HEMORRHAGIC STROKE A 3-IN-1 MEDICAL REFERENCE Medical Dictionary Bibliography & Annotated Research Guide TO I NTERNET
R EFERENCES
HEMORRHAGIC STROKE 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., 1960Hemorrhagic Stroke: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00529-8 1. Hemorrhagic Stroke-Popular works. I. Title.
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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.
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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on hemorrhagic stroke. 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 HEMORRHAGIC STROKE ........................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Hemorrhagic Stroke ...................................................................... 4 E-Journals: PubMed Central ....................................................................................................... 21 The National Library of Medicine: PubMed ................................................................................ 22 CHAPTER 2. NUTRITION AND HEMORRHAGIC STROKE ................................................................. 35 Overview...................................................................................................................................... 35 Finding Nutrition Studies on Hemorrhagic Stroke ..................................................................... 35 Federal Resources on Nutrition ................................................................................................... 36 Additional Web Resources ........................................................................................................... 37 CHAPTER 3. ALTERNATIVE MEDICINE AND HEMORRHAGIC STROKE ........................................... 39 Overview...................................................................................................................................... 39 National Center for Complementary and Alternative Medicine.................................................. 39 Additional Web Resources ........................................................................................................... 44 General References ....................................................................................................................... 46 CHAPTER 4. PATENTS ON HEMORRHAGIC STROKE........................................................................ 47 Overview...................................................................................................................................... 47 Patents on Hemorrhagic Stroke ................................................................................................... 47 Patent Applications on Hemorrhagic Stroke................................................................................ 49 Keeping Current .......................................................................................................................... 50 CHAPTER 5. PERIODICALS AND NEWS ON HEMORRHAGIC STROKE.............................................. 51 Overview...................................................................................................................................... 51 News Services and Press Releases................................................................................................ 51 Academic Periodicals covering Hemorrhagic Stroke.................................................................... 53 CHAPTER 6. RESEARCHING MEDICATIONS .................................................................................... 55 Overview...................................................................................................................................... 55 U.S. Pharmacopeia....................................................................................................................... 55 Commercial Databases ................................................................................................................. 56 APPENDIX A. PHYSICIAN RESOURCES ............................................................................................ 61 Overview...................................................................................................................................... 61 NIH Guidelines............................................................................................................................ 61 NIH Databases............................................................................................................................. 63 Other Commercial Databases....................................................................................................... 65 APPENDIX B. PATIENT RESOURCES ................................................................................................. 67 Overview...................................................................................................................................... 67 Patient Guideline Sources............................................................................................................ 67 Finding Associations.................................................................................................................... 69 APPENDIX C. FINDING MEDICAL LIBRARIES .................................................................................. 71 Overview...................................................................................................................................... 71 Preparation................................................................................................................................... 71 Finding a Local Medical Library.................................................................................................. 71 Medical Libraries in the U.S. and Canada ................................................................................... 71 ONLINE GLOSSARIES.................................................................................................................. 77 Online Dictionary Directories ..................................................................................................... 81 HEMORRHAGIC STROKE DICTIONARY............................................................................... 83 INDEX .............................................................................................................................................. 121
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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 hemorrhagic stroke 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 hemorrhagic stroke, 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 hemorrhagic stroke, 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 hemorrhagic stroke. 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 hemorrhagic stroke, 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 hemorrhagic stroke. The Editors
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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.
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CHAPTER 1. STUDIES ON HEMORRHAGIC STROKE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on hemorrhagic stroke.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and hemorrhagic stroke, 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 “hemorrhagic stroke” (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: •
Warning Issued on PPA Source: Healthy Weight Journal. 115(2):18. March/April 2001. Summary: The Food and Drug Administration (FDA) has issued a warning to remove phenylpropanolamine (PPA) from all diet and drug products. PPA is used in many over-the-counter weight loss products and in cough and cold medications. PPA increases the risk of hemorrhagic stroke, or bleeding into the brain. Yale University researchers found an increased risk of hemorrhagic stroke among women within 3 days of taking diet pills. FDA concludes that PPA is not safe for continued use, and although the risk of hemorrhagic stroke is low, use of these products does not warrant the increased risk.
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Preexisting Dementia in Stroke Patients: Baseline Frequency, Associated Factors, and Outcome Source: Stroke. 28(12): 2429-2436. December 1997. Summary: This journal article describes a study of the baseline frequency of dementia in stroke patients, associated factors, and outcomes. The participants were patients admitted to the acute stroke unit of the Lille University Hospital in Lille, France. A total of 202 patients with ischemic or hemorrhagic stroke, aged 42 to 101 years, were enrolled. The patients were assessed for preexisting dementia within 48 hours of stroke onset using a French translation of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Six months later, survivors underwent a battery of neuropsychological tests that assessed a range of cognitive functions, functional impairment, and psychiatric symptoms. Thirty-three patients had preexisting dementia according to the IQCODE; the dementia had been previously diagnosed in only one case. Logistic regression analysis revealed that female gender, a family history of dementia, leukoaraiosis, and cerebral atrophy were independently associated with preexisting dementia. All of the survivors with prestroke dementia met the criteria for dementia at the 6-month neuropsychological evaluation. The authors conclude that some patients with poststroke dementia may have had unrecognized preexisting dementia. 4 tables, 68 references.
Federally Funded Research on Hemorrhagic Stroke The U.S. Government supports a variety of research studies relating to hemorrhagic stroke. 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 hemorrhagic stroke. 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 hemorrhagic stroke. The following is typical of the type of information found when searching the CRISP database for hemorrhagic stroke: •
Project Title: A MOUSE MODEL OF CEREBRAL CAVERNOUS MALFORMATIONS Principal Investigator & Institution: Plummer, Nicholas W.; Molecular Genetics and Microbiology; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 01-DEC-2001 Summary: (Verbatim from the Applicant's Abstract) Cerebral cavernous malformations (CCM) are vascular abnormalities in the brain which cause migraines seizures, and hemorrhagic stroke. Recently, mutations in the RAP1A-interacting gene CCM1 (KRIT1)
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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).
