, 287, 292, 329 Intestinal Mucosa, 287, 329 Intestine, 255, 287, 289 Intoxication, 134, 287, 331 Intravascular, 27, 48, 78, 91, 136, 280, 288 Intravenous, 37, 42, 72, 94, 112, 114, 115, 123, 141, 152, 162, 193, 276, 286, 288 Intrinsic, 26, 245, 253, 282, 288 Intubation, 221, 258, 288 Inulin, 278, 288

342

Invasive, 34, 51, 140, 176, 288, 292 Involuntary, 253, 273, 275, 288, 297, 314, 320 Ion Channels, 6, 28, 30, 288 Ion Transport, 27, 288 Ionizing, 246, 272, 288, 313 Ions, 253, 256, 260, 268, 270, 283, 288, 308 Irradiation, 142, 288, 332 Ischemia, 133, 137, 148, 149, 150, 156, 252, 281, 288, 297, 315 Ischemic stroke, 179, 217, 288 Isoenzyme, 265, 289 Isozymes, 176, 289 Isradipine, 165, 289 J Jaundice, 185, 283, 289 Joint, 157, 222, 227, 251, 289, 323, 324 K Kb, 202, 289 Keto, 74, 289 Kidney Disease, 103, 125, 129, 202, 207, 223, 289 Kidney Failure, 171, 181, 271, 289 Kidney Failure, Acute, 289 Kidney Failure, Chronic, 289 Kinetics, 10, 61, 256, 289 L Labyrinth, 261, 286, 289, 302, 318, 330 Large Intestine, 267, 287, 289, 314, 320 Latent, 76, 289 Lentivirus, 21, 289 Lethal, 16, 41, 51, 125, 290 Leucocyte, 272, 290 Leukemia, 4, 206, 277, 290 Leukocytes, 17, 154, 254, 259, 279, 290, 328 Leukotrienes, 250, 269, 290 Library Services, 236, 290 Life cycle, 254, 290 Life Expectancy, 12, 290 Ligament, 290, 311 Ligands, 287, 290 Ligation, 103, 290 Linkage, 16, 93, 161, 290 Lipid, 57, 61, 63, 250, 258, 270, 287, 289, 290, 296 Lipid A, 61, 290 Lipophilic, 135, 290 Lipopolysaccharide, 112, 279, 290 Lipoprotein, 61, 142, 279, 290, 291 Liposome, 26, 171, 173, 290 Liver Cirrhosis, 171, 181, 290 Liver scan, 291, 317

343

Liver Transplantation, 99, 116, 291 Lobe, 93, 248, 259, 291, 303 Localization, 27, 285, 291 Localized, 33, 47, 50, 134, 135, 170, 243, 270, 280, 286, 291, 306, 307, 318, 328 Loop, 38, 282, 291 Low-density lipoprotein, 180, 290, 291 Lubricants, 291 Lubrication, 170, 291 Luciferase, 20, 291 Lumbar, 65, 291 Lumen, 7, 23, 54, 250, 271, 291 Lung Transplantation, 12, 69, 86, 93, 95, 103, 172, 191, 291 Lupus, 96, 116, 123, 165, 166, 248, 249, 291, 324 Lymph, 252, 259, 271, 291, 317, 322 Lymph node, 252, 259, 291, 317 Lymphatic, 271, 286, 291, 294, 320, 321 Lymphocyte, 58, 249, 291, 292, 293 Lymphoid, 248, 265, 290, 291 Lymphoma, 206, 291 Lysine, 171, 281, 283, 292 Lytic, 58, 292, 319 M Macrophage, 8, 83, 166, 172, 292 Magnetic Resonance Angiography, 92, 292 Magnetic Resonance Imaging, 5, 122, 292, 317 Maintenance therapy, 114, 292 Major Histocompatibility Complex, 280, 292 Malabsorption, 206, 292 Malformation, 41, 292 Malignancy, 141, 292 Malignant, 96, 105, 137, 138, 156, 206, 244, 249, 250, 292, 296, 298, 309, 313, 317 Malignant tumor, 292, 296, 309 Malnutrition, 245, 252, 292, 296 Mammary, 140, 264, 292 Manifest, 36, 133, 292 Matrix metalloproteinase, 31, 182, 292 McMaster, 112, 292 Mechanical ventilation, 41, 255, 292 Meconium, 66, 292 Meconium Aspiration, 66, 292 Medial, 26, 28, 31, 44, 48, 180, 250, 293, 301 Median survival time, 12, 293 Mediate, 7, 51, 57, 135, 138, 174, 178, 293 Mediator, 17, 158, 168, 293, 319 Medical Staff, 268, 293