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have been identified in dominant inherited CCM type1. We will develop an animal model of CCM by targeted mutation of the mouse Ccm1 gene. Insertion of a LacZ reporter gene in the Ccm1 locus will allow us to investigate the developmental and cellspecific expression pattern of CCm1. Using heterozygous mutant mice, we will test the "two-hit" hypothesis of lesion formation which predicts that the vascular malformation in heterozygous human patients are due to somatic mutation resulting in complete loss of CCM1 at the site of the lesion. The phenotype of homozygous mutant mice will illuminate unidentified functions of Ccm1 during vasculogenesis or development of other organs. Fibroblast cells cultured from mutant mice will be used to investigate the role of Ccm1 in cell proliferation a Rapla signaling pathways. These experiments will help to explain the formation of CCM in human patients and shed light on basic aspects of vascular morphology and development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AGING BRAIN--CEREBROVASCULAR MECHANISM & AMYLOID BETA Principal Investigator & Institution: Zlokovic, Berislav V.; Professor and Associate Chair; Neurosurgery; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-MAY-1999; Project End 30-APR-2004 Summary: This proposal represents investigators from the University of Southern California, Columbia University and State University of New York at Stony Brook Schools of Medicine who participate in a multi-disciplinary program on Cerebrovascular Mechanisms in the Aging Brain. The goal of the program is to advance current knowledge regarding the role of vasculature in the aging brain and major CNS disorders in elderly that predispose to cerebrovascular amyloidosis (e.g., Alzheimer's Disease and related amyloid-beta-peptide (Abeta) disorders, such as hereditary cerebral hemorrhage with amyloidosis Dutch type), Abeta-related vascular injury, brain damage and stroke. We will apply concepts and techniques developed in cerebrovascular biology, blood-brain barrier (BBB) and cerebrospinal fluid physiology, molecular biology, molecular genetics, transgene mice with age-dependent vascular risk factors, and tissues and cell cultures from patients diagnosed with AD. The program consists of five Research Projects and three Core resources. Project 1, Dr. Zlokovic will study the role of BBB and brain clearance in regulating Abeta concentrations in cerebral vessel wall and brain. Project the role of BBB and brain clearance in regulating Abeta concentrations in cerebral vessel wall and brain. Project 2, Dr. Van Nostrand will study Abeta production by cerebrovascular smooth muscle cells in relation to amyloidosis. Project, Dr. Stern will study the role of receptor for advanced glycation and end products in acute and chronic cerebrovascular perturbation caused by Abeta and strokerisk factors. Project 44, Drs. Schreiber and Zlokovic will delineate the roles of Abeta dn amyloid in vascular hemostasis in relation to ischemic or hemorrhagic stroke. Project 5, Drs. Kalra and Rhodin will study the role of Abeta in migration of monocytes across the BBB and vascular wall. Core A is the administrative facility. Core B, Dr. Mackic and Kim will provide animal and cell culture facility. Core C, Dr. Miller will provide neuropathologic analysis. The integrated and complementary scientific research projects will provide a molecular and therapeutic rationale to prevent accumulation of Abeta and formation of amyloid in cerebral blood vessels and brain, and counteract agedependent mechanisms responsible for abnormal vascular responses, injury and brain damage. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ANIMAL MODELS FOR CEREBRAL AMYLOID ANGIOPATHY Principal Investigator & Institution: Levy, Efrat; Nathan S. Kline Institute for Psych Res Psychiatric Research Orangeburg, Ny 10962 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 28-FEB-2007 Summary: A L68Q variant cystatin C forms the amyloid deposited in cerebral vessel walls of patients with hereditary cerebral hemorrhage with amyloidosis, Icelandic type. There are several indications that cystatin C also has a pathogenic role in Alzheimer's disease (AD), in cerebral amyloid angiopathy and in cerebral hemorrhage. A) Cystatin C colocalizes with amyloid beta in amyloid deposits in the brains of AD patients. The risk of cerebral hemorrhage increases in AD patients when high levels of cystatin C are present in cerebrovascular amyloid beta deposits. B) Cystatin C binds amyloid beta and its precursor and affects amyloid precursor protein processing. C) Both proteins accumulate in pyramidal neurons within the cerebral cortex. D) Recent genetic data suggest that the human cystatin C gene is a recessive risk gene for late-onset AD. We have generated lines of transgenic mice designed to provide disease models for cystatin C-cerebral amyloid angiopathy. High transgene expression was observed in the brain and plasma of these mice. Several aging transgenic mice overexpressing wild type or L68Q variant human cystatin C exhibited gross- or micro-hemorrhages but fibrillar amyloid deposits were not detectable in the brains of these mice. We hypothesize that accumulation of nonfibrillar cystatin C may contribute to hemorrhagic strokes. We propose to: 1) Characterize these transgenic mice, including: a) determination of cystatin C levels in the brains and peripheral tissues of young, mature, and aged mice; b) perform standard necropsies on a similar panel of mice, including immunostaining for cystatin C and amyloid deposition; c) seek evidence of macro- or micro-hemorrhages using appropriate staining techniques; 2) Study the mechanism by which high concentration of cystatin C causes hemorrhages: test the possibilities that cystatin C accumulation is toxic to vessel walls, alters coagulation and/or complement pathways, or both; and 3) Study the effect of cystatin C on amyloid beta deposition and cerebral hemorrhage in mice overexpressing human amyloid precursor protein, crossbred with cystatin C transgenic mice. The proposed animal models are crucial for understanding the etiology of cerebral amyloid angiopathy and hemorrhage and for the development of rational therapeutic interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BLOOD MARKERS OF ACUTE ISCHEMIC STROKE Principal Investigator & Institution: Sharp, Frank R.; Professor; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: The diagnosis of cute stroke is based upon clinical findings and brain imaging. Blood markers of acute ischemic stroke or tPA-induced hemorrhage would be useful for initiating early treatment with tPA (tissue plasminogen activator) and related agents. This proposal will examine white blood cell RNA expression following ischemic compared to hemorrhagic stroke because microarray technology can survey thousands of RNAs at one time and because transcriptional responses can be rapid. Moreover, preliminary data in rodents shows a unique genomic response of white blood cells one day following ischemic stroke and hemorrhagic stroke when compared to each other and when compared to controls. This proposal will demonstrate the blood genomic changes at 24h following ischemic strokes and intracerebral hemorrhages in patients that do or do not receive tPA. The first aim will use human oligonucleotide arrays to
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examine the white blood cell genomic response at 24h after ischemic stroke, 24h after intracerebral hemorrhages, and in age, race and sex-matched control patients without neurological disease. We will show that there is a specific blood genomic profile that correlates with ischemic strokes compared to intracerebral hemorrhage and control patients; and that there is a blood genomic profile that correlates with intracerebral hemorrhages as compared to control and ischemic stroke patients. The second aim will use olgionucleo9tide microarrays to examine the blood genomic response at 24H in ischemic stroke patients that receive tPA+ eptifibatide by 3 hours. The blood genomic expression patterns in patients with tPA associated hemorrhages will be compared to those without hemorrhages as assessed by CT/MRI. One of the long-term goals as to identify, among the genes induced at 24h following an ischemic stroke in order to be able to diagnose ischemic cerebral events between 2 and 24h after the stroke using a blood test. Another long-term goal is to identify a set of genes in peripheral white blood cells at 2h after stroke that would be associated with tPA-associated intracerebral hemorrhages that might help guide the dose or decision to give thrombolytics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CEREBRAL CONSUMPTION
MICROCIRCULATON
DURING
ALCOHOL
Principal Investigator & Institution: Mayhan, William G.; Professor; Physiology and Biophysics; University of Nebraska Medical Center Omaha, Ne 681987835 Timing: Fiscal Year 2002; Project Start 01-JAN-1999; Project End 31-DEC-2004 Summary: Chronic (heavy) consumption of alcohol has been recognized as a major contributing factor in the pathogenesis of many vascular diseases, including diseases of the brain. A large body of evidence suggests that chronic consumption of alcohol predisposes to the development of both hemorrhagic and thromboembolic stroke. Mechanisms by which chronic consumption of alcohol predispose to cerebrovascular abnormalities, including stroke, however, are not clear. The studies proposed in this application will determine the effects of chronic alcohol consumption on the cerebral microcirculation. The central hypothesis of this application is that chronic alcohol consumption predisposes to cerebrovascular abnormalities by altering cellular processes which modulate reactivity of cerebral blood vessels. To examine this central hypothesis, we will conduct two series of experiments. The first series of experiments will examine the temporal effect of chronic alcohol consumption on important cellular signaling pathways (nitric oxide synthase, ATP-sensitive potassium channels and adenylate cyclase which produce dilatation of cerebral arterioles. We will also determine the mechanisms which may account for impaired dilatation of cerebral arterioles during chronic alcohol consumption and examine the morphology of cerebral arterioles. The second series of experiments will examine the temporal effect of chronic alcohol consumption on the distribution of microvascular pressure in the cerebral circulation. We will examine the distribution of cerebral microvascular pressure under basal conditions and during changes in arterial pressure. We believe that these studies will provide the first comprehensive examination of the effects of chronic alcohol consumption on the cerebral microcirculation and will provide valuable insights into factors which contribute to the pathogenesis of cerebrovascular abnormalities, possibly ischemic and hemorrhagic stroke, during chronic alcohol consumption. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CEREBRAL MICROVASCULAR ENDOTHELIN PRODUCTION Principal Investigator & Institution: Yakubu, Momoh A.; Ctr/Cardiovascular Diseases; Texas Southern University 3201 Wheeler Ave Houston, Tx 77004 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 29-SEP-2004 Summary: (provided by the applicant): Cerebral hemorrhage is the main cause of abnormal cerebral arteriolar constriction resulting in cerebral ischemia that leads to paralysis, mental and physical disabilities, and deaths. Despite progress in the diagnosis of subarachnoid hemorrhage (SAH), SAH-induced cerebral vasospasm remains one of treatable causes of morbidity and mortality in patients. The mechanism(s) by which cerebral arterial narrowing occurs following hemorrhage remain largely unknown, but modification of cerebral microvascular responses is prominent, and characterized by impaired vasodilator and increased vasoconstrictor mechanisms in cerebral arteries. Several factors may contribute to the observed alterations of pial arteriolar reactivity. Increased endothelin-1 (ET-1) production has been consistently observed and ET-1 has been implicated as a possible mediator of cerebral hemorrhage-induced vasospasm. However, the mechanism(s) by which increased ET-1 production occurs are not known. The proposed experiments are designed to test the hypothesis that by-products of hemolyzed blood clots {oxyhemoglobin (OxyHb), lysophosphatidic acid (LPA), or serotonin (5-HT)} stimulate ET-1 production via activation of protein kinase C (PKC). To test this hypothesis, two specific aims will be addressed using primary culture of cerebral microvascular endothelial cells. 1) To characterize the effects of OxyHb, LPA, or 5-HT on El-I production and 2) to determine the cellular mechanism(s) by which these vasospasmogenic agents released from blood clots stimulate El-I production. To accomplish these aims, primary cell culture, molecular biological, immunoblotting, and immunoprecipitation techniques will be employed to investigate the mechanism(s) involved in the regulation of ET-1 production by these blood by-products. The results from the proposed research will have important therapeutic implications for survivors of SAH, who experience complications that include paralysis, mental and physical derangement, loss of sight and hearing. Our understanding of the mechanisms underlying the consequences of SAH will make it possible for early and appropriate intervention to prevent or reduce these complications from hemorrhagic stroke. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CONSTRAINT INDUCED MOVEMENT THERAPY IN SUBACUTE STROKE Principal Investigator & Institution: Grotta, James C.; Professor; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-AUG-2007 Summary: (provided by the applicant): SPECIFIC AIMS: 1. Evaluate the effects of two weeks of treatment with Constraint Induced Movement therapy (CIMT) combined with behavioral training of the paretic upper limb on motor recovery in patients with ischemic or hemorrhagic stroke who are initially treated within 14 days poststroke. 2. Investigate reorganization of cortical motor representation using transcranial magnetic stimulation (TMS) after two weeks of combined CIMT and behavioral training of the paretic upper limb in patients who begin treatment within 14 days after onset of ischemic or hemorrhagic stroke. 3. Using transcranial magnetic stimulation, investigate the relationship between changes in cortical representation and improvement in motor function of the affected upper limb in patients treated within 14 days after sustaining ischemic or hemorrhagic stroke. HYPOTHESES: 1. CIMT given daily for two weeks
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concomitant with behavioral training of the affected upper limb facilitates motor recovery relative to an equal number of sessions of traditional therapy in patients who are initially treated by day 14 after ischemic or hemorrhagic stroke. 2. Combined CIMT and behavioral training of the affected upper limb administered daily for 2 weeks beginning by day 14 post-stroke will increase cortical representation of the affected hand as measured by TMS. 3. Improved motor function of the affected upper limb will be related to the post treatment increase in cortical representation on TMS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORE--BLOOD AND TISSUE SPECIMEN Principal Investigator & Institution: Vinters, Harry V.; Professor and Chief; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-MAY-2008 Summary: (provided by the applicant): This Core will serve as a vital resource center for blood and tissue-based studies integral to the completion of investigational projects, related to aggressive, interventional treatment of cerebral hemorrhage and ischemic infarcts. It will bring to analyses of blood and tissues derived from study patients a wealth of expertise in morphoanatomical techniques pertinent to stroke pathogenesis, and provide access to key investigators of samples of brain tissue derived from biopsy and autopsy specimens of study patients. The core will support Project 1, the MR RESCUE trial, in which intravascular thrombus material will be removed in the course of therapeutic thrombectomy. The core will assist investigators studying the biochemical pathogenesis of thrombus formation, and its possible importance in evolution of cerebral infarcts, and will assist investigators in correlating their findings with light microscopic/ultrastructural features of the thrombi. The core will also provide support to Project 2, the HEME Surgery trial, in which brain tissue originating from 'clot' evacuations carried out in patients with spontaneous intracerebral (parenchymal) hemorrhage will be carefully evaluated for both the likely etiology of hemorrhage and the tissue response to intracerebral blood, and readied for studies of differential gene expression employing qualitative, real-time RT-PCR and cDNA arrays. The Core will store blood samples from appropriate patients for DNA analysis, and provide these to researchers following appropriate review of their investigational goals and projects. The Core will serve as an important 'blood and brain tissue' resource to SPOTRIAS investigators at UCLA, and a larger network of investigators with interests in the treatment of acute ischemic and hemorrhagic stroke. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DIETARY PATTERNS AND RISK OF CARDIOVASCULAR DISEASE Principal Investigator & Institution: Hu, Frank B.; Nutrition; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-AUG-1998; Project End 31-JAN-2005 Summary: This new application presents plans to study, prospectively, the association between dietary patterns and risk of coronary heart disease (CHD), ischemic stroke, and hemorrhagic stroke in cohort studies of 121,700 women age 30 to 55 years at baseline in 1976 (the Nurses; Health Study; NHS) and 51,529 men aged 40-75 years at baseline in 1986 (the Health Professionals Follow-up Study; HPFS). Food consumption data were collected through semiquantitative food frequency questionnaires at baseline and during follow-up in each of the cohorts. Dietary patterns are derived from the food consumption data using factor analysis, cluster analysis, and dietary indexes (based on
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prevailing dietary recommendations). In addition, using existing datasets from dietary validation studies in sub-samples of the two cohorts, the investigators propos to evaluate the reproducibility and validity of dietary patterns defined by factor/cluster analysis and dietary indexes. Further, using prospectively collected and stored bloods in the NHS (n-32, 826) during 1989-1990 and the HPFS (n-18, 000) during 1993-1994, we propose to examine whether observed associations between dietary patterns and CHD are explained by (or mediated through) plasma biochemical measurements (including serum lipids, thrombotic factors, antioxidants, fasting insulin, and homocysteine levels) in a nested case-control design; and they propose to assess prospectively the relationship between dietary patterns and these biomarkers in the control samples. The funded NHS and HPFS will provide follow-up and documentation of CHD and stroke in addition to covariate information. Assays of biomarkers in the two cohorts are funded through other grants. Overall, the large size of these cohorts, the prospective design, the high follow-up rates, and the availability of archived blood specimens provide a unique opportunity to study the relationship between overall dietary patterns and cardiovascular disease in an extremely cost-efficient manner. This would be the first study to characterize dietary patterns in large cohorts of men and women and relate dietary patterns to CHD and stroke. Finally, this project will enable evaluation of prevailing dietary recommendations in relation to both biomarkers of risk as well as clinical cardiovascular diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENE MALFORMATIONS
DISCOVERY
FOR
CEREBRAL
CAVERNOUS