Medicament, 145, 170, 171, 177, 180, 181, 293 MEDLINE, 203, 205, 207, 293 Melanin, 293, 305, 328 Melanocytes, 293 Melanoma, 157, 206, 293 Membrane Glycoproteins, 293 Membrane Proteins, 258, 293 Memory, 134, 135, 154, 266, 293 Meninges, 259, 265, 269, 293, 321, 322 Meningitis, 186, 293 Menopause, 166, 293, 308 Menstruation, 269, 293 Mental Disorders, 129, 293, 309, 312 Mental Health, iv, 4, 129, 202, 204, 227, 294, 309, 312 Mental Retardation, 208, 225, 294 Mercury, 275, 294 Mesenchymal, 18, 272, 294 Mesenteric, 174, 294, 308 Mesentery, 294 Metabolite, 162, 260, 268, 270, 294, 309, 313 Metaplasia, 94, 294 Metastasis, 292, 294 Methionine, 268, 294 Methotrexate, 193, 294 MI, 108, 136, 137, 148, 150, 155, 173, 178, 241, 294 Mibefradil, 165, 294 Microbe, 294, 327 Microbiology, 244, 252, 294 Microcirculation, 290, 294, 307 Microorganism, 261, 294, 303, 331 Micro-organism, 294, 306, 319 Microscopy, 8, 12, 253, 294 Migration, 7, 46, 142, 146, 168, 295 Milrinone, 161, 295 Mitochondria, 295, 297, 301 Mitosis, 250, 295 Mitral Valve, 77, 108, 295 Mixed Connective Tissue Disease, 109, 295 Mobility, 57, 295 Modeling, 33, 61, 269, 295 Modification, 172, 180, 246, 277, 295, 313 Modulator, 16, 43, 295 Molecule, 23, 25, 31, 54, 123, 135, 150, 166, 172, 179, 249, 253, 257, 262, 265, 268, 269, 271, 273, 279, 283, 295, 302, 303, 307, 311, 313, 314, 319, 327, 329 Monitor, 265, 295, 300

Pulmonary hypertension

Monoclonal, 37, 283, 288, 295, 313, 332 Monocrotaline, 11, 47, 54, 84, 116, 119, 295 Monocyte, 123, 172, 177, 180, 295 Monophosphate, 135, 169, 170, 295 Morphine, 295, 297 Morphology, 52, 295 Motility, 45, 165, 166, 169, 170, 179, 193, 295, 319 Motion Sickness, 296, 297 Mucilaginous, 292, 296 Mucosa, 147, 277, 291, 296 Mucositis, 296, 326 Mucus, 296, 328 Multicenter study, 7, 296 Multiple Myeloma, 103, 296 Multiple Organ Failure, 136, 296 Multiple sclerosis, 176, 243, 296 Muscle Fibers, 251, 296, 297, 328 Muscle Relaxation, 10, 39, 51, 256, 296, 298 Muscular Atrophy, 207, 296 Muscular Dystrophies, 269, 296 Mydriatic, 267, 296 Myelin, 296 Myelofibrosis, 94, 296 Myeloproliferative Disorders, 107, 296 Myocardial Ischemia, 138, 145, 148, 166, 247, 296 Myocardial Reperfusion, 296, 297, 315 Myocardial Reperfusion Injury, 297, 315 Myocarditis, 24, 189, 297 Myocardium, 52, 248, 294, 295, 296, 297 Myometrium, 19, 297 Myopathy, 168, 177, 297 Myosin, 14, 19, 297, 328 Myotonic Dystrophy, 207, 297 N Narcosis, 297 Narcotic, 123, 295, 297 Natriuresis, 168, 297 Nausea, 179, 297, 328 NCI, 1, 128, 201, 261, 297 Near Drowning, 147, 297 Needle biopsy, 216, 275, 297 Neonatal period, 3, 298 Neonatologist, 6, 30, 56, 298 Neoplasia, 206, 298 Neoplasm, 298, 317 Neoplastic, 283, 291, 298 Nephropathy, 154, 164, 168, 177, 289, 298 Nephrosis, 298 Nephrotic, 169, 170, 298