Principal Investigator & Institution: Marchuk, Douglas A.; Associate Professor; Molecular Genetics and Microbiology; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: (provided by the applicant): Cerebral cavernous malformations (CCMs) of the brain are vascular lesions, which are present in up to 0.4% of the general population and often are accompanied by seizures, migraine, hemorrhagic stroke and other neurological outcomes. These lesions can occur sporadically, or as an autosomal dominant trait. Our group has recently identified the CCM1 gene, which is responsible for the majority of all familial CCMs and principally the cause for the familial form of CCMs in the Hispanic population (Sahoo et al., 1999). With the discovery of the CCM1 gene, we have developed a significant insight into the pathology of this "familial stroke." There are two additional CCM genes that remain to be identified, CCM2 on chromosome 7p and CCM3 on chromosome 3q. We will utilize our previously successful approach for positional cloning, which employs a strong computational approach to transcript identification in order to identify positional candidates for sequencing. We believe that the resources will have accumulated and the approach we have established will allow us to identify the genes for CCM2 and CCM3. After identifying the genes responsible for CCM2 and CCM3, we will begin to investigate their role in the cell, and in particular, their role in the pathophysiology of CCM. These types of experiments include overall protein expression patterns in the embryo and the adult, cellular compartment localization studies, and a search for interacting proteins using the yeast two-hybrid screen. These data will provide the molecular/cellular framework from which to launch a more detailed analysis of these proteins in a future proposal. Our ultimate objective is to aid in understanding the fundamental mechanisms responsible for different forms of familial neurovascular disease. The availability of a model, where the primary genetic determinates have been identified
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unambiguously, will greatly expedite the search for the basic mechanisms involved in "familial stroke" and to a better understanding of neurovascular disease, in general. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HELICOPTER TRANSPORT AND OUTCOME IN HEMORRHAGIC STROKE Principal Investigator & Institution: Bear, Taylor C.; Akron General Medical Center 400 Wabash Ave Akron, Oh 44307 Timing: Fiscal Year 2003; Project Start 01-SEP-2003 Summary: (provided by applicant): Since its introduction into civilian medicine in the early 1970's, the helicopter has made significant improvements in the care of patients, particularly in rural or isolated areas. The benefit and improved outcomes have been largely demonstrated in victims of trauma or patients suffering acute myocardial infarction. The role of aeromedical transport in non-traumatic hemorrhagic stroke is unknown. This is a retrospective, multi-center, cohort study designed to evaluate the outcome, interventions, and procedural care after helicopter transport in non-traumatic hemorrhagic stroke. Study groups include helicopter-transported (HT) patients with SAH or sICH, which will be compared with non-helicopter-transported (NHT) patients with SAil or sICH. Helicopter-transported patients are selected from a recently completed database of stroke patients transported by on helicopter program. HT and NHT patients will be matched on appropriate socio-demographic variables and diseasespecific indices including GCS grade scores and location of hemorrhage in sICH patients. Charts will be reviewed for TISS scores, hospital procedures, and DNR status. Thirty-day mortality will be determined using the social security death index and state death records. Estimated sample size is 400 patients. Primary endpoint is to determine mortality between HT and NHT patients. Additional endpoints include study of TISS scores, number and type of procedures and the role of DNR in these two patient groups. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: INFLAMMATION MARKERS OVER TIME IN CARDIOVASCULAR DISEASE Principal Investigator & Institution: Tracy, Russell P.; Professor; Pathology; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405 Timing: Fiscal Year 2002; Project Start 13-APR-1992; Project End 30-NOV-2003 Summary: The majority of myocardial infarction and stroke events occur in those over the age of 65. We have demonstrated during the previous grant period that measures of subclinical cardiovascular disease (CVD) and markers of inflammation and blood clotting are powerful risk factors for clinical CVD, myocardial infarction (MI) and CHD death in individuals aged 65+. We believe that measurements of these factors in proximity to the event, together with measures of subclinical disease, will significantly improve the identification of those older individuals most likely to have a clinical CVD event. We have three specific aims: 1) to measure markers of inflammation, such as fibrinogen, C-reactive protein, and ICAM-1 in sequential samples from the Cardiovascular Health Study, representing years 2, 5, 6, 7, 9, 10 of the study; 2) to measure in the same way selected cytokines and cytokine-related factors, such as IL-6, IL-1b and soluble IL-2 receptor; and 3) to measure in the same way markers of hemostatic and fibrinolytic activation, such as factor V/Va. Plasmin-a2 Anti-plasmin Complex, and D-dimer. We will evaluate each of the chosen markers as a risk factor for three outcomes: incident coronary heart disease (CHD) including fatal and non-fatal
12
Hemorrhagic Stroke
non-hemorrhagic stroke; and incident cancer of the breast, lung, colon and prostate. With these data we will test two major hypotheses: 1) prediction of events is stronger when measurements are done closer in time ( 1 year); and 2) changes in the levels of markers over time (e.g., between baseline and the most proximate measure, or between the two most proximate measures) will be better predictors of events than a single measurement. We believe that markers will be more closely associated with MI and CHD death than with other manifestations of atherosclerotic disease such as stroke. Since there is growing evidence that inflammatory markers are related to risk of cancer, the cancer comparison group will provide information as to the specificity of these markers for CHD. It is likely our results will have important implications for prevention, diagnosis, and future therapeutic interventions in cardiovascular disease in the elderly. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MELANOCORTIN SIGNALING IN HYPERTENSION Principal Investigator & Institution: Wachira, James; Morgan State University Baltimore, Md 21251 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 28-FEB-2007 Summary: The long-term objectives of this study are to better understand the role of the brain in hypertension. Hypertension is a major contributor to health disparity among minorities and a major cause for both ischemic or hemorrhagic strokes and chronic brain injury. Currently, the causes for most cases of essential hypertension as well as changes in brain signal tranduction pathways during hypertension are not well understood. However, an aberration in neural blood-pressure control mechanisms is known to be necessary for the persistence of raised blood pressure. Melanocortins have been implicated in autonomic control of blood pressure with gamma-2-MSH demonstrating the highest potency in increasing blood pressure and heart rate. Previous studies have also demonstrated an increase in intracellular Ca2+ and protein kinase C (PKC) translocation in rat brain-stem synaptosomes treated with gamma-2-MSH. Modulation of the PKC signaling pathway by gamma-2-MSH was also observed in a brain-stem neuronal cell line transfected with a neural melanocortin receptor, MC3-R. This study will test the hypothesis that melanocortins function in autonomic neurons by modulating signal transduction systems that are coupled to specific neurotransmitter systems. The first aim is to identify changes in neural melanocortin signal transduction in stroke-prone spontaneous hypertensive rat (SHR-SP) brain. Hypothalamus and brain stem slices from SHR-SP and control Wistar Kyoto (WKY) rats will be treated with melanocortins in the presence of agonists for putative melanocortin-sensitive neurotransmitter systems (adrenergic, serotonergic and dopaminergic) and the phosphorylation patterns of total proteins and specific signal transduction components analyzed. Secondly, changes in second messenger molecules will be assayed using ELISA/RIA procedures. The second aim will seek to characterize signaling through the melanocortin 3-receptor (MC3-R) in vitro. Similar studies will be performed in MC3-R trasfected neuronal cells, followed by the analysis of expression and activation of protein kinase A (PKA), protein kinase B (PKB) and PKC SerFFhr kinases, upon treatment with gamma-2- MSH. This study will therefore provide important insights into the role and mechanism of neural melanocortin signaling system in autonomic functions and also identify neural signal transduction cascades that play a potential role in hypertension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MR ASSESSMENT OF MAGNESIUM IN ACUTE STROKE Principal Investigator & Institution: Kidwell, Stella M.; Assistant Clinical Professor; Neurology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 02-APR-1999; Project End 31-MAR-2004 Summary: The objectives of this project are to demonstrate that 1) intravenous magnesium is beneficial in acute ischemic stroke as evidenced by decrease in the growth of infarct volume over time as measured by diffusion weighted magnetic resonance imaging (DWI); 2) DWI is a valuable surrogate outcome measure in acute ischemic stroke clinical trials; 3) diffusion/perfusion mismatch is a useful entry criterion for neuroprotective treatment in acute stroke clinical trials; and 4) intravenous magnesium is safe and potentially beneficial in intracerebral hemorrhage. During the first phase of the project, objectives 1-3 will be assessed by conducting a randomized, double-blind, placebo controlled trial to evaluate the efficacy of intravenous magnesium as a neuroprotective agent in acute ischemic stroke. The trial will use diffusion/perfusion magnetic resonance imaging as a surrogate outcome marker. 150 patients will be enrolled within 12 hours of symptom onset at 3 UCLA-associated hospitals. The second phase of this project will be a parallel pilot randomized, double-blind, placebocontrolled trial to evaluate the safety and explore the efficacy of intravenous magnesium in acute intracerebral hemorrhage, enrolling 40 patients. Additional data will be collected to assess the diffusion/perfusion MR signature of acute intracerebral hemorrhage. The findings of this project will have direct relevance to future treatment of acute ischemic and hemorrhagic stroke as well as to the design of future trials of neuroprotective agents. The results will help establish the utility of novel diffusion/perfusion MR techniques as demonstrating physiologic, objective changes that can be used as entry and outcome criteria in evaluating stroke patients. During the award period, in addition to serving as the principal investigator of these trials, Dr. Kidwell will pursue in-depth didactic multidisciplinary training in biostatistics, epidemiology, clinimetrics and magnetic resonance radiology. She will be mentored by Drs. Jeffrey Saver, Sidney Starkman, Jeffry Alger, and Barbara Vickrey. At the completion of this training, Dr. Kidwell will have acquired all requisite experience and skills to function as an independent investigator in clinical studies of novel magnetic resonance stroke imaging techniques, pivotal trials of promising therapeutic agents, and studies of the pathophysiology of acute human cerebral ischemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NC-758 HEMORRHAGE
FOR
PREVENTION
OF
RECURRENT
CEREBRAL
Principal Investigator & Institution: Greenberg, Steven M.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2006 Summary: (provided by the applicant): There is no known therapy for Cerebral Amyloid Angiopathy (CAA), an important cause of hemorrhagic stroke and other clinical syndromes in the elderly. The pathologic basis of CAA-related stroke is deposition of the Amyloid B-peptide (AB) in cerebral vessels, and resultant degeneration of the vessel wall. We propose a multi-center, phase II pilot study of the safety, tolerability, and preliminary efficacy of NC-758 for secondary prevention of recurrent CAA-related intracerebral hemorrhage. NC-758 is a small molecule designed to compete with glycosaminoglycans for binding to AB. Preliminary studies have
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Hemorrhagic Stroke
demonstrated that this compound penetrates to the CNS, inhibits AB fibril formation and AB-induced cellular toxicity, and reduces severity of CAA in a transgenic mouse model without evidence for major intrinsic toxicity. The proposed trial builds on progress by the Principal Investigator in the diagnosis and staging of CAA. Participants will be survivors of lobar hemorrhagic stroke, considered at high-risk for recurrence based on baseline gradient-echo MRI scan, or apolipoprotein-E genotype. An anticipated 280 patients will be screened at 20 participating sites, and 210 patients randomized to receive low-dose NC-758, high-dose NC-758, or placebo. Patients will be treated for a 16-month period, and followed for adverse clinical events, laboratory abnormalities, and recurrent stroke or decline in cognitive, functional, or neurologic status. At 8 and 16 months of treatment, subjects will undergo follow-up MRI scans to determine the appearance of new hemorrhagic lesions during treatment. The proposed sample size is calculated to have high likelihood of detecting major adverse effects associated with NC-758, and for detecting a 50% reduction in appearance of new symptomatic and asymptomatic hemorrhages. In addition to testing a promising agent for CAA, the proposed study will generate the organization and pilot data to serve as a springboard for future trials of emerging anti-amyloid treatments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEW POLYMER CEREBRAL ANEURYSM FILLER DEVICE Principal Investigator & Institution: Lee, Jeffrey A.; Neurovasx, Inc. 2355 Polaris Ln N, Ste 116 Plymouth, Mn 55447 Timing: Fiscal Year 2003; Project Start 30-SEP-2001; Project End 30-NOV-2004 Summary: (provided by applicant): Hemorrhagic stroke following aneurysmal rupture represents 15% to 30% of all strokes, with greater than 40,000 deaths per year attributed to acute aneurysmal rupture in the United States alone. Additionally, another 28,000 to 36,000 acutely ruptured aneurysms are treated per year in the U.S. The incidence of an intracranial aneurysm in the general population has been estimated to be between 1.5% to 8%. Current treatment options for cerebral aneurysm fall into two categories: surgical and interventional. Surgical procedures involve a long, delicate operation that has significant risk and a long period of postoperative rehabilitation and critical care. Recently, with the advent of neuro-interventional devices such as the Guglielmi detachable platinum coils (GDCs), a new endovascular modality for the treatment of cerebral aneurysms has become available. Our goal is to develop an endovascularly placed polymer aneurysm filler technology for treatment of aneurysms that is designed to address the shortcomings of interventional aneurysm treatment with platinum coils. We are developing a polymer filler material to be delivered in much the same way that a meallic coil is implanted. We anticipate that a packing density of at least 70% can be achieved. This substantially greater filling capability combined with the polymeric surface and surface-coating technologies will allow for permanent healing at the neck of the aneurysm. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NON-INVASIVE PNEUMOTHORAX DETECTOR Principal Investigator & Institution: Kelsch, Daniel N.; Engineering Program Mgr; Biomec, Inc. 1771 E 30Th St Cleveland, Oh 441144407 Timing: Fiscal Year 2003; Project Start 30-SEP-2000; Project End 30-APR-2005 Summary: Pneumothorax, while easily treatable, can become life threatening if not detected at any early stage. Current methods for diagnosing pneumothorax (chest x-ray,
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chest CT scan) are not possible for emergency squads and not practical for long-term monitoring of critical care patients. A portable handheld pneumothorax detector that is inexpensive, accurate, and non-invasive therefore would be very attractive. In Phase I, we investigated the feasibility of such a device, based on micropower impulse radar (MIR) technology. In animal studies (swine model), we are determined that pneumothorax as small as 30 ml were clearly detectable by the MIR device. This level of detection is important for the feasibility, since it is below the threshold of clinical significance. In Phase II, we propose to further optimize the MIR characteristics of the device and the signal algorithms. We will then acquire scans on human subjects to confirm the correlation of the MIR measure to the chest x-ray, which is the present standard of care. After finalizing the device parameters, we will continue with device development, miniaturization, and packaging. This research will result in a design ready for commercialization that fulfills the need for a non- invasive pneumothorax detector. PROPOSED COMMERCIAL APPLICATIONS: A handheld inexpensive pneumothorax will be commercially attractive to emergency medical personnel and trauma clinicians. Also, it would be useful for patient monitoring in critical care units. The combined market for these applications if very large. With further development, the device may be tunable to detect other trauma conditions, such as hemotoma and hemorrhagic stroke. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OPTICAL COHERENCE DOMAIN REFLECTOMETRY IN BRAIN PROBES Principal Investigator & Institution: Huang, David; Surgery; Cleveland Clinic Lerner Col/Med-Cwru Cleveland, Oh 44195 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): The goal of this project is to develop optical coherence domain reflectometry (OCDR) for accurate image guided placement of treatment probes in deep-brain structures. Refined guidance would greatly enhance the effectiveness and safety of deep-brain stimulation (DBS) with implanted electrodes. DBS is an FDA-approved treatment for Parkinson's disease and essential tremor that provides long-term relief of symptoms when medications are inadequate. It is also a promising therapy for intractable dystonia, epilepsy, and obsessive-compulsive disorder. Although effective, DBS is not currently a first-line treatment because of difficulties with precise placement, as well as risks of causing hemorrhagic stroke and other complications. Moreover, lengthy intraoperative electrical recordings and stimulus-response observations are currently required to position the probe. An embedded OCDR sensor may provide information on brain structures several millimeters ahead of the probe tip, enabling more precise, rapid, and safe placement. These improvements would allow DBS to benefit more patients. OCDR-guided deepbrain probes could also provide precise delivery of therapeutic vehicles in gene therapy, neurotransplantation, neuro-ablation, and pharmacologic treatments. The investigators include an original developer of OCDR and optical coherence tomography (OCT) in biomedical applications and an expert practitioner and developer of the DBS technique. The combined expertise of this team will take several promising approaches to using OCDR to identify brain tissue types (cortex, tracts, nuclei, and blood vessels) through a miniature probe. The following Specific Aims are proposed: Aim 1: Develop a combined OCDR/microelectrode brain probe. Aim 2: Distinguish brain tissue types using a dualwavelength OCDR system that measures tissue reflectivity, attenuation, hydration, and birefringence. Aim 3: Detect blood vessels by Doppler shift and broadening of OCDR
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Hemorrhagic Stroke