344

Nervous System, 134, 135, 141, 152, 166, 168, 185, 207, 243, 252, 253, 256, 259, 266, 277, 279, 290, 293, 295, 296, 298, 299, 301, 305, 308, 319, 323, 324, 325 Networks, 20, 44, 298 Neural, 36, 298 Neuroblastoma, 142, 298 Neurologic, 3, 179, 298 Neuromuscular, 219, 243, 298, 315 Neuromuscular Blockade, 219, 298 Neuromuscular Junction, 243, 298, 315 Neuromuscular Junction Diseases, 298, 315 Neuronal, 256, 297, 298 Neurons, 179, 266, 276, 298, 299, 323, 324 Neurophysiology, 266, 298 Neuroretinitis, 298, 316 Neurotoxic, 299 Neurotoxins, 185, 299 Neurotransmitter, 243, 244, 246, 251, 255, 279, 282, 288, 299, 300, 318, 319, 323, 329 Neutral Red, 135, 299 Neutrons, 246, 288, 299, 313 Neutrophil, 123, 299 Nicardipine, 165, 299 Nicotine, 299, 301 Nifedipine, 165, 299 Night Blindness, 299, 316 Nimodipine, 165, 299 Nisoldipine, 165, 299 Nitrendipine, 165, 299 Nitrogen, 48, 123, 162, 179, 185, 245, 246, 265, 274, 289, 300, 328 Nitrogen Dioxide, 162, 300 Nitrogen Oxides, 48, 300 Nitroglycerin, 77, 133, 149, 300 Norepinephrine, 7, 19, 168, 179, 244, 299, 300 Normotensive, 41, 300 Nuclear, 26, 33, 43, 57, 102, 225, 253, 273, 276, 295, 300 Nuclei, 178, 246, 248, 277, 292, 295, 299, 300, 301, 312 Nucleic acid, 157, 180, 277, 300 Nucleus, 248, 250, 252, 253, 260, 265, 266, 273, 276, 299, 300, 310, 312, 324 Nutritional Status, 216, 300 O Occult, 217, 300 Ocular, 80, 300 Odds Ratio, 300, 314 Odour, 250, 300

345

Oligohydramnios, 166, 301 Oliguria, 289, 301 Oncogene, 206, 301 Oncogenic, 287, 289, 301 Oocytes, 49, 301 Opacity, 257, 266, 301 Open Reading Frames, 289, 301 Opsin, 301, 316 Optic Chiasm, 284, 301 Optic Disk, 264, 267, 301 Optic Nerve, 298, 301, 303, 316 Organ Culture, 7, 301 Organ Transplantation, 229, 301 Organelles, 47, 266, 293, 301, 303, 307 Organogenesis, 18, 301 Orgasm, 170, 301 Osmolality, 179, 301 Osmoles, 301, 302 Osmotic, 245, 284, 301, 302 Ossicles, 302 Ossification, 302 Osteogenesis, 186, 302 Osteopetrosis, 96, 105, 302 Osteoporosis, 154, 165, 166, 302, 309 Otitis, 186, 302 Otitis Media, 186, 302 Otosclerosis, 186, 302 Outpatient, 121, 123, 302 Ovaries, 302, 314 Ovary, 273, 279, 302 Overdose, 276, 302 Ovulation, 166, 302 Ovum, 278, 290, 302, 309, 331 Oxidants, 32, 302 Oxidation, 21, 142, 154, 243, 249, 281, 302 Oxidation-Reduction, 302 Oxides, 48, 300, 303 Oxygen Consumption, 13, 175, 247, 272, 273, 303, 315 Oxygenase, 23, 59, 79, 303 Oxygenation, 46, 47, 167, 189, 281, 282, 284, 303 Oxygenator, 257, 274, 303 P Pachymeningitis, 293, 303 Palliative, 303, 325 Pancreas, 166, 243, 254, 267, 277, 287, 303, 328 Pancreatic, 157, 206, 303 Pancreatic cancer, 157, 206, 303 Parietal, 248, 303, 308 Parotid, 303, 317

Paroxysmal, 206, 247, 280, 303, 305, 331 Parturition, 50, 303 Patch, 14, 35, 40, 264, 303 Patch-Clamp Techniques, 35, 303 Patent ductus arteriosus, 66, 72, 303 Pathogen, 179, 286, 303 Pathogenesis, 13, 18, 22, 27, 30, 33, 43, 47, 55, 57, 58, 60, 62, 98, 106, 119, 146, 181, 189, 303 Pathologic, 10, 17, 243, 247, 250, 254, 264, 283, 304, 321 Pathologic Processes, 250, 304 Pathophysiology, 18, 29, 41, 46, 48, 51, 58, 60, 62, 69, 71, 142, 168, 185, 304 Patient Education, 213, 234, 236, 241, 304 Patient Selection, 114, 304 Pelvic, 304, 311 Pelvis, 243, 284, 286, 291, 302, 304, 329 Penicillamine, 192, 193, 304 Penicillin, 248, 304, 329 Penis, 170, 304, 309 Peptide, 36, 64, 109, 117, 135, 136, 137, 138, 146, 148, 150, 168, 188, 246, 304, 307, 311 Peptide T, 137, 138, 150, 304 Perceived risk, 22, 304 Percutaneous, 78, 136, 137, 142, 152, 174, 304 Perforation, 276, 304 Perfusion, 33, 40, 59, 102, 123, 178, 214, 225, 284, 304 Pericardial Effusion, 82, 304 Pericarditis, 24, 304 Pericardium, 304, 324 Perinatal, 6, 19, 25, 51, 56, 60, 94, 148, 186, 304 Perioperative, 21, 90, 215, 304 Peripheral blood, 10, 41, 105, 305 Peripheral Nervous System, 299, 305, 323, 329 Peripheral Vascular Disease, 32, 142, 143, 146, 168, 169, 170, 171, 177, 181, 305 Pertussis, 50, 70, 81, 96, 305, 331 Phagocyte, 302, 305 Pharmaceutical Preparations, 165, 305 Pharmacokinetic, 156, 172, 305 Pharmacologic, 6, 10, 19, 51, 57, 141, 247, 280, 305, 327 Pharmacotherapy, 38, 73, 305 Phenotype, 9, 15, 16, 25, 41, 43, 305 Phentermine, 49, 81, 112, 305 Phenyl, 145, 160, 162, 305 Phenylalanine, 305, 328

Pulmonary hypertension

Phosphodiesterase, 52, 65, 117, 133, 143, 144, 149, 161, 169, 171, 176, 247, 271, 295, 305, 306, 317 Phosphodiesterase Inhibitors, 143, 144, 169, 176, 177, 306 Phospholipases, 306, 319 Phospholipids, 249, 257, 274, 287, 290, 306 Phosphorus, 256, 306 Phosphorylated, 14, 306 Phosphorylation, 9, 14, 16, 26, 154, 306 Photocoagulation, 261, 306 Phototherapy, 157, 306 Phrenic Nerve, 306, 315 Physical Examination, 122, 125, 278, 306 Physiology, 7, 9, 28, 32, 44, 51, 56, 60, 69, 70, 74, 76, 78, 79, 80, 81, 83, 85, 92, 94, 95, 98, 100, 106, 108, 109, 110, 270, 271, 277, 298, 306, 315, 330 Pigments, 253, 257, 306, 307, 316 Pilot study, 6, 102, 306 Pituitary Gland, 168, 306 Placenta, 273, 275, 306, 309 Placental Insufficiency, 19, 306 Plants, 245, 251, 256, 278, 282, 288, 295, 299, 300, 306, 317, 327, 328 Plaque, 35, 248, 307 Plasma cells, 248, 296, 307 Plasma protein, 41, 245, 271, 307 Plasmid, 26, 307, 329 Plasmin, 100, 275, 307 Plasminogen, 181, 182, 275, 307 Plasminogen Activators, 307 Plastids, 301, 307 Platelet Activation, 307, 319 Platelet Aggregation, 17, 39, 179, 180, 272, 284, 300, 307, 310, 326 Platelet-Derived Growth Factor, 23, 307 Platelets, 15, 17, 106, 154, 166, 178, 300, 307, 325, 326 Platinum, 176, 291, 307 Plethysmograph, 175, 307 Pleura, 308 Pleural, 59, 308 Pneumonia, 11, 147, 263, 308 Pneumonitis, 24, 308 Pneumothorax, 293, 308 Poisoning, 287, 294, 297, 301, 308, 318 Polycystic, 207, 308 Polymers, 172, 308, 311 Polymorphism, 10, 22, 93, 308 Polysaccharide, 249, 308, 311 Pons, 253, 255, 308

346

Portal Hypertension, 31, 93, 308 Portal Vein, 308 Posterior, 178, 251, 253, 259, 260, 268, 303, 308 Postmenopausal, 154, 224, 302, 308 Postnatal, 47, 60, 186, 308, 321 Postoperative, 115, 138, 155, 218, 276, 296, 308 Postsynaptic, 298, 308, 319 Potassium, 40, 84, 243, 245, 308 Potassium Channels, 84, 243, 308 Potentiation, 308, 319 Practice Guidelines, 204, 214, 215, 219, 308 Precipitating Factors, 185, 280, 309 Preclinical, 24, 38, 163, 309 Precursor, 168, 248, 250, 265, 269, 272, 300, 305, 307, 309, 328, 329 Prednisolone, 309 Prednisone, 192, 309 Preeclampsia, 136, 137, 138, 148, 150, 165, 166, 309 Prenatal, 20, 41, 138, 186, 270, 309 Preoperative, 114, 225, 309 Prevalence, 42, 158, 300, 309 Priapism, 123, 309 Primary Prevention, 224, 309 Probe, 54, 309 Prodrug, 260, 309, 313 Progeria, 81, 309 Progesterone, 309, 322 Prognostic factor, 94, 310 Progression, 8, 9, 15, 21, 33, 38, 142, 177, 178, 182, 248, 310 Progressive disease, 12, 310 Projection, 266, 300, 301, 310, 314 Proline, 171, 252, 261, 283, 310 Promoter, 11, 22, 25, 49, 57, 59, 310 Prone, 61, 310 Prophase, 301, 310, 324 Prophylaxis, 156, 157, 310 Proportional, 301, 310 Prospective study, 72, 310 Prostaglandin, 6, 51, 74, 112, 113, 116, 127, 143, 163, 170, 171, 272, 310, 326 Prostaglandin Endoperoxides, 272, 310, 326 Prostaglandins A, 143, 163, 310 Prostaglandins B, 143, 163, 311 Prostaglandins D, 311 Prostaglandins F, 311 Prostate, 137, 138, 157, 206, 253, 254, 311, 328