spectrum. Aim 4: Develop analysis & display software to identify tissues and guide probe advance. The OCDR brain probe technology will be validated in the laboratory and tested in a rat model. The practical knowledge gained in this pilot project will be used to develop a clinical OCDR-guided deep-brain probe for human DBS studies. Successful completion of this project would greatly benefit patients with many neurologic and psychiatric disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PORTABLE NON-INVASIVE ACOUSTIC IDENTIFICATION OF STROKE Principal Investigator & Institution: Sewell, John M.; Active Signal Technologies, Inc. 13025 Beaver Dam Rd Cockeysville, Md 21030 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-AUG-2004 Summary: (provided by applicant): Active Signal Technologies, in partnership with the Brain Attack Team of the University of Maryland Medical Center, proposes to refine and test a novel portable, non-invasive system that will enable rapid identification of stroke. Approximately 750,000 people suffer a stroke each year and over 80% of these are ischemic. Yet only 1% of this number receives medical treatment such as TPA that is known to dissolve clots and promote favorable outcome if administered within 3 hours of onset. Among the many causes of this serious health and ultimately economic problem is the inability to rapidly differentiate ischemic from hemorrhagic strokes to allow intervention. The device is a small non-invasive system that measures the acoustic signature of the brain and compares it with the patient's arterial waveform. Active Signal will add code to calculate those signal features identified in Phase I as indicative of the patient's stroke condition, and the team will clinically test on 200 patients the hypotheses for stroke identification determined in Phase I. The system will be miniaturized for EMS units to use at the scene of injury. This would significantly increase the percentage of ischemic stroke patients who would receive time-sensitive therapies, reducing disability and medical costs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: THE RELATIONSHIP OF SERUM PROTEINS TO STROKE SEVERITY Principal Investigator & Institution: Jauch, Edward C.; Asst. Professor; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: The approval of tissue plasminogen activator (tPA) for use in acute ischemic stroke by the FDA in 1996 dramatically changed the treatment of stroke. Yet, many patients who are potential candidates do not receive thrombolytics due to the treating physician's concern of hemorrhage. New diagnostic tests to identify patients at increased risk of tPA-associated hemorrhage, to predict long-term outcome, and to measure therapeutic efficacy would ve very useful to physicians who treat acute stroke patients with tPA or other therapies. This proposal will examine the relationship of serum proteins to baseline stroke severity, clinical and radiographic outcome, response to therapy, and the risk of intracerebral hemorrhage after tPA+/- eptifibatide therapy in the CLEAR Trial. In Aim 1, based on our preliminary findings, two serum proteins, S100 and myelin basic protein (MBP), will be studied over the first 24 hours from presentation. Changes and peaks in S100 and MBP concentrations will be correlated with the severity of neurologic deficit, volume of infarct on CT and magnetic resonance imaging, flow in the middle cerebral artery as measured by magnetic resonance
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angiography, presence of intracerebral hemorrhage, and long-term outcome. Aim 2 will employ a proteomics approach to identify plasma proteins that are associated with intracerebral hemorrhage following administration of tPA. Pretreatment plasma from patients who do not develop intracerebral hemorrhage. A long-term goal of this study is to develop serum marker assays as independent measures of prognosis and therapeutic efficacy. Such tools would be useful in the design of new clinical therapeutic trials and the selection of therapies in acute stroke. Long-term goals associated with the proteomics study include developing rapid assays that could be used to identify patients at increased risk of hemorrhage to better select patients for thrombolytic therapy. Additionally, the protein library created by this project could help identify new proteins associated with ischemic stroke leading to improved diagnostic assays with increased sensitivity, specificity, and accuracy for cerebral ischemia. Overall, this project in conjunction with Project 3, represents a unique opportunity to compare both a proteomics and genomics approach in a single disease condition, thereby complementing each strategy's strengths. We expect this project will lead to the development of further proteomics and genomics studies of ischemic and hemorrhagic stroke. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE ROLE OF ZINC IN FOCAL ISCHEMIC BRAIN INJURY Principal Investigator & Institution: Lee, Jin-Moo; Neurology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2003; Project Start 25-SEP-2000; Project End 31-JUL-2005 Summary: (provided by applicant): This is an application for a competitive supplement to the three-year Mentored Clinical Scientist Development (K08) Award. The original K08 grant entitled, "The role of zinc in focal ischemic brain injury," was awarded on 7/1/00. However, in 12/01 (1.5 years into the grant), the applicant's mentor, Dr. Dennis Choi left the institution, prompting a change in mentors (to Dr. Chung Y. Hsu, with comentors, Dr. Mark Goldberg and Dr. David Holtzman) and a change in research direction. For the past 9 months, the applicant has been pursuing this new direction, studying the pathogenesis of spontaneous intracerebral hemorrhage in cerebral amyloid angiopathy (CAA). In particular, he has found that the amyloid beta peptide induces the expression and activity of the extracellular matrix-degrading protease, matrix metalloproteinase-9 (MMP-9), in cultures of cerebral endothelial cells. Furthermore, vascular MMP-9-like immunoreactivity was found in aged mice carrying the double Swedish mutation of the amyloid precursor protein (APPsw, a rodent model of CAA), but not in younger mice. The central hypothesis of this proposal is that amyloid beta, which accumulates in cerebral blood vessels in CAA, induces vascular MMP-9 activity and contributes to the development of spontaneous hemorrhagic stroke. Due to space limitations a complete application detailing the new proposal is not possible; however, Specific Aims, preliminary studies, and a brief outline of research design is included in this proposal. The goal of the applicant during this extension is to pursue the project outlined above and to receive additional training in molecular biology, microscopy and in developing animal models for disease. The additional two years of funding will allow protected time to accumulate data and publications that will put the applicant in a position to apply for independent funding (R21 or R01) and, ultimately, develop into an independent investigator. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TISSUE VIABILITY IN STROKE BY SODIUM MR IMAGING Principal Investigator & Institution: Thulborn, Keith R.; Professor of Medicine; Radiology; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2003; Project Start 20-APR-2000; Project End 31-JAN-2005 Summary: Tissue sodium concentration (TSC), as measured by sodium imaging, will be correlated with diffusion (apparent diffusion coefficient, ADC) and perfusion (relative cerebral blood volume, rCBV; tissue transit time, TTT; arrival time, TA) from proton MRI over the first 12 hours of embolic stroke in a non-human primate model. These quantitative MR imaging parameters will be correlated with histological markers of tissue status including TTC, H&E and TUNEL staining. The goal is to establish if TSC an be used as a measure of tissue viability in assessment of acute stroke. Early intervention with thrombolysis enhances the clinical outcome if the tissue is still viable. As reperfusion of infarcted tissue increases the risk of adverse hemorrhage, the FDA approves a limited window of acceptable risk-benefit ratio of 3 hours from the onset of neurological symptoms in a non-hemorrhagic stroke. A rapid method for assessment of tissue viability in this setting would aid in tailoring clinical management to the pathophysiology of each patient. The central hypothesis is that there is a critical increase in TSC due to loss of sodium ion homeostasis in a region of restricted diffusion (reduced ADC) that indicates a significant loss of tissue viability in stroke. An acute embolic stroke model in a non-human primate is used to determine if a critical threshold of TSC defines tissue viability during the natural progression of stroke thereby predicting recovery following reperfusion after thrombolysis with recombinant tissue plasminogen activator (rt-PA) This animal model is required to establish the magnitude and rate of change of TSC in a well-controlled setting that can be applied in the clinical setting. Other proton MRI parameters used clinically in stroke are water diffusion and perfusion. The same comprehensive, yet efficient MRI protocol as I have used in MRI examinations of both acute and sub-acute stroke patients, allows TSC, ADC and blood pool perfusion parameters or rCBV, TTT and TA to be correlated in this acute stroke model and compared to histological parameters of necrosis and apoptosis. The novel twisted projection imaging acquisition produces high quality, high-resolution sodium images while echo-planar imaging is used for diffusion and perfusion imaging. A dualfrequency, dual-quadrature, 23NA/1H RF coil ensures co-registration of images and maps in minimum time without moving the subject. This well-controlled animal model examines if there is a critical TSC threshold that accurately predicts tissue viability as part of this comprehensive MR imaging protocol being used for clinical management of acute stroke. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TRANSGENIC MODEL FOR CEREBRAL AMYLOID ANGIOPATHY Principal Investigator & Institution: Van Nostrand, William E.; Professor; Medicine; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2002; Project Start 01-MAY-1998; Project End 31-JUL-2007 Summary: (provided by applicant): Cerebrovascular deposition of the amyloid a-protein (Aa), a condition known as cerebral amyloid angiopathy (CAA), is a common pathological feature of patients with Alzheimer's disease (AD) and several related hereditary cerebral hemorrhage with amyloidosis (HCHWA) disorders. Aa is proteolytically derived from its parent molecule the amyloid a-protein precursor (AaPP). Apolipoprotein E (ApoE) genotype can facilitate both cerebrovascular Aa deposition and hemorrhagic stroke. It is significant that CAA accounts for up to 20% of