347

Prostatic Hyperplasia, 311 Protease, 151, 311 Protective Agents, 256, 311 Protein Binding, 11, 311 Protein C, 10, 21, 24, 39, 47, 59, 245, 246, 250, 252, 290, 311, 328 Protein Kinases, 26, 311 Protein S, 22, 39, 146, 207, 254, 277, 311, 317, 324 Proteinuria, 165, 168, 296, 309, 311 Proteoglycan, 61, 311 Proteolytic, 182, 262, 275, 307, 311 Proteome, 26, 311 Protocol, 4, 31, 42, 123, 126, 312 Protons, 246, 283, 288, 312, 313 Proximal, 170, 268, 312, 318 Psychiatry, 42, 312, 322, 330 Psychic, 261, 293, 312, 318 Psychoactive, 312, 331 Public Health, 53, 170, 204, 312 Public Policy, 203, 312 Pulmonary Alveoli, 284, 312 Pulmonary Artery, 9, 15, 21, 22, 23, 26, 28, 30, 32, 33, 34, 35, 38, 45, 50, 52, 55, 57, 61, 73, 88, 92, 96, 100, 106, 115, 123, 164, 175, 214, 254, 269, 295, 303, 312, 330 Pulmonary Circulation, 5, 28, 29, 34, 44, 45, 47, 51, 56, 60, 113, 132, 133, 143, 178, 184, 284, 312 Pulmonary Diffusing Capacity, 113, 312 Pulmonary Edema, 11, 59, 65, 134, 289, 312 Pulmonary Embolism, 17, 215, 221, 312 Pulmonary Fibrosis, 9, 11, 212, 312 Pulmonary Veins, 36, 41, 312 Pulmonary Ventilation, 123, 284, 312, 315 Pulse, 34, 86, 175, 241, 295, 312 Pupil, 267, 296, 312 Purpura, 222, 312 Pyloric Stenosis, 165, 166, 312 Q Quality of Life, 5, 34, 38, 313 Quaternary, 147, 313 R Race, 295, 313 Radiation, 142, 157, 247, 272, 274, 276, 287, 288, 292, 313, 317, 331 Radiation therapy, 274, 276, 287, 288, 313, 332 Radioactive, 142, 255, 280, 283, 285, 287, 288, 291, 300, 301, 313, 317, 332 Radioimmunotherapy, 313

Radioisotope, 313, 327 Radiolabeled, 288, 313, 332 Radiological, 304, 313 Radiotherapy, 94, 255, 288, 313, 332 Ramipril, 167, 313 Randomized, 7, 46, 125, 269, 313 Randomized clinical trial, 46, 313 Rarefaction, 180, 313 Reactive Oxygen Species, 7, 12, 26, 48, 313 Reagent, 291, 314 Receptors, Serotonin, 314, 319 Recombinant, 11, 45, 173, 180, 314, 329 Recombination, 22, 132, 277, 314 Rectum, 250, 255, 262, 267, 275, 277, 286, 289, 311, 314 Recurrence, 260, 314 Red blood cells, 29, 32, 273, 281, 303, 314, 317 Red Nucleus, 251, 314 Reductase, 294, 314 Refer, 1, 140, 255, 262, 291, 299, 313, 314, 318, 327 Reflex, 167, 314 Refraction, 314, 321 Refractory, 63, 94, 270, 314 Regimen, 46, 52, 261, 269, 305, 314 Regurgitation, 82, 104, 314 Relative risk, 53, 314 Relaxin, 193, 314 Remission, 292, 314 Renal Artery, 284, 315 Renal failure, 136, 138, 160, 164, 168, 169, 170, 173, 315 Renin, 41, 66, 168, 248, 256, 315 Renin-Angiotensin System, 256, 315 Renovascular, 156, 315 Reperfusion, 190, 297, 315 Reperfusion Injury, 190, 315 Reproductive cells, 278, 282, 315 Research Support, 31, 315 Respiration, 73, 99, 113, 152, 156, 157, 250, 256, 295, 315, 316 Respirator, 292, 315, 330 Respiratory distress syndrome, 25, 112, 137, 147, 152, 157, 165, 166, 255, 315 Respiratory failure, 274, 282, 315, 330 Respiratory Paralysis, 4, 315 Respiratory System, 165, 166, 315, 329 Restoration, 296, 315, 316, 331 Resuscitation, 71, 257, 316 Retina, 72, 80, 260, 263, 264, 267, 298, 301, 316, 317

Pulmonary hypertension

Retinal, 65, 267, 301, 316 Retinitis, 186, 316 Retinitis Pigmentosa, 186, 316 Retinoblastoma, 206, 316 Retinol, 316 Retinopathy, 105, 154, 267, 316 Retroviral vector, 277, 316 Retrovirus, 21, 24, 316 Rheumatism, 67, 97, 284, 316 Rheumatoid, 58, 218, 302, 316 Rheumatoid arthritis, 58, 218, 316 Rhodopsin, 301, 316 Ribonuclease, 295, 316 Ribonucleoside Diphosphate Reductase, 283, 316 Ribose, 152, 244, 317 Ribosome, 317, 327 Risk factor, 36, 42, 53, 101, 126, 283, 310, 314, 317 Rod, 261, 317 Rolipram, 144, 177, 317 Ryanodine, 28, 317 S Salivary, 267, 303, 317, 323 Salivary glands, 267, 317 Saphenous, 61, 140, 264, 317 Saphenous Vein, 61, 140, 264, 317 Saponins, 317, 322 Sarcoidosis, 110, 317 Sarcoma, 24, 317 Scans, 22, 122, 317 Schizoid, 317, 331 Schizophrenia, 317, 331 Schizotypal Personality Disorder, 317, 331 Scimitar Syndrome, 65, 318 Scleroderma, 31, 67, 104, 105, 119, 164, 168, 192, 193, 213, 214, 250, 295, 318 Sclerosis, 79, 100, 112, 164, 168, 207, 250, 296, 318 Screening, 39, 50, 121, 156, 157, 161, 167, 226, 261, 318 Second Messenger Systems, 318 Secretion, 10, 260, 272, 282, 287, 296, 318, 329 Secretory, 152, 318 Sedative, 152, 252, 318 Segregation, 314, 318 Seizures, 303, 318, 321 Sella, 306, 318 Semen, 311, 318 Semicircular canal, 286, 318 Senescence, 36, 309, 318

348

Senile, 302, 318 Sepsis, 138, 147, 276, 318 Septal, 12, 64, 72, 90, 96, 105, 248, 318 Septic, 94, 137, 141, 148, 219, 251, 318 Septicemia, 185, 318 Septum, 90, 152, 251, 318 Septum Pellucidum, 318 Sequence Homology, 304, 319 Sequencing, 39, 319 Serologic, 285, 319 Serotonin, 22, 28, 45, 57, 62, 82, 88, 89, 93, 107, 189, 266, 275, 299, 305, 314, 319, 328 Serous, 271, 308, 319 Serum, 9, 47, 74, 92, 142, 245, 262, 265, 289, 291, 295, 319, 324, 328 Sex Determination, 207, 319 Shedding, 20, 319 Shock, 94, 116, 136, 137, 141, 147, 148, 150, 219, 319, 327 Shock, Septic, 150, 319 Shunt, 5, 66, 83, 90, 100, 123, 319 Side effect, 133, 149, 152, 157, 178, 195, 197, 244, 247, 254, 265, 268, 319, 326 Signal Transduction, 19, 22, 29, 39, 43, 57, 58, 161, 258, 287, 319 Signs and Symptoms, 121, 185, 314, 319 Skeletal, 261, 265, 296, 309, 319, 320, 328 Skeleton, 243, 275, 289, 310, 319, 320 Skull, 265, 320, 324 Sleep apnea, 42, 45, 68, 73, 92, 219, 320 Small intestine, 260, 269, 283, 287, 320 Smoke Inhalation Injury, 274, 320 Sneezing, 305, 319, 320 Social Environment, 313, 320 Social Support, 127, 320 Social Work, 124, 320 Sodium, 68, 86, 99, 140, 144, 245, 270, 272, 279, 297, 299, 320 Sodium Bicarbonate, 140, 144, 320 Solid tumor, 248, 320 Solvent, 253, 301, 302, 320 Somatic, 261, 295, 301, 305, 320 Sound wave, 263, 320, 328 Spasm, 192, 320 Spasmodic, 305, 320 Specialist, 230, 267, 321 Species, 33, 35, 57, 123, 135, 141, 146, 151, 258, 261, 268, 272, 279, 283, 290, 295, 301, 313, 319, 321, 322, 323, 327, 331 Specificity, 4, 18, 38, 54, 82, 133, 149, 176, 245, 256, 321 Spectrophotometry, 176, 321