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cases of spontaneous primary intracerebral hemorrhage. Moreover, CAA is most severe in HCHWA patients often resulting in early recurrent and fatal intracerebral hemorrhages. The reason as to why there is preferential cerebrovascular Aa deposition in HCHWA disorders leading to hemorrhagic stroke and how ApoE may facilitate these pathological processes remains unresolved. We have shown that certain HCHWA mutant forms of Aa, which exhibit a loss or change in charge at peptide residues 22 or 23, possess enhanced pathogenic properties towards cultured cerebrovascular cells. In addition, ApoE genotype can further influence the pathogenic effects of Aa in these in vitro paradigms. However, many of these issues can be better studied in valid in vivo models for CAA. Therefore, the overall hypotheses that forms the basis of this proposal is that expression of HCHWA mutant AaPP in transgenic mice will lead to the preferential development of CAA and human ApoE genotype can further influence this pathology and promote cerebral hemorrhage. The broad objectives of this proposal are two-fold. First, we will compare the pathological consequences of neuronal overexpression of several human AaPP forms yielding either wild-type or CAA mutant Aa with regards to the development of CAA. The CAA mutant forms AaPP will contain either a single Dutch E22Q AB substitution or double Dutch/Iowa E22Q,D23N Aa substitutions. Second, the influence of human ApoE genotype on Aa deposition, the development of CAA, and cerebral hemorrhage will be investigated in these in vivo models. These proposed studies stem from our overall focus and continuing work on investigating the role of ABPP and its derived fragment A6 in the development of CAA, loss of vessel wall integrity, and hemorrhagic stroke. Completion of these specific aims will produce valuable models for both the further study of pathogenic mechanisms in CAA and in vivo systems to develop and test therapeutic strategies to mitigate cerebrovascular Aa deposition and the subsequent pathological consequence of hemorrhagic stroke. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: UCLA SPOTRIAS CENTER APPLICATION Principal Investigator & Institution: Saver, Jeffrey L.; Neurology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-MAY-2008 Summary: Acute stroke is a common and devastating disorder, the 3rd leading cause of death and the leading cause of adult disability in the US. This application to establish a Specialized Program of Translational Research in Acute Stroke Center at UCLA proposes an integrated research/training program to develop innovative therapies for acute ischemic and hemorrhagic stroke. Three research projects are proposed. Project 1, "The MR and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) Trial," will determine whether diffusion-perfusion MRI can identify patients who will benefit substantially from mechanical embolectomy with the Concentric Clot Retriever device for acute ischemic stroke up to 8 hrs from symptom onset. This study is a multicenter, randomized, controlled phase 2 trial of endovascular clot retrieval versus conventional medical care in 120 patients with large vessel, anterior circulation ischemic stroke 0-8 hrs from onset. Project 2, the "Hemorrhage Evacuation Employing MR-Guided Endoscopic Surgery (HEME-Surgery) Trial," is a phase 2, randomized, controlled, 60 patient trial of magnetic resonance guided endoscopic surgical evacuation vs. medical therapy within 24 h of acute intracerebral hemorrhage. This trial tests an innovative, minimally invasive surgical technique, applied early after onset, utilizing standard and novel clinical measures of outcome. In addition, studies interrogating the fundamental pathophysiology of brain injury in human ICH are proposed delineating differential
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gene expression, tissue morphometrics, and multimodal MR signatures in the perihematomal region. In Project 3, "Optimizing and Accelerating Prehospital Care of Acute Stroke," 3 inter-related studies will: prospectively validate a novel field measure of stroke severity, the Los Angeles Motor Scale (LAMS); improve dispatcher recognition of stroke by testing a new dispatcher-specific version of the Los Angeles Prehospital Stroke Screen (LAPSS-Dispatch); and demonstrate the feasibility, validity, and impact upon care of paramedic use of a novel, point of care test that assays 5 serum biomarkers to distinguish true stroke from nonstroke in the field. Five Cores will support the Projects: A) Patient Access, B) Blood / Tissue Specimen, C) Biostatistics / Data Management, D) Neuroimaging, E) Career Development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: UNRUPTURED INTRACRANIAL ANEURYSMS: NEUROLOGIC OUTCOME Principal Investigator & Institution: Torner, James C.; Professor and Head; Epidemiology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2004; Project Start 15-MAR-2004; Project End 28-FEB-2008 Summary: (provided by applicant): Unruptured Intracranial Aneurysms (UIA) constitute a significant public health problem in the United States, which is growing in magnitude. The economic and social implications of optimizing clinical practice in this area are striking, given the considerable and escalating frequency with which UIAs are now detected in the population. The prevention of unnecessary death and disability related to UIA depends to a large degree upon a better understanding of the natural history of these lesions, as well as the short- and long-term benefits and risks associated with their repair. The current proposal represents a continuation of the prospective component of the International Study of Unruptured Intracranial Aneurysms (ISUIA). Its primary objectives center around defining the long-term risks of UIA rupture and other UIA natural history outcomes, risk factors associated with these natural history outcomes, long-term outcomes associated with endovascular and surgical repair of these lesions, and predictors of good and poor treatment outcomes. The first two phases of ISUIA have provided substantial and unique information regarding short-term prospective natural history and treatment outcomes, and have established that shortterm prospective natural history rupture rates are different than retrospective natural history rupture rates. The current proposal utilizes the large ISUIA cohort of patients established over the past ten years to provide vital long-term clinical information, which would otherwise be unobtainable. The current proposal involves the follow-up of living cases with UIA among the 4,060 cases in the prospective cohort, including 1,692 cases in the unoperated cohort and 2,368 cases in the cohort, which had UIA repair. The additional follow-up will allow the estimation of ten-year hemorrhage rates, and other outcome measures beyond the currently available five-year rates. It will also provide critical information on the long-term durability and effectiveness of endovascular and surgical treatment procedures, which are important in making clinical decisions regarding optimal management. Primary analyses will examine neurologic outcome, specifically fatal and non-fatal intracranial hemorrhagic strokes, secondary to aneurismal rupture and morbidity/mortality following UIA treatment. Secondary analyses will examine other aneurismal complications, such as ischemic stroke and death from all causes, including retreatment, durability of treatment, and functional endpoints, including Rankin, Barthel, and SF36 scores. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: UNRUPTURED INTRACRANIAL ANEURYSMS--NEUROLOGICAL OUTCOME Principal Investigator & Institution: Wiebers, David O.; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 19-SEP-1991; Project End 31-AUG-2003 Summary: Unruptured intracranial aneurysms (UIA) constitute a significant public health problem in the United States (which is growing in magnitude). The prevention of hemorrhagic stroke in patients with UIA may be possible with a better understanding of the natural history of these lesions as well as the short and long-term benefits and risks associated with their repair. The current proposal represents a continuation of the first phase of the International Study of Unruptured Intracranial Aneurysms (ISUIA). Its primary objectives are to 1) define a critical aneurysm size above which there is a significant risk of future rupture among patients with UIA and no history of subarachnoid hemorrhage (SAH); 2) compare the risk of future rupture of UIA, disability, and death among patients with and without a history of prior SAH from a different source and to determine whether or not the risk of future rupture varies directly with aneurysmal size among patients with a history of prior SAH; and 3) define the surgical and endovascular morbidity and mortality involved with repair of UIA across a broad spectrum of populations, surgeons, and interventional neuroradiologists with special reference to the size and location of the aneurysm, history of SAH from another source, and other confounding variables such as age and associated medical conditions. The current proposal involves the prospective entry and follow-up of 2400 new cases with UIA (3500 total cases were entered in Phase I), and the continued followup of living cases with UIA entered to date at the 53 participating centers. The primary analysis will examine neurologic outcome, specifically, fatal and non-fatal intracranial hemorrhagic stroke secondary to aneurysmal rupture. Secondary analyses will examine other aneurysmal complications such as ischemic stroke and death from all causes. The prognostic significance of several independent clinical and radiological variables with respect to stroke due to aneurysmal rupture and mortality will also be analyzed using a Cox proportional hazards model. In addition, extensive planning has been undertaken to establish a molecular genetics component to this study to identify specific genetic defects predisposing the development and rupture of intracranial aneurysms. Funding for this component will be requested via a separate proposal submitted as a supplement to the current application. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, 3 4
Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.