349

Spectrum, 106, 177, 321 Sperm, 260, 278, 282, 315, 321 Spinal cord, 225, 255, 259, 260, 269, 293, 298, 303, 305, 309, 314, 315, 321, 322, 323 Spinal Cord Diseases, 315, 321 Spinal Stenosis, 65, 321 Spleen, 291, 317, 321 Splenomegaly, 115, 302, 321 Sporadic, 16, 22, 316, 321 Stabilization, 48, 55, 224, 321 Staging, 317, 321 Status Epilepticus, 138, 148, 321 Steel, 261, 321 Stem cell transplantation, 105, 321 Stem Cells, 321 Stenosis, 36, 64, 102, 108, 142, 146, 166, 321, 322 Stent, 154, 321 Sterility, 265, 286, 322 Steroid, 166, 265, 317, 322 Stimulant, 227, 266, 268, 282, 305, 322, 329 Stimulus, 29, 51, 56, 154, 263, 268, 269, 270, 273, 286, 288, 314, 322, 325 Stomach, 152, 243, 267, 273, 277, 283, 297, 320, 321, 322 Stool, 262, 286, 289, 322 Streptococcal, 62, 322 Streptococcus, 322 Stress, 6, 12, 22, 23, 37, 44, 45, 52, 55, 60, 100, 154, 157, 181, 252, 257, 265, 297, 316, 322 Stricture, 321, 322 Stroke, 36, 39, 129, 137, 138, 148, 153, 165, 166, 168, 169, 170, 177, 202, 257, 281, 288, 322 Stupor, 297, 322 Subacute, 8, 286, 322 Subarachnoid, 136, 137, 138, 148, 150, 156, 280, 322 Subclavian, 97, 252, 255, 322 Subclavian Artery, 322 Subclavian Vein, 97, 252, 255, 322 Subclinical, 286, 318, 322 Subcutaneous, 121, 269, 309, 322 Submaxillary, 272, 322 Subspecies, 321, 323 Substance P, 146, 294, 318, 323 Substrate, 51, 134, 169, 272, 323 Suction, 303, 323 Sudden death, 17, 181, 323 Superior vena cava, 99, 103, 255, 323 Superoxide, 45, 89, 153, 323

Superoxide Dismutase, 45, 323 Supplementation, 52, 144, 323 Support group, 228, 323 Suppression, 179, 323 Supraventricular, 164, 168, 323 Surfactant, 59, 74, 157, 173, 323 Sympathetic Nervous System, 7, 168, 252, 323 Sympathomimetic, 267, 272, 300, 305, 323 Symphysis, 260, 311, 323 Symptomatic, 13, 125, 323 Symptomatology, 319, 323 Synapse, 244, 298, 323, 324, 327 Synaptic, 299, 319, 324 Systemic lupus erythematosus, 91, 248, 249, 295, 324 Systolic, 5, 107, 109, 123, 178, 181, 284, 324 T Tachycardia, 36, 252, 268, 324 Tachykinins, 146, 324 Tachyphylaxis, 38, 324 Tachypnea, 252, 293, 324 Telangiectasia, 97, 192, 207, 324 Temporal, 16, 18, 25, 60, 93, 280, 324 Teratogenic, 267, 324 Testis, 273, 279, 324 Tetracycline, 16, 23, 324 Thalamic, 251, 324 Thalamic Diseases, 251, 324 Thalassemia, 253, 324 Thalidomide, 103, 193, 325 Theophylline, 177, 325 Therapeutics, 27, 116, 121, 122, 125, 133, 143, 161, 190, 196, 325 Thigh, 275, 325 Third Ventricle, 284, 325 Thoracic, 7, 64, 69, 73, 78, 88, 90, 91, 93, 95, 99, 108, 115, 145, 267, 308, 322, 325 Thoracic Surgery, 64, 69, 78, 90, 95, 115, 145, 325 Thorax, 98, 101, 216, 243, 291, 323, 325 Threonine, 304, 325 Threshold, 247, 283, 325 Thrombin, 275, 307, 311, 325 Thrombocytes, 307, 325 Thrombocytopenia, 247, 325 Thromboembolism, 164, 225, 227, 325 Thrombolytic, 217, 307, 325 Thrombolytic Therapy, 217, 325 Thrombomodulin, 89, 311, 325 Thrombopenia, 249, 325 Thromboses, 249, 325

Pulmonary hypertension

Thrombosis, 18, 73, 78, 88, 96, 97, 141, 153, 159, 176, 287, 311, 322, 325 Thromboxanes, 250, 269, 310, 325 Thrombus, 264, 286, 288, 296, 297, 307, 325, 326, 330 Thymidine, 9, 142, 157, 326 Thyroid, 326, 328 Tidal Volume, 284, 326 Tin, 307, 326 Tinnitus, 302, 326 Tolazoline, 92, 326 Tomography, 35, 113, 262, 317, 326 Tone, 10, 17, 23, 28, 30, 35, 43, 45, 51, 54, 58, 133, 145, 146, 149, 166, 300, 326 Tonus, 326 Tooth Preparation, 244, 326 Topical, 165, 166, 283, 320, 326 Torsion, 286, 326 Toxaemia, 309, 326 Toxic, iv, 112, 113, 144, 152, 153, 162, 253, 272, 295, 298, 299, 320, 324, 326, 327 Toxicity, 27, 39, 124, 153, 163, 171, 269, 294, 326 Toxicology, 16, 39, 40, 54, 204, 327 Toxin, 50, 271, 327 Tracer, 61, 327 Traction, 261, 327 Transcriptase, 316, 327 Transcription Factors, 15, 25, 26, 28, 43, 45, 47, 56, 57, 327 Transcutaneous, 108, 327 Transduction, 29, 30, 39, 319, 327 Transfection, 8, 25, 26, 27, 57, 132, 254, 277, 327 Transfusion, 122, 123, 327 Transgenes, 21, 327 Translation, 21, 139, 160, 246, 327 Translational, 21, 47, 327 Transmitter, 243, 288, 293, 300, 327 Transplantation, 5, 13, 21, 86, 95, 98, 99, 104, 105, 114, 144, 180, 222, 260, 285, 289, 292, 327 Trauma, 137, 148, 221, 224, 327 Triad, 282, 327 Tricuspid Atresia, 264, 327 Tricuspid Valve, 125, 327 Trophic, 7, 60, 327 Tropism, 18, 328 Tropomyosin, 328 Troponin, 19, 74, 328 Tryptophan, 262, 319, 328 Tuberous Sclerosis, 207, 328