With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.
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and type “hemorrhagic stroke” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for hemorrhagic stroke in the PubMed Central database: •
Phenylpropanolamine and hemorrhagic stroke in women. by [No authors listed]; 2001 Mar 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=80844
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Tauroursodeoxycholic acid reduces apoptosis and protects against neurological injury after acute hemorrhagic stroke in rats. by Rodrigues CM, Sola S, Nan Z, Castro RE, Ribeiro PS, Low WC, Steer CJ.; 2003 May 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156330
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 hemorrhagic stroke, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “hemorrhagic stroke” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for hemorrhagic stroke (hyperlinks lead to article summaries): •
A quality-of-life instrument for young hemorrhagic stroke patients. Author(s): Hamedani AG, Wells CK, Brass LM, Kernan WN, Viscoli CM, Maraire JN, Awad IA, Horwitz RI. Source: Stroke; a Journal of Cerebral Circulation. 2001 March; 32(3): 687-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11239188
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After correcting for worse baseline characteristics, women treated with thrombolytic therapy for acute myocardial infarction have the same mortality and morbidity as men except for a higher incidence of hemorrhagic stroke. The Investigators of the International Tissue Plasminogen Activator/Streptokinase Mortality Study. Author(s): White HD, Barbash GI, Modan M, Simes J, Diaz R, Hampton JR, Heikkila J, Kristinsson A, Moulopoulos S, Paolasso EA, et al. Source: Circulation. 1993 November; 88(5 Pt 1): 2097-103. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8222103
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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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Age-related changes in risk factor effects on the incidence of thromboembolic and hemorrhagic stroke. Author(s): Abbott RD, Curb JD, Rodriguez BL, Masaki KH, Popper JS, Ross GW, Petrovitch H. Source: Journal of Clinical Epidemiology. 2003 May; 56(5): 479-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12812823
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Alcohol and hemorrhagic stroke in Santiago, Chile. A case-control study. Author(s): Diaz V, Cumsille MA, Bevilacqua JA. Source: Neuroepidemiology. 2003 November-December; 22(6): 339-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14557684
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Alcohol and hemorrhagic stroke. The Honolulu Heart Program. Author(s): Donahue RP, Abbott RD, Reed DM, Yano K. Source: Jama : the Journal of the American Medical Association. 1986 May 2; 255(17): 2311-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3959320
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Alcohol drinking and risk of hemorrhagic stroke. Author(s): Klatsky AL, Armstrong MA, Friedman GD, Sidney S. Source: Neuroepidemiology. 2002 May-June; 21(3): 115-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12006774
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alpha(1)-antichymotrypsin polymorphism: a risk factor for hemorrhagic stroke in normotensive subjects. Author(s): Obach V, Revilla M, Vila N, Cervera A A, Chamorro A A. Source: Stroke; a Journal of Cerebral Circulation. 2001 November; 32(11): 2588-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11692021
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Ask the doctor. I am a 70-year-old man with high blood pressure that I control with medication, diet, and exercise. My mother, aunt, and maternal grandfather all died in their 50s after a single stroke. Is there an inherited tendency to hemorrhagic stroke? Are there any precautions I can take? Author(s): Lee TH. Source: Harvard Heart Letter : from Harvard Medical School. 2002 June; 12(10): 8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12079827
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Aspirin and hemorrhagic stroke. Author(s): Mayo NE, Levy AR, Goldberg MS. Source: Stroke; a Journal of Cerebral Circulation. 1991 September; 22(9): 1213-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1926268
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Aspirin and risk of hemorrhagic stroke. Author(s): Desbiens NA, Schmitt CM, Panda ML. Source: Jama : the Journal of the American Medical Association. 1999 August 25; 282(8): 732-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10463704
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Aspirin and risk of hemorrhagic stroke. Author(s): Tokuda Y, Kato J. Source: Jama : the Journal of the American Medical Association. 1999 August 25; 282(8): 732; Author Reply 732-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10463703
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Aspirin and risk of hemorrhagic stroke. Author(s): Colwell JA. Source: Jama : the Journal of the American Medical Association. 1999 August 25; 282(8): 731-2; Author Reply 732-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10463702
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Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials. Author(s): He J, Whelton PK, Vu B, Klag MJ. Source: Jama : the Journal of the American Medical Association. 1998 December 9; 280(22): 1930-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9851479
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Aspirin and the risk of hemorrhagic stroke. Author(s): Rosenberg R. Source: The Journal of Family Practice. 1999 March; 48(3): 169-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10086752
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Asymptomatic pheochromocytoma. Diagnosis after hemorrhagic stroke in a middleaged patient. Author(s): Redman JC, Peloso OA, Milne RL, Kaminsky NI, Ellis SC, Wolfel DA, Martinez PU. Source: Postgraduate Medicine. 1983 April; 73(4): 279, 282-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6835878
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Body mass index and ischemic and hemorrhagic stroke: a prospective study in Korean men. Author(s): Song YM, Sung J, Davey Smith G, Ebrahim S. Source: Stroke; a Journal of Cerebral Circulation. 2004 April; 35(4): 831-6. Epub 2004 March 04. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15001798
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Circadian variability in hemorrhagic stroke. Author(s): Casetta I, Granieri E, Portaluppi F, Manfredini R. Source: Jama : the Journal of the American Medical Association. 2002 March 13; 287(10): 1266-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11886317
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Clinical diagnosis of ischemic versus hemorrhagic stroke: applicability of existing scores in the emergency situation and proposal of a new score. Author(s): Sturmer T, Schlindwein G, Kleiser B, Roempp A, Brenner H. Source: Neuroepidemiology. 2002 January-February; 21(1): 8-17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11744820
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Comparison of effect of glycoprotein IIb/IIIa inhibitors during percutaneous coronary interventions on risk of hemorrhagic stroke in patients >or=75 years of age versus those