350

Tumor marker, 254, 328 Tumor Necrosis Factor, 325, 328 Tunica, 270, 296, 328 Type 2 diabetes, 223, 328 Tyrosine, 14, 328 U Ubiquitin, 48, 328 Ulcer, 328 Ulceration, 137, 328 Ulcerative colitis, 138, 328 Ultrasound test, 125, 328 Unconscious, 247, 266, 284, 328 Urea, 97, 250, 289, 328 Uremia, 138, 289, 315, 328 Urethra, 253, 304, 311, 328, 329 Urinary, 165, 166, 278, 286, 301, 328, 329 Urinary tract, 301, 329 Urine, 249, 250, 253, 254, 265, 268, 272, 281, 286, 289, 297, 301, 311, 328, 329 Urogenital, 166, 278, 329 Urokinase, 181, 182, 329 Uterus, 170, 243, 259, 264, 293, 297, 302, 309, 329 V Vaccine, 312, 329 Vacuoles, 271, 301, 329 Vagina, 170, 259, 293, 329 Vaginal, 170, 291, 329 Valine, 304, 329 Valves, 167, 329 Vascular endothelial growth factor, 23, 37, 55, 60, 92, 329 Vasculitis, 146, 329 Vasoactive, 31, 46, 51, 64, 75, 109, 134, 135, 137, 138, 150, 158, 159, 168, 169, 188, 329 Vasoactive Intestinal Peptide, 158, 159, 329 Vasodilatation, 113, 329 Vasodilation, 23, 35, 40, 45, 50, 51, 52, 103, 135, 147, 151, 152, 159, 170, 174, 185, 270, 284, 329 Vasodilator Agents, 159, 329 Vasomotor, 17, 329 Vector, 18, 21, 26, 180, 327, 329 Vena, 61, 330 Venoms, 299, 330 Venous blood, 123, 167, 175, 259, 330 Venous Thrombosis, 218, 330 Ventilation, 47, 139, 178, 257, 282, 330 Ventilator, 292, 315, 330 Ventricle, 5, 103, 139, 178, 251, 264, 295, 312, 324, 325, 327, 330

351

Ventricular Dysfunction, 21, 62, 92, 164, 168, 330 Ventricular Function, 5, 37, 52, 115, 330 Ventricular Remodeling, 5, 330 Venules, 254, 256, 271, 294, 330 Verapamil, 165, 276, 330 Vertebrae, 321, 330 Vertebral, 253, 330 Vertigo, 302, 330 Vesicular, 251, 330 Vestibule, 261, 286, 318, 330 Veterinary Medicine, 203, 330 Viral, 22, 27, 38, 58, 132, 135, 270, 278, 301, 316, 327, 330, 331 Viral vector, 132, 331 Viremia, 319, 331 Virulence, 326, 331 Virus, 24, 72, 123, 132, 155, 252, 259, 271, 277, 278, 279, 307, 316, 327, 330, 331 Visual field, 301, 316, 331 Vitamin A, 286, 316, 331 Vitreous, 260, 267, 316, 331 Vitreous Hemorrhage, 267, 331

Vitro, 6, 7, 9, 11, 15, 16, 21, 23, 25, 26, 31, 33, 34, 36, 39, 40, 44, 48, 54, 55, 59, 60, 75, 132, 141, 142, 151, 156, 176, 177, 178, 277, 281, 285, 331 Vivo, 6, 7, 16, 18, 20, 21, 23, 25, 31, 36, 44, 48, 54, 55, 59, 142, 148, 150, 154, 156, 277, 281, 285, 302, 326, 331 Voltage-gated, 14, 30, 49, 331 W White blood cell, 249, 253, 290, 291, 292, 295, 296, 299, 307, 331 Whooping Cough, 305, 331 Withdrawal, 42, 331 Womb, 329, 331 Wound Healing, 287, 292, 331 X Xenograft, 248, 331 X-ray, 122, 240, 241, 262, 263, 276, 288, 300, 313, 317, 331 X-ray therapy, 288, 331 Y Yeasts, 305, 332 Z Zymogen, 311, 332

Pulmonary hypertension

352

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